A Hadoop-Based Method to Predict Potential Effective Drug Combination

PubMed Central

Xiong, Yi; Xu, Qian; Wei, Dongqing

2014-01-01

Combination drugs that impact multiple targets simultaneously are promising candidates for combating complex diseases due to their improved efficacy and reduced side effects. However, exhaustive screening of all possible drug combinations is extremely time-consuming and impractical. Here, we present a novel Hadoop-based approach to predict drug combinations by taking advantage of the MapReduce programming model, which leads to an improvement of scalability of the prediction algorithm. By integrating the gene expression data of multiple drugs, we constructed data preprocessing and the support vector machines and naïve Bayesian classifiers on Hadoop for prediction of drug combinations. The experimental results suggest that our Hadoop-based model achieves much higher efficiency in the big data processing steps with satisfactory performance. We believed that our proposed approach can help accelerate the prediction of potential effective drugs with the increasing of the combination number at an exponential rate in future. The source code and datasets are available upon request. PMID:25147789

Differentiating between anthropogenic and geological sources of nitrate using multiple geochemical tracers

NASA Astrophysics Data System (ADS)

Linhoff, B.; Norton, S.; Travis, R.; Romero, Z.; Waters, B.

2017-12-01

Nitrate contamination of groundwater is a major problem globally including within the Albuquerque Basin in New Mexico. Ingesting high concentrations of nitrate (> 10 mg/L as N) can lead to an increased risk of cancer and to methemoglobinemia in infants. Numerous anthropogenic sources of nitrate have been identified within the Albuquerque Basin including fertilizers, landfills, multiple sewer pipe releases, sewer lagoons, domestic septic leach fields, and a nitric acid line outfall. Furthermore, groundwater near ephemeral streams often exhibits elevated NO3 concentrations and high NO3/Cl ratios incongruous with an anthropogenic source. These results suggest that NO3 can be concentrated through evaporation beneath ephemeral streams and mobilized via irrigation or land use change. This study seeks to use extensive geochemical analyses of groundwater and surface water to differentiate between various sources of NO3 contamination. The U.S. Geological Survey collected 54 groundwater samples from wells and six samples from ephemeral streams from within and from outside of areas of known nitrate contamination. To fingerprint the sources of nitrate pollution, samples were analyzed for major ions, trace metals, nutrients, dissolved gases, δ15N and δ18O in NO3, δ15N within N2 gas, and, δ2H and δ18O in H2O. Furthermore, most sites were sampled for artificial sweeteners and numerous contaminants of emerging concern including pharmaceutical drugs, caffeine, and wastewater indicators. This study will also investigate the age distribution of groundwater and the approximate age of anthropogenic NO3 contamination using 3He/4He, δ13C, 14C, 3H, as well as pharmaceutical drugs and artificial sweeteners with known patent and U.S. Food and Drug Administration approval dates. This broad suite of analytes will be used to differentiate between naturally occurring and multiple anthropogenic NO3 sources, and to potentially determine the approximate date of NO3 contamination.

Streets, drugs, and the economy of sex in the age of AIDS.

PubMed

Weeks, M R; Grier, M; Romero-Daza, N; Puglisi-Vasquez, M J; Singer, M

1998-01-01

Drug addicted women whose economic and social base is urban streets face limited options for income generation and multiple dangers of predation, assault, arrest, and illness. Exchanging sex for money or drugs offers one important source of income in this context. Yet the legal, social, and safety risks associated with these exchanges reduce the likelihood of regular safer sex practices during these encounters, thereby increasing the risk of HIV infection. Such conditions lead women engaged in sexual exchanges for money to varied and complex responses influenced by multiple and often contradictory pressures, both personal and contextual. Street-recruited women drug users in an AIDS prevention program in Hart-ford, Connecticut reported a range of condom use when engaging in sex for money exchanges. This paper explores their differences by ethnicity, economic resources, and drug use, and analyzes these and other factors that impact on street risks through sexual income generation. Surveys and in-depth interviews with drug-addicted women sex workers describe their various approaches to addressing multiple risks on the streets and suggest significant effort by women in these contexts to avoid the many risks, including HIV infection.

Trends in Adolescent Alcohol and Other Drug Use: Findings from Three Sentinel Sites in South Africa (1997-2001)

ERIC Educational Resources Information Center

Parry, Charles D. H.; Myers, Bronwyn; Morojele, Neo K.; Flisher, Alan J.; Bhana, Arvin; Donson, Hilton; Pluddemann, Andreas

2004-01-01

This paper aims to provide surveillance information about the extent and consequences of alcohol and other drug (AOD) use by adolescents for three sentinel sites in South Africa (Cape Town, Durban and Gauteng province). From 1997 to 2001, data were gathered from multiple sources, including specialist treatment centres, trauma units, school…

[Rational use of psychotropic drugs and social communication role].

PubMed

Montero, F

1994-06-01

Extra-clinical factors about the influences affecting the prescription and use of drugs are reviewed. Special attention is given to regulatory agencies, the pharmaceutical industry, and mass media. The problems and public health consequences of the irrational use of drugs are rarely documented in Latin America. Analysis of these factors, information sources, and rational use of psychotropic drugs will require multiple strategies such as social communication and policy formulation to define goals and objectives related to population information, doctors' and individual citizens' decision making processes, and participation of consumers in improving the use of psychotropic drugs.

Micropropagation and in vitro flowering of Rauvolfia tetraphylla; a potent source of anti-hypertension drugs.

PubMed

Sarma, D; Sarma, S; Baruah, A

1999-04-01

A simple protocol for in vitro mass multiplication of Rauvolfia tetraphylla (Apocynaceae) has been developed. The endophytic microflora was controlled by adopting integrated measures. Multiple shoot development was achieved on MS + Kin (0.1-0.2 mg/l) + BAP (0.4-0.5 mg/l) media. Rooting from in vitro shoots occurred on NAA containing media. In vitro flowering was induced in shoot multiplication media.

Similarity-based prediction for Anatomical Therapeutic Chemical classification of drugs by integrating multiple data sources.

PubMed

Liu, Zhongyang; Guo, Feifei; Gu, Jiangyong; Wang, Yong; Li, Yang; Wang, Dan; Lu, Liang; Li, Dong; He, Fuchu

2015-06-01

Anatomical Therapeutic Chemical (ATC) classification system, widely applied in almost all drug utilization studies, is currently the most widely recognized classification system for drugs. Currently, new drug entries are added into the system only on users' requests, which leads to seriously incomplete drug coverage of the system, and bioinformatics prediction is helpful during this process. Here we propose a novel prediction model of drug-ATC code associations, using logistic regression to integrate multiple heterogeneous data sources including chemical structures, target proteins, gene expression, side-effects and chemical-chemical associations. The model obtains good performance for the prediction not only on ATC codes of unclassified drugs but also on new ATC codes of classified drugs assessed by cross-validation and independent test sets, and its efficacy exceeds previous methods. Further to facilitate the use, the model is developed into a user-friendly web service SPACE ( S: imilarity-based P: redictor of A: TC C: od E: ), which for each submitted compound, will give candidate ATC codes (ranked according to the decreasing probability_score predicted by the model) together with corresponding supporting evidence. This work not only contributes to knowing drugs' therapeutic, pharmacological and chemical properties, but also provides clues for drug repositioning and side-effect discovery. In addition, the construction of the prediction model also provides a general framework for similarity-based data integration which is suitable for other drug-related studies such as target, side-effect prediction etc. The web service SPACE is available at http://www.bprc.ac.cn/space. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Exploiting heterogeneous publicly available data sources for drug safety surveillance: computational framework and case studies.

PubMed

Koutkias, Vassilis G; Lillo-Le Louët, Agnès; Jaulent, Marie-Christine

2017-02-01

Driven by the need of pharmacovigilance centres and companies to routinely collect and review all available data about adverse drug reactions (ADRs) and adverse events of interest, we introduce and validate a computational framework exploiting dominant as well as emerging publicly available data sources for drug safety surveillance. Our approach relies on appropriate query formulation for data acquisition and subsequent filtering, transformation and joint visualization of the obtained data. We acquired data from the FDA Adverse Event Reporting System (FAERS), PubMed and Twitter. In order to assess the validity and the robustness of the approach, we elaborated on two important case studies, namely, clozapine-induced cardiomyopathy/myocarditis versus haloperidol-induced cardiomyopathy/myocarditis, and apixaban-induced cerebral hemorrhage. The analysis of the obtained data provided interesting insights (identification of potential patient and health-care professional experiences regarding ADRs in Twitter, information/arguments against an ADR existence across all sources), while illustrating the benefits (complementing data from multiple sources to strengthen/confirm evidence) and the underlying challenges (selecting search terms, data presentation) of exploiting heterogeneous information sources, thereby advocating the need for the proposed framework. This work contributes in establishing a continuous learning system for drug safety surveillance by exploiting heterogeneous publicly available data sources via appropriate support tools.

Evaluation of multiple comparison correction procedures in drug assessment studies using LORETA maps.

PubMed

Alonso, Joan Francesc; Romero, Sergio; Mañanas, Miguel Ángel; Rojas, Mónica; Riba, Jordi; Barbanoj, Manel José

2015-10-01

The identification of the brain regions involved in the neuropharmacological action is a potential procedure for drug development. These regions are commonly determined by the voxels showing significant statistical differences after comparing placebo-induced effects with drug-elicited effects. LORETA is an electroencephalography (EEG) source imaging technique frequently used to identify brain structures affected by the drug. The aim of the present study was to evaluate different methods for the correction of multiple comparisons in the LORETA maps. These methods which have been commonly used in neuroimaging and also simulated studies have been applied on a real case of pharmaco-EEG study where the effects of increasing benzodiazepine doses on the central nervous system measured by LORETA were investigated. Data consisted of EEG recordings obtained from nine volunteers who received single oral doses of alprazolam 0.25, 0.5, and 1 mg, and placebo in a randomized crossover double-blind design. The identification of active regions was highly dependent on the selected multiple test correction procedure. The combined criteria approach known as cluster mass was useful to reveal that increasing drug doses led to higher intensity and spread of the pharmacologically induced changes in intracerebral current density.

Toward multimodal signal detection of adverse drug reactions.

PubMed

Harpaz, Rave; DuMouchel, William; Schuemie, Martijn; Bodenreider, Olivier; Friedman, Carol; Horvitz, Eric; Ripple, Anna; Sorbello, Alfred; White, Ryen W; Winnenburg, Rainer; Shah, Nigam H

2017-12-01

Improving mechanisms to detect adverse drug reactions (ADRs) is key to strengthening post-marketing drug safety surveillance. Signal detection is presently unimodal, relying on a single information source. Multimodal signal detection is based on jointly analyzing multiple information sources. Building on, and expanding the work done in prior studies, the aim of the article is to further research on multimodal signal detection, explore its potential benefits, and propose methods for its construction and evaluation. Four data sources are investigated; FDA's adverse event reporting system, insurance claims, the MEDLINE citation database, and the logs of major Web search engines. Published methods are used to generate and combine signals from each data source. Two distinct reference benchmarks corresponding to well-established and recently labeled ADRs respectively are used to evaluate the performance of multimodal signal detection in terms of area under the ROC curve (AUC) and lead-time-to-detection, with the latter relative to labeling revision dates. Limited to our reference benchmarks, multimodal signal detection provides AUC improvements ranging from 0.04 to 0.09 based on a widely used evaluation benchmark, and a comparative added lead-time of 7-22 months relative to labeling revision dates from a time-indexed benchmark. The results support the notion that utilizing and jointly analyzing multiple data sources may lead to improved signal detection. Given certain data and benchmark limitations, the early stage of development, and the complexity of ADRs, it is currently not possible to make definitive statements about the ultimate utility of the concept. Continued development of multimodal signal detection requires a deeper understanding the data sources used, additional benchmarks, and further research on methods to generate and synthesize signals. Copyright © 2017 Elsevier Inc. All rights reserved.

Following the money: Mapping the sources and funding flows of alcohol and other drug treatment in Australia.

PubMed

Chalmers, Jenny; Ritter, Alison; Berends, Lynda; Lancaster, Kari

2016-05-01

The structures of health systems impact on patient outcomes. We present and analyse the first detailed mapping of who funds alcohol and other drug (AOD) treatment and the channels and intermediaries through which funding flows from the funding sources to treatment providers. The study involved a literature review of AOD treatment financing and existing diagrammatic representations of the structure of the Australian health system. We interviewed 190 key informants to particularise the AOD treatment sector, and undertook two case examples of government funded non-government organisations providing AOD treatment. Funding sources include the Australian and state and territory governments, philanthropy, fund-raising and clients themselves. While funding sources align with the health sector generally and the broader social services sector, the complexity of flows from source to treatment service and the number of intermediaries are noteworthy. So too are the many sources of funding drawn on by some treatment providers. Diversification is both beneficial and disadvantageous for non-government treatment providers, adding to administrative workloads, but smoothing the risk of funding shortfalls. Government funders benefit from sharing risk. Circuitous funding flows multiply the funding sources drawn on by services and put distance between the funding source and the service provider. This leads to concerns over lack of transparency about what is being purchased and challenges for the multiply funded service provider in maintaining programs and service models amid multiple and sometimes competing funding and accountability frameworks. [Chalmers J, Ritter A, Berends L, Lancaster K. Following the money: Mapping the sources and funding flows of alcohol and other drug treatment in Australia. Drug Alcohol Rev 2016;35:255-262]. © 2015 Australasian Professional Society on Alcohol and other Drugs.

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

PubMed

Liang, Chen; Sun, Jingchun; Tao, Cui

2015-01-01

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

Evolving models of the immunopathogenesis of T-cell mediated drug allergy: the role of host, pathogens, and drug response

PubMed Central

White, Katie D.; Chung, Wen-Hung; Hung, Shuen-Iu; Mallal, Simon; Phillips, Elizabeth J.

2015-01-01

Immune-mediated adverse drug reactions (IM-ADRs) are an underrecognized source of preventable morbidity, mortality, and cost. Increasingly, genetic variation in the HLA loci is associated with risk of severe reactions, highlighting the importance of T-cell immune responses in the mechanisms of both B-cell mediated and primary T-cell mediated IM-ADRs. In this review, we summarize the role of host genetics, microbes and drugs in the development of IM-ADRs, expand upon the existing models of IM-ADR pathogenesis to address multiple unexplained observations, discuss the implications of this work in clinical practice today, and describe future applications for pre-clinical drug toxicity screening, drug design, and development. PMID:26254049

Antimicrobial resistance of Escherichia coli isolates from broiler chickens and humans

PubMed Central

Miles, Tricia D; McLaughlin, Wayne; Brown, Paul D

2006-01-01

Background Antimicrobial usage is considered the most important factor promoting the emergence, selection and dissemination of antimicrobial-resistant microorganisms in both veterinary and human medicine. The aim of this study was to investigate the prevalence and genetic basis of tetracycline resistance in faecal Escherichia coli isolates from healthy broiler chickens and compare these data with isolates obtained from hospitalized patients in Jamaica. Results Eighty-two E. coli strains isolated from faecal samples of broiler chickens and urine and wound specimens of hospitalized patients were analyzed by agar disc diffusion to determine their susceptibility patterns to 11 antimicrobial agents. Tetracycline resistance determinants were investigated by plasmid profiling, transformations, and amplification of plasmid-borne resistance genes. Tetracycline resistance occurred at a frequency of 82.4% in avian isolates compared to 43.8% in human isolates. In addition, among avian isolates there was a trend towards higher resistance frequencies to kanamycin and nalidixic acid (p < 0.05), while a greater percentage of human isolates were resistant to chloramphenicol and gentamicin (p < 0.05). Multiple drug resistance was found in isolates from both sources and was usually associated with tetracycline resistance. Tetracycline-resistant isolates from both avian and human sources contained one or several plasmids, which were transmissible by transformation of chemically-competent E. coli. Tetracycline resistance was mediated by efflux genes tetB and/or tetD. Conclusion The present study highlights the prevalence of multiple drug resistant E. coli among healthy broiler chickens in Jamaica, possibly associated with expression of tetracycline resistance. While there did not appear to be a common source for multiple drug resistance in the strains from avian or human origin, the genes encoding resistance are similar. These results suggest that genes are disseminated in the environment and warrant further investigation of the possibility for avian sources acting as reservoirs for tetracycline resistance. PMID:16460561

Text mining for adverse drug events: the promise, challenges, and state of the art.

PubMed

Harpaz, Rave; Callahan, Alison; Tamang, Suzanne; Low, Yen; Odgers, David; Finlayson, Sam; Jung, Kenneth; LePendu, Paea; Shah, Nigam H

2014-10-01

Text mining is the computational process of extracting meaningful information from large amounts of unstructured text. It is emerging as a tool to leverage underutilized data sources that can improve pharmacovigilance, including the objective of adverse drug event (ADE) detection and assessment. This article provides an overview of recent advances in pharmacovigilance driven by the application of text mining, and discusses several data sources-such as biomedical literature, clinical narratives, product labeling, social media, and Web search logs-that are amenable to text mining for pharmacovigilance. Given the state of the art, it appears text mining can be applied to extract useful ADE-related information from multiple textual sources. Nonetheless, further research is required to address remaining technical challenges associated with the text mining methodologies, and to conclusively determine the relative contribution of each textual source to improving pharmacovigilance.

Editorial for Special Issue on Herbal Medicines and Natural Products.

PubMed

Zhou, Zhi-Wei; Zhou, Shu-Feng

2015-11-16

Herbal medicines and natural products have been the most productive source of drug development and there is a large line of evidence on the applications of herbal medicines and natural products for the management of body function and the treatment of aliments. The multiple bioactive components in herbal medicines and natural products can explain the multiple targets effect in their medical applications. The increasing usage of state-of-art computational, molecular biological, and analytical chemistry techniques will promote the exploration of the pharmacological effect of previously inaccessible sources of herbal medicines and natural products. Notably, with the increasing reports on the safety issues regarding the medical use of herbal medicines and natural products, the awareness of pharmacovigilance in herbal medicines and natural products needs to be strengthened. To prevent the adverse drug reactions related to herbal medicines and natural products, physicians need to be aware of potential risks and alert patients in the use of herbal medicines and natural products.

Exploiting Nanotechnology to Overcome Tumor Drug Resistance: Challenges and Opportunities

PubMed Central

Kirtane, Ameya; Kalscheuer, Stephen; Panyam, Jayanth

2013-01-01

Tumor cells develop resistance to chemotherapeutic drugs through multiple mechanisms. Overexpression of efflux transporters is an important source of drug resistance. Efflux transporters such as P-glycoprotein reduce intracellular drug accumulation and compromise drug efficacy. Various nanoparticle-based approaches have been investigated to overcome efflux-mediated resistance. These include the use of formulation excipients that inhibit transporter activity and co-delivery of the anticancer drug with a specific inhibitor of transporter function or expression. However, the effectiveness of nanoparticles can be diminished by poor transport in the tumor tissue. Hence, adjunct therapies that improve the intratumoral distribution of nanoparticles may be vital to the successful application of nanotechnology to overcome tumor drug resistance. This review discusses the mechanisms of tumor drug resistance and highlights the opportunities and challenges in the use of nanoparticles to improve the efficacy of anticancer drugs against resistant tumors. PMID:24036273

A natural history of botanical therapeutics

PubMed Central

Schmidt, Barbara; Ribnicky, David M.; Poulev, Alexander; Logendra, Sithes; Cefalu, William T.; Raskin, Ilya

2010-01-01

Plants have been used as a source of medicine throughout history and continue to serve as the basis for many pharmaceuticals used today. Although the modern pharmaceutical industry was born from botanical medicine, synthetic approaches to drug discovery have become standard. However, this modern approach has led to a decline in new drug development in recent years and a growing market for botanical therapeutics that are currently available as dietary supplements, drugs, or botanical drugs. Most botanical therapeutics are derived from medicinal plants that have been cultivated for increased yields of bioactive components. The phytochemical composition of many plants has changed over time, with domestication of agricultural crops resulting in the enhanced content of some bioactive compounds and diminished content of others. Plants continue to serve as a valuable source of therapeutic compounds because of their vast biosynthetic capacity. A primary advantage of botanicals is their complex composition consisting of collections of related compounds having multiple activities that interact for a greater total activity. PMID:18555851

The Application of the Open Pharmacological Concepts Triple Store (Open PHACTS) to Support Drug Discovery Research

PubMed Central

Ratnam, Joseline; Zdrazil, Barbara; Digles, Daniela; Cuadrado-Rodriguez, Emiliano; Neefs, Jean-Marc; Tipney, Hannah; Siebes, Ronald; Waagmeester, Andra; Bradley, Glyn; Chau, Chau Han; Richter, Lars; Brea, Jose; Evelo, Chris T.; Jacoby, Edgar; Senger, Stefan; Loza, Maria Isabel; Ecker, Gerhard F.; Chichester, Christine

2014-01-01

Integration of open access, curated, high-quality information from multiple disciplines in the Life and Biomedical Sciences provides a holistic understanding of the domain. Additionally, the effective linking of diverse data sources can unearth hidden relationships and guide potential research strategies. However, given the lack of consistency between descriptors and identifiers used in different resources and the absence of a simple mechanism to link them, gathering and combining relevant, comprehensive information from diverse databases remains a challenge. The Open Pharmacological Concepts Triple Store (Open PHACTS) is an Innovative Medicines Initiative project that uses semantic web technology approaches to enable scientists to easily access and process data from multiple sources to solve real-world drug discovery problems. The project draws together sources of publicly-available pharmacological, physicochemical and biomolecular data, represents it in a stable infrastructure and provides well-defined information exploration and retrieval methods. Here, we highlight the utility of this platform in conjunction with workflow tools to solve pharmacological research questions that require interoperability between target, compound, and pathway data. Use cases presented herein cover 1) the comprehensive identification of chemical matter for a dopamine receptor drug discovery program 2) the identification of compounds active against all targets in the Epidermal growth factor receptor (ErbB) signaling pathway that have a relevance to disease and 3) the evaluation of established targets in the Vitamin D metabolism pathway to aid novel Vitamin D analogue design. The example workflows presented illustrate how the Open PHACTS Discovery Platform can be used to exploit existing knowledge and generate new hypotheses in the process of drug discovery. PMID:25522365

Leveraging 3D chemical similarity, target and phenotypic data in the identification of drug-protein and drug-adverse effect associations.

PubMed

Vilar, Santiago; Hripcsak, George

2016-01-01

Drug-target identification is crucial to discover novel applications for existing drugs and provide more insights about mechanisms of biological actions, such as adverse drug effects (ADEs). Computational methods along with the integration of current big data sources provide a useful framework for drug-target and drug-adverse effect discovery. In this article, we propose a method based on the integration of 3D chemical similarity, target and adverse effect data to generate a drug-target-adverse effect predictor along with a simple leveraging system to improve identification of drug-targets and drug-adverse effects. In the first step, we generated a system for multiple drug-target identification based on the application of 3D drug similarity into a large target dataset extracted from the ChEMBL. Next, we developed a target-adverse effect predictor combining targets from ChEMBL with phenotypic information provided by SIDER data source. Both modules were linked to generate a final predictor that establishes hypothesis about new drug-target-adverse effect candidates. Additionally, we showed that leveraging drug-target candidates with phenotypic data is very useful to improve the identification of drug-targets. The integration of phenotypic data into drug-target candidates yielded up to twofold precision improvement. In the opposite direction, leveraging drug-phenotype candidates with target data also yielded a significant enhancement in the performance. The modeling described in the current study is simple and efficient and has applications at large scale in drug repurposing and drug safety through the identification of mechanism of action of biological effects.

Using resources for scientific-driven pharmacovigilance: from many product safety documents to one product safety master file.

PubMed

Furlan, Giovanni

2012-08-01

Current regulations require a description of the overall safety profile or the specific risks of a drug in multiple documents such as the Periodic and Development Safety Update Reports, Risk Management Plans (RMPs) and Signal Detection Reports. In a resource-constrained world, the need for preparing multiple documents reporting the same information results in shifting the focus from a thorough scientific and medical evaluation of the available data to maintaining compliance with regulatory timelines. Since the aim of drug safety is to understand and characterize product issues to take adequate risk minimization measures rather than to comply with bureaucratic requirements, there is the need to avoid redundancy. In order to identify core drug safety activities that need to be undertaken to protect patient safety and reduce the number of documents reporting the results of these activities, the author has reviewed the main topics included in the drug safety guidelines and templates. The topics and sources that need to be taken into account in the main regulatory documents have been found to greatly overlap and, in the future, as a result of the new Periodic Safety Update Report structure and requirements, in the author's opinion this overlap is likely to further increase. Many of the identified inter-document differences seemed to be substantially formal. The Development Safety Update Report, for example, requires separate presentation of the safety issues emerging from different sources followed by an overall evaluation of each safety issue. The RMP, instead, requires a detailed description of the safety issues without separate presentation of the evidence derived from each source. To some extent, however, the individual documents require an in-depth analysis of different aspects; the RMP, for example, requires an epidemiological description of the indication for which the drug is used and its risks. At the time of writing this article, this is not specifically required by other documents. The author has identified signal detection (intended not only as adverse event disproportionate reporting, but including non-clinical, laboratory, clinical analysis data and literature screening) and characterization as the basis for the preparation of all drug safety documents, which can be viewed as different ways of presenting the results of this activity. Therefore, the author proposes to merge all the aggregate reports required by current regulations into a single document - the Drug Safety Master File. This report should contain all the available information, from any source, regarding the potential and identified risks of a drug. It should be a living document updated and submitted to regulatory authorities on an ongoing basis.

Phenome-driven disease genetics prediction toward drug discovery.

PubMed

Chen, Yang; Li, Li; Zhang, Guo-Qiang; Xu, Rong

2015-06-15

Discerning genetic contributions to diseases not only enhances our understanding of disease mechanisms, but also leads to translational opportunities for drug discovery. Recent computational approaches incorporate disease phenotypic similarities to improve the prediction power of disease gene discovery. However, most current studies used only one data source of human disease phenotype. We present an innovative and generic strategy for combining multiple different data sources of human disease phenotype and predicting disease-associated genes from integrated phenotypic and genomic data. To demonstrate our approach, we explored a new phenotype database from biomedical ontologies and constructed Disease Manifestation Network (DMN). We combined DMN with mimMiner, which was a widely used phenotype database in disease gene prediction studies. Our approach achieved significantly improved performance over a baseline method, which used only one phenotype data source. In the leave-one-out cross-validation and de novo gene prediction analysis, our approach achieved the area under the curves of 90.7% and 90.3%, which are significantly higher than 84.2% (P < e(-4)) and 81.3% (P < e(-12)) for the baseline approach. We further demonstrated that our predicted genes have the translational potential in drug discovery. We used Crohn's disease as an example and ranked the candidate drugs based on the rank of drug targets. Our gene prediction approach prioritized druggable genes that are likely to be associated with Crohn's disease pathogenesis, and our rank of candidate drugs successfully prioritized the Food and Drug Administration-approved drugs for Crohn's disease. We also found literature evidence to support a number of drugs among the top 200 candidates. In summary, we demonstrated that a novel strategy combining unique disease phenotype data with system approaches can lead to rapid drug discovery. nlp. edu/public/data/DMN © The Author 2015. Published by Oxford University Press.

ClinicalTrials.gov and Drugs@FDA: A comparison of results reporting for new drug approval trials

PubMed Central

Schwartz, Lisa M.; Woloshin, Steven; Zheng, Eugene; Tse, Tony; Zarin, Deborah A.

2016-01-01

Background Pharmaceutical companies and other trial sponsors must submit certain trial results to ClinicalTrials.gov. The validity of these results is unclear. Purpose To validate results posted on ClinicalTrials.gov against publicly-available FDA reviews on Drugs@FDA. Data sources ClinicalTrials.gov (registry and results database) and Drugs@FDA (medical/statistical reviews). Study selection 100 parallel-group, randomized trials for new drug approvals (1/2013 – 7/2014) with results posted on ClinicalTrials.gov (3/15/2015). Data extraction Two assessors systematically extracted, and another verified, trial design, primary/secondary outcomes, adverse events, and deaths. Results The 100 trials were mostly phase 3 (90%) double-blind (92%), placebo-controlled (73%), representing 32 drugs from 24 companies. Of 137 primary outcomes from ClinicalTrials.gov, 134 (98%) had corresponding data in Drugs@FDA, 130 (95%) had concordant definitions, and 107 (78%) had concordant results; most differences were nominal (i.e. relative difference < 10%). Of 100 trials, primary outcome results in 14 could not be validated . Of 1,927 secondary outcomes from ClinicalTrials.gov, 1,061 (55%) definitions could be validated and 367 (19%) had results. Of 96 trials with ≥ 1 serious adverse event in either source, 14 could be compared and 7 were discordant. Of 62 trials with ≥ 1 death in either source, 25 could be compared and 17 were discordant. Limitations Unknown generalizability to uncontrolled or crossover trial results. Conclusion Primary outcome definitions and results were largely concordant between ClinicalTrials.gov and Drugs@FDA. Half of secondary outcomes could not be validated because Drugs@FDA only includes “key outcomes” for regulatory decision-making; nor could serious adverse events and deaths because Drugs@FDA frequently only includes results aggregated across multiple trials. PMID:27294570

Screening the Medicines for Malaria Venture Pathogen Box across Multiple Pathogens Reclassifies Starting Points for Open-Source Drug Discovery

PubMed Central

Sykes, Melissa L.; Jones, Amy J.; Shelper, Todd B.; Simpson, Moana; Lang, Rebecca; Poulsen, Sally-Ann; Sleebs, Brad E.

2017-01-01

ABSTRACT Open-access drug discovery provides a substantial resource for diseases primarily affecting the poor and disadvantaged. The open-access Pathogen Box collection is comprised of compounds with demonstrated biological activity against specific pathogenic organisms. The supply of this resource by the Medicines for Malaria Venture has the potential to provide new chemical starting points for a number of tropical and neglected diseases, through repurposing of these compounds for use in drug discovery campaigns for these additional pathogens. We tested the Pathogen Box against kinetoplastid parasites and malaria life cycle stages in vitro. Consequently, chemical starting points for malaria, human African trypanosomiasis, Chagas disease, and leishmaniasis drug discovery efforts have been identified. Inclusive of this in vitro biological evaluation, outcomes from extensive literature reviews and database searches are provided. This information encompasses commercial availability, literature reference citations, other aliases and ChEMBL number with associated biological activity, where available. The release of this new data for the Pathogen Box collection into the public domain will aid the open-source model of drug discovery. Importantly, this will provide novel chemical starting points for drug discovery and target identification in tropical disease research. PMID:28674055

Screening the Medicines for Malaria Venture Pathogen Box across Multiple Pathogens Reclassifies Starting Points for Open-Source Drug Discovery.

PubMed

Duffy, Sandra; Sykes, Melissa L; Jones, Amy J; Shelper, Todd B; Simpson, Moana; Lang, Rebecca; Poulsen, Sally-Ann; Sleebs, Brad E; Avery, Vicky M

2017-09-01

Open-access drug discovery provides a substantial resource for diseases primarily affecting the poor and disadvantaged. The open-access Pathogen Box collection is comprised of compounds with demonstrated biological activity against specific pathogenic organisms. The supply of this resource by the Medicines for Malaria Venture has the potential to provide new chemical starting points for a number of tropical and neglected diseases, through repurposing of these compounds for use in drug discovery campaigns for these additional pathogens. We tested the Pathogen Box against kinetoplastid parasites and malaria life cycle stages in vitro Consequently, chemical starting points for malaria, human African trypanosomiasis, Chagas disease, and leishmaniasis drug discovery efforts have been identified. Inclusive of this in vitro biological evaluation, outcomes from extensive literature reviews and database searches are provided. This information encompasses commercial availability, literature reference citations, other aliases and ChEMBL number with associated biological activity, where available. The release of this new data for the Pathogen Box collection into the public domain will aid the open-source model of drug discovery. Importantly, this will provide novel chemical starting points for drug discovery and target identification in tropical disease research. Copyright © 2017 Duffy et al.

An assessment of risk behaviours to HIV/AIDS vulnerability among young female garment workers in Bangladesh.

PubMed

Sayem, A; Popsci, M

2010-02-01

This study attempted to assess the risk behaviours for HIV/AIDS among female garment workers aged 15-24 years.A total of 300 garment workers in Dhaka city were assessed with a semi-structured interview. Their knowledge of HIV/AIDS was moderate with high rates of misperception regarding modes of transmission. Further, symptoms of possible sexually transmitted infections (STIs) such as genital ulcer disease and vaginal discharge were prevalent, and risk behaviours such as low use of condoms, multiple sex partners and drug abuse were also found. Logistic regression identified that women who sourced information through radio/television, health service providers or friends had higher age at first intercourse and higher HIV/AIDS knowledge scores and were more likely to use condoms. Those who gained information through radio/television or health service providers and those who abused drugs were more likely to have sex with multiple sex partners, while information gained through health service providers, and higher HIV/AIDS knowledge were protective against drug abuse, whereas sex with multiple partners was a predictor of drug abuse. We conclude that in Bangladesh, female garment workers are at risk of HIV/AIDS due to low education, lack of knowledge, STIs and risky behaviour.

Fluorometric assay for phenotypic differentiation of drug-resistant HIV mutants

PubMed Central

Zhu, Qinchang; Yu, Zhiqiang; Kabashima, Tsutomu; Yin, Sheng; Dragusha, Shpend; El-Mahdy, Ahmed F. M.; Ejupi, Valon; Shibata, Takayuki; Kai, Masaaki

2015-01-01

Convenient drug-resistance testing of viral mutants is indispensable to effective treatment of viral infection. We developed a novel fluorometric assay for phenotypic differentiation of drug-resistant mutants of human immunodeficiency virus-I protease (HIV-PR) which uses enzymatic and peptide-specific fluorescence (FL) reactions and high-performance liquid chromatography (HPLC) of three HIV-PR substrates. This assay protocol enables use of non-purified enzyme sources and multiple substrates for the enzymatic reaction. In this study, susceptibility of HIV mutations to drugs was evaluated by selective formation of three FL products after the enzymatic HIV-PR reaction. This proof-of-concept study indicates that the present HPLC-FL method could be an alternative to current phenotypic assays for the evaluation of HIV drug resistance. PMID:25988960

Text Mining for Adverse Drug Events: the Promise, Challenges, and State of the Art

PubMed Central

Harpaz, Rave; Callahan, Alison; Tamang, Suzanne; Low, Yen; Odgers, David; Finlayson, Sam; Jung, Kenneth; LePendu, Paea; Shah, Nigam H.

2014-01-01

Text mining is the computational process of extracting meaningful information from large amounts of unstructured text. Text mining is emerging as a tool to leverage underutilized data sources that can improve pharmacovigilance, including the objective of adverse drug event detection and assessment. This article provides an overview of recent advances in pharmacovigilance driven by the application of text mining, and discusses several data sources—such as biomedical literature, clinical narratives, product labeling, social media, and Web search logs—that are amenable to text-mining for pharmacovigilance. Given the state of the art, it appears text mining can be applied to extract useful ADE-related information from multiple textual sources. Nonetheless, further research is required to address remaining technical challenges associated with the text mining methodologies, and to conclusively determine the relative contribution of each textual source to improving pharmacovigilance. PMID:25151493

Malaysians' Preferences and Concerns Regarding Seeking Information About Illegal Drugs.

PubMed

Chie, Qiu Ting; Tam, Cai Lian; Bonn, Gregory

2018-01-01

A brief survey asked Malaysians if they had searched for information about illegal drugs and their thoughts about the information available. Two hundred and eighty participants from four states: Selangor, Penang, Malacca, and Johor filled out a paper-and-pencil survey including both multiple choice and open-ended written questions. Quantitative analyses of closed-ended, and thematic analyses of open-ended data indicated the following: Half of participants had, at some point, actively searched for information about drug use; 28% reported searching at least once per month. Participants generally (79%) preferred to obtain information online, but 62% also reported sharing and obtaining information about drugs in face-to-face interactions with friends and others. Concerns regarding the reliability of information, such as the presence of conflicting or contradictory messages from multiple sources, was a common theme in open ended responses. Of those who searched for information, about 70% reported desiring more detailed information about different drugs, in particular about their various side effects and risks. It is suggested that drug information campaigns, particularly those aimed at university students, might better focus on providing accurate, detailed information about the risks and other issues involved in various types of drug use, rather than one-size-fits-all messages. Given the varied and confusing nature of information already available, overly simplistic anti-drug messages may be ineffective, if not counterproductive.

Malaysians' Preferences and Concerns Regarding Seeking Information About Illegal Drugs

PubMed Central

Chie, Qiu Ting; Tam, Cai Lian; Bonn, Gregory

2018-01-01

A brief survey asked Malaysians if they had searched for information about illegal drugs and their thoughts about the information available. Two hundred and eighty participants from four states: Selangor, Penang, Malacca, and Johor filled out a paper-and-pencil survey including both multiple choice and open-ended written questions. Quantitative analyses of closed-ended, and thematic analyses of open-ended data indicated the following: Half of participants had, at some point, actively searched for information about drug use; 28% reported searching at least once per month. Participants generally (79%) preferred to obtain information online, but 62% also reported sharing and obtaining information about drugs in face-to-face interactions with friends and others. Concerns regarding the reliability of information, such as the presence of conflicting or contradictory messages from multiple sources, was a common theme in open ended responses. Of those who searched for information, about 70% reported desiring more detailed information about different drugs, in particular about their various side effects and risks. It is suggested that drug information campaigns, particularly those aimed at university students, might better focus on providing accurate, detailed information about the risks and other issues involved in various types of drug use, rather than one-size-fits-all messages. Given the varied and confusing nature of information already available, overly simplistic anti-drug messages may be ineffective, if not counterproductive. PMID:29868548

Predicting Adverse Drug Effects from Literature- and Database-Mined Assertions.

PubMed

La, Mary K; Sedykh, Alexander; Fourches, Denis; Muratov, Eugene; Tropsha, Alexander

2018-06-06

Given that adverse drug effects (ADEs) have led to post-market patient harm and subsequent drug withdrawal, failure of candidate agents in the drug development process, and other negative outcomes, it is essential to attempt to forecast ADEs and other relevant drug-target-effect relationships as early as possible. Current pharmacologic data sources, providing multiple complementary perspectives on the drug-target-effect paradigm, can be integrated to facilitate the inference of relationships between these entities. This study aims to identify both existing and unknown relationships between chemicals (C), protein targets (T), and ADEs (E) based on evidence in the literature. Cheminformatics and data mining approaches were employed to integrate and analyze publicly available clinical pharmacology data and literature assertions interrelating drugs, targets, and ADEs. Based on these assertions, a C-T-E relationship knowledge base was developed. Known pairwise relationships between chemicals, targets, and ADEs were collected from several pharmacological and biomedical data sources. These relationships were curated and integrated according to Swanson's paradigm to form C-T-E triangles. Missing C-E edges were then inferred as C-E relationships. Unreported associations between drugs, targets, and ADEs were inferred, and inferences were prioritized as testable hypotheses. Several C-E inferences, including testosterone → myocardial infarction, were identified using inferences based on the literature sources published prior to confirmatory case reports. Timestamping approaches confirmed the predictive ability of this inference strategy on a larger scale. The presented workflow, based on free-access databases and an association-based inference scheme, provided novel C-E relationships that have been validated post hoc in case reports. With refinement of prioritization schemes for the generated C-E inferences, this workflow may provide an effective computational method for the early detection of potential drug candidate ADEs that can be followed by targeted experimental investigations.

Utilizing Ayurvedic literature for the identification of novel phytochemical inhibitors of botulinum neurotoxin A

USDA-ARS?s Scientific Manuscript database

Ethnopharmacological relevance: Ayurveda, an ancient holistic system of health care practiced on the Indian subcontinent, utilizes a number of multi-plant formulations and is considered by many as a potential source for novel treatments, as well as the identification of new drugs. Our aim is to iden...

75 FR 54073 - Medicaid Program; Withdrawal of Determination of Average Manufacturer Price, Multiple Source Drug...

Federal Register 2010, 2011, 2012, 2013, 2014

2010-09-03

... hospital that is located outside of a Metropolitan Statistical Area for Medicare payment regulations and... reserved. 4. Section 447.510 is amended by-- A. Republishing paragraph (a) introductory text. B. Revising.... Revising the introductory text of paragraph (b). C. Revising paragraph (c). The revisions read as follows...

From the Children’s Oncology Group: Evidence-based recommendations for PEG-asparaginase nurse monitoring, hypersensitivity reaction management, and patient/family education

PubMed Central

Woods, Deborah; Winchester, Kari; Towerman, Alison; Gettinger, Katie; Carey, Christina; Timmermann, Karen; Langley, Rachel; Browne, Emily

2017-01-01

PEG-aspariginase is a backbone chemotherapy agent in pediatric acute lymphoblastic leukemia and in some non-Hodgkin lymphoma therapies. Nurses lack standardized guidelines for monitoring patients receiving PEG-asparaginase and for educating patients/families about hypersensitivity reaction risks. An electronic search of six databases using publication years 2000–2015 and multiple professional organizations and clinical resources was conducted. Evidence sources were reviewed for topic applicability. Each of the final 23 sources was appraised by two team members. The GRADE system was used to assign a quality and strength rating for each recommendation. Multiple recommendations were developed: four relating to nurse monitoring of patients during and after drug administration, eight guiding hypersensitivity reaction management, and four concerning patient/family educational content. These strong recommendations were based on moderate, low, or very-low quality evidence. Several recommendations relied upon generalized drug hypersensitivity guidelines. Additional research is needed to safely guide PEG-asparaginase monitoring, hypersensitivity reaction management and patient/family education. Nurses administering PEG-asparaginase play a critical role in the early identification and management of hypersensitivity reactions. PMID:28602129

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

PubMed

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

2017-08-01

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

Determination of the sources and antimicrobial resistance patterns of Salmonella isolated from the poultry industry in Southern Ethiopia.

PubMed

Abdi, Reta Duguma; Mengstie, Fisseha; Beyi, Ashenafi Feyisa; Beyene, Takele; Waktole, Hika; Mammo, Bedasso; Ayana, Dinka; Abunna, Fufa

2017-05-18

Ethiopia set an ambitious masterplan to increase chicken meat and egg production from 2015 to 2020. Poultry breeding, multiplication and distribution centers in the country have received executive order to import, amplify and distribute commercial chickens to end users. The biosecurity and the pathogen fauna of the centers have not been evaluated as to whether the centers could implement the mission effectively without any risk. Thus, the aim of this study was to evaluate the biosecurity practices and the pathogen prevalence, risk factors and their antimicrobial resistance (AMR) using Salmonella as case study. Routine farm workers of the centers were interviewed about the different management (biosecurity) practices using a checklist. Samples (n = 270) from different sources consisting of chicken's cloacal swab (n = 244), personnel hand swab (n = 9) and bedding (n = 17) were collected from three chicken multiplication centers. Standard bacteriological methods were used for the isolation of Salmonella. Disk diffusion method was used for drug sensitivity testing. Antimicrobials were often over prescribed without confirming the cause of ill health and without susceptibility testing. The general biosecurity and flock management practices were substandard. Salmonella was isolated from 45 (16.7%) of the 270 samples. Its prevalence was significantly (p<0.05) associated with location of the multiplication center, 27% at Bonga and 10.6% at Hawassa. Sample type was also significantly (p<0.05) affected in that it was higher in the bedding (35.3%) and personnel hand swabs (33.3%) than in the chicken cloaca (14.8%), which demonstrates the poor biosecurity and personnel hygienic practices in the centers. All of the 45 isolates (100%) exhibited resistance to kanamycin and sulfamethoxazole-trimethoprim, nalidixic acid (97.8%), ampicillin (97.8%), cefoxitin (97.8%), streptomycin (97.8%) tetracycline (97.8%), chloramphenicol (91.3%), ciprofloxacin (31.1%), and gentamicin (0%). Alarmingly, 42 isolates (93.4%) exhibited multidrug resistance (MDR) to ≥ 8 drugs and all 45 isolates had resistance to ≥ 3 drugs. The high rate of Salmonella isolation from (i) bedding, (ii) personnel hand swabs (iii) chickens, (iv) presence of more MDR isolates, (v) coupled with poor biosecurity practices in the centers could pose a risk for spreading of pathogens and drug resistant genes to the smallholder chicken producers and the public. We conclude that the poultry breeding, multiplication and distribution centers in Ethiopia, as they stand currently, seem to be a source of pathogens and AMR isolates at least for Salmonella. Therefore, strict biosecurity, personnel safety, prudent drug use, regular monitoring and traceability of Salmonella serotypes or genotypes and AMR are recommended.

ISOLATED FROM CLINICAL AND ENVIRONMENTAL SOURCES IN NORTHEAST THAILAND.

PubMed

Mala, Wanida; Kaewkes, Wanlop; Tattawasart, Unchalee; Wongwajana, Suwin; Faksri, Kiatichai; Chomvarin, Chariya

2016-09-01

Emergence of multiple drug resistance in Vibrio cholerae has been increasing around the world including Northeast Thailand. In this study, 92 isolates of V. cholerae (50 O1 and 42 non-O1/non-O139 isolates) from clinical and environmental sources in Northeast Thailand were randomly selected and investigated for the presence of SXT element, class 1 integron and antimicrobial resistance genes. Genotypic-phenotypic concordance of antimicrobial resistance was also determined. Using PCR-based assays, 79% of V. cholerae isolates were positive for SXT element, whereas only 1% was positive for class 1 integron. SXT element harbored antimicrobial resistance genes, dfrA1 or dfr18, floR, strB, sul2, and tetA. Overall phenotypic-genotypic concordance of antimicrobial resistance was 78%, with highest and lowest value being for trimethoprim (83%) and chloramphenicol (70%), respectively. Ninety-two percent of V. cholerae O1 strains isolated from clinical sources harbored both dfrA1 (O1-specific trimethoprim resistance gene) and dfr18 (non-O1-specific trimethoprim resistance gene), whereas only 5% of V. cholerae non-O1/non-O139 strains harbored both genes. All V. cholerae O1 isolated from environmental source harbored dfr18 but 48% of V. cholerae non-O1/non-O139 harbored dfrA1. This study indicates that SXT element was the main contributor to the circulation of multiple-drug resistance determinants in V. cholerae strains in Northeast Thailand and that genetic exchange of SXT element can occur in both V. cholerae O1 and non-O1/non-O139 strains from clinical and environmental sources.

Drugs, Devices, and Desires: A Problem-Based Learning Course in the History of Medicine

ERIC Educational Resources Information Center

Levitt, Sarah; McKeage, Anne; Rangachari, P. K.

2013-01-01

Problem-based learning (PBL) is well suited for courses in the history of medicine, where multiple perspectives exist and information has to be gleaned from different sources. A student, an archivist, and a teacher offer three perspectives about a senior level course where students explored the antecedents and consequences of medical technology.…

ADEpedia: a scalable and standardized knowledge base of Adverse Drug Events using semantic web technology.

PubMed

Jiang, Guoqian; Solbrig, Harold R; Chute, Christopher G

2011-01-01

A source of semantically coded Adverse Drug Event (ADE) data can be useful for identifying common phenotypes related to ADEs. We proposed a comprehensive framework for building a standardized ADE knowledge base (called ADEpedia) through combining ontology-based approach with semantic web technology. The framework comprises four primary modules: 1) an XML2RDF transformation module; 2) a data normalization module based on NCBO Open Biomedical Annotator; 3) a RDF store based persistence module; and 4) a front-end module based on a Semantic Wiki for the review and curation. A prototype is successfully implemented to demonstrate the capability of the system to integrate multiple drug data and ontology resources and open web services for the ADE data standardization. A preliminary evaluation is performed to demonstrate the usefulness of the system, including the performance of the NCBO annotator. In conclusion, the semantic web technology provides a highly scalable framework for ADE data source integration and standard query service.

An integrated modelling framework for neural circuits with multiple neuromodulators.

PubMed

Joshi, Alok; Youssofzadeh, Vahab; Vemana, Vinith; McGinnity, T M; Prasad, Girijesh; Wong-Lin, KongFatt

2017-01-01

Neuromodulators are endogenous neurochemicals that regulate biophysical and biochemical processes, which control brain function and behaviour, and are often the targets of neuropharmacological drugs. Neuromodulator effects are generally complex partly owing to the involvement of broad innervation, co-release of neuromodulators, complex intra- and extrasynaptic mechanism, existence of multiple receptor subtypes and high interconnectivity within the brain. In this work, we propose an efficient yet sufficiently realistic computational neural modelling framework to study some of these complex behaviours. Specifically, we propose a novel dynamical neural circuit model that integrates the effective neuromodulator-induced currents based on various experimental data (e.g. electrophysiology, neuropharmacology and voltammetry). The model can incorporate multiple interacting brain regions, including neuromodulator sources, simulate efficiently and easily extendable to large-scale brain models, e.g. for neuroimaging purposes. As an example, we model a network of mutually interacting neural populations in the lateral hypothalamus, dorsal raphe nucleus and locus coeruleus, which are major sources of neuromodulator orexin/hypocretin, serotonin and norepinephrine/noradrenaline, respectively, and which play significant roles in regulating many physiological functions. We demonstrate that such a model can provide predictions of systemic drug effects of the popular antidepressants (e.g. reuptake inhibitors), neuromodulator antagonists or their combinations. Finally, we developed user-friendly graphical user interface software for model simulation and visualization for both fundamental sciences and pharmacological studies. © 2017 The Authors.

An integrated modelling framework for neural circuits with multiple neuromodulators

PubMed Central

Vemana, Vinith

2017-01-01

Neuromodulators are endogenous neurochemicals that regulate biophysical and biochemical processes, which control brain function and behaviour, and are often the targets of neuropharmacological drugs. Neuromodulator effects are generally complex partly owing to the involvement of broad innervation, co-release of neuromodulators, complex intra- and extrasynaptic mechanism, existence of multiple receptor subtypes and high interconnectivity within the brain. In this work, we propose an efficient yet sufficiently realistic computational neural modelling framework to study some of these complex behaviours. Specifically, we propose a novel dynamical neural circuit model that integrates the effective neuromodulator-induced currents based on various experimental data (e.g. electrophysiology, neuropharmacology and voltammetry). The model can incorporate multiple interacting brain regions, including neuromodulator sources, simulate efficiently and easily extendable to large-scale brain models, e.g. for neuroimaging purposes. As an example, we model a network of mutually interacting neural populations in the lateral hypothalamus, dorsal raphe nucleus and locus coeruleus, which are major sources of neuromodulator orexin/hypocretin, serotonin and norepinephrine/noradrenaline, respectively, and which play significant roles in regulating many physiological functions. We demonstrate that such a model can provide predictions of systemic drug effects of the popular antidepressants (e.g. reuptake inhibitors), neuromodulator antagonists or their combinations. Finally, we developed user-friendly graphical user interface software for model simulation and visualization for both fundamental sciences and pharmacological studies. PMID:28100828

Phenome-driven disease genetics prediction toward drug discovery

PubMed Central

Chen, Yang; Li, Li; Zhang, Guo-Qiang; Xu, Rong

2015-01-01

Motivation: Discerning genetic contributions to diseases not only enhances our understanding of disease mechanisms, but also leads to translational opportunities for drug discovery. Recent computational approaches incorporate disease phenotypic similarities to improve the prediction power of disease gene discovery. However, most current studies used only one data source of human disease phenotype. We present an innovative and generic strategy for combining multiple different data sources of human disease phenotype and predicting disease-associated genes from integrated phenotypic and genomic data. Results: To demonstrate our approach, we explored a new phenotype database from biomedical ontologies and constructed Disease Manifestation Network (DMN). We combined DMN with mimMiner, which was a widely used phenotype database in disease gene prediction studies. Our approach achieved significantly improved performance over a baseline method, which used only one phenotype data source. In the leave-one-out cross-validation and de novo gene prediction analysis, our approach achieved the area under the curves of 90.7% and 90.3%, which are significantly higher than 84.2% (P < e−4) and 81.3% (P < e−12) for the baseline approach. We further demonstrated that our predicted genes have the translational potential in drug discovery. We used Crohn’s disease as an example and ranked the candidate drugs based on the rank of drug targets. Our gene prediction approach prioritized druggable genes that are likely to be associated with Crohn’s disease pathogenesis, and our rank of candidate drugs successfully prioritized the Food and Drug Administration-approved drugs for Crohn’s disease. We also found literature evidence to support a number of drugs among the top 200 candidates. In summary, we demonstrated that a novel strategy combining unique disease phenotype data with system approaches can lead to rapid drug discovery. Availability and implementation: nlp.case.edu/public/data/DMN Contact: rxx@case.edu PMID:26072493

Guidelines for conducting pharmaceutical budget impact analyses for submission to public drug plans in Canada.

PubMed

Marshall, Deborah A; Douglas, Patrick R; Drummond, Michael F; Torrance, George W; Macleod, Stuart; Manti, Orlando; Cheruvu, Lokanadha; Corvari, Ron

2008-01-01

Until now, there has been no standardized method of performing and presenting budget impact analyses (BIAs) in Canada. Nevertheless, most drug plan managers have been requiring this economic data to inform drug reimbursement decisions. This paper describes the process used to develop the Canadian BIA Guidelines; describes the Guidelines themselves, including the model template; and compares this guidance with other guidance on BIAs. The intended audience includes those who develop, submit or use BIA models, and drug plan managers who evaluate BIA submissions. The Patented Medicine Prices Review Board (PMPRB) initiated the development of the Canadian BIA Guidelines on behalf of the National Prescription Drug Utilisation Information System (NPDUIS). The findings and recommendations from a needs assessment with respect to BIA submissions were reviewed to inform guideline development. In addition, a literature review was performed to identify existing BIA guidance. The detailed guidance was developed on this basis, and with the input of the NPDUIS Advisory Committee, including drug plan managers from multiple provinces in Canada and a representative from the Canadian Agency for Drugs and Technologies in Health. A Microsoft Excel-based interactive model template was designed to support BIA model development. Input regarding the guidelines and model template was sought from each NPDUIS Advisory Committee member to ensure compatibility with existing drug plan needs. Decisions were made by consensus through multiple rounds of review and discussion. Finally, BIA guidance in Canadian provinces and other countries were compared on the basis of multiple criteria. The BIA guidelines consist of three major sections: Analytic Framework, Inputs and Data Sources, and Reporting Format. The Analytic Framework section contains a discussion of nine general issues surrounding BIAs (model design, analytic perspective, time horizon, target population, costing, scenarios to be compared, the characterisation of uncertainty, discounting, and validation methods). The Inputs and Data Sources section addresses methods for market size estimation, comparator selection, scenario forecasting and drug price estimation. The Reporting Format section describes methods for BIA reporting. The new Canadian BIA Guidelines represent a significant departure from the limited guidance that was previously available from some of the provinces, because they include specific details of the methods of performing BIAs. The Canadian BIA Guidelines differ from the Principles of Good Research Practice for BIAs developed by the International Society for Pharmacoeconomic and Outcomes Research (ISPOR), which provide more general guidance. The Canadian BIA Guidelines and template build upon existing guidance to address the specific requirements of each of the participating drug plans in Canada. Both have been endorsed by the NPDUIS Steering Committee and the PMPRB for the standardization of BIA submissions.

Emerging and recurrent issues in drug development.

PubMed

Anello, C

This paper reviews several emerging and recurrent issues relating to the drug development process. These emerging issues include changes to the FDA regulatory environment, internationalization of drug development, advances in computer technology and visualization tools, and efforts to incorporate meta-analysis methodology. Recurrent issues include: renewed interest in statistical methods for handling subgroups in the design and analysis of clinical trials; renewed interest in alternatives to the 'intention-to-treat' analysis in the presence of non-compliance in randomized clinical trials; renewed interest in methodology to address the multiplicities resulting from a variety of sources inherent in the drug development process, and renewed interest in methods to assure data integrity. These emerging and recurrent issues provide a continuing challenge to the international community of statisticians involved in drug development. Moreover, the involvement of statisticians with different perspectives continues to enrich the field and contributes to improvement in the public health.

CellProfiler and KNIME: open source tools for high content screening.

PubMed

Stöter, Martin; Niederlein, Antje; Barsacchi, Rico; Meyenhofer, Felix; Brandl, Holger; Bickle, Marc

2013-01-01

High content screening (HCS) has established itself in the world of the pharmaceutical industry as an essential tool for drug discovery and drug development. HCS is currently starting to enter the academic world and might become a widely used technology. Given the diversity of problems tackled in academic research, HCS could experience some profound changes in the future, mainly with more imaging modalities and smart microscopes being developed. One of the limitations in the establishment of HCS in academia is flexibility and cost. Flexibility is important to be able to adapt the HCS setup to accommodate the multiple different assays typical of academia. Many cost factors cannot be avoided, but the costs of the software packages necessary to analyze large datasets can be reduced by using Open Source software. We present and discuss the Open Source software CellProfiler for image analysis and KNIME for data analysis and data mining that provide software solutions which increase flexibility and keep costs low.

High-Risk Obtainment of Prescription Drugs by Older Adults in New Jersey: The Role of Prescription Opioids.

PubMed

Gold, Sarah L; Powell, Kristen Gilmore; Eversman, Michael H; Peterson, N Andrew; Borys, Suzanne; Hallcom, Donald K

2016-10-01

To explore the high-risk ways in which older adults obtain prescription opioids and to identify predictors of obtaining prescription opioids from high-risk sources, such as obtaining the same drug from multiple doctors, sharing drugs, and stealing prescription pads. Logistic regression analyses of cross-sectional survey data from the New Jersey Older Adult Survey on Drug Use and Health, a representative random-sample survey. Adults aged 60 and older (N = 725). Items such as obtaining prescriptions for the same drug from more than one doctor and stealing prescription drugs were measured to determine high-risk obtainment of prescription opioids. Almost 15% of the sample used high-risk methods of obtaining prescription opioids. Adults who previously used a prescription opioid recreationally had three times the risk of high-risk obtainment of prescription opioids. These findings illustrate the importance of strengthening prescription drug monitoring programs to reduce high-risk use of prescription drugs in older adults by alerting doctors and pharmacists to potential prescription drug misuse and interactions. © 2016, Copyright the Authors Journal compilation © 2016, The American Geriatrics Society.

Vaginal drug distribution modeling.

PubMed

Katz, David F; Yuan, Andrew; Gao, Yajing

2015-09-15

This review presents and applies fundamental mass transport theory describing the diffusion and convection driven mass transport of drugs to the vaginal environment. It considers sources of variability in the predictions of the models. It illustrates use of model predictions of microbicide drug concentration distribution (pharmacokinetics) to gain insights about drug effectiveness in preventing HIV infection (pharmacodynamics). The modeling compares vaginal drug distributions after different gel dosage regimens, and it evaluates consequences of changes in gel viscosity due to aging. It compares vaginal mucosal concentration distributions of drugs delivered by gels vs. intravaginal rings. Finally, the modeling approach is used to compare vaginal drug distributions across species with differing vaginal dimensions. Deterministic models of drug mass transport into and throughout the vaginal environment can provide critical insights about the mechanisms and determinants of such transport. This knowledge, and the methodology that obtains it, can be applied and translated to multiple applications, involving the scientific underpinnings of vaginal drug distribution and the performance evaluation and design of products, and their dosage regimens, that achieve it. Copyright © 2015 Elsevier B.V. All rights reserved.

A New Data Representation Based on Training Data Characteristics to Extract Drug Name Entity in Medical Text

PubMed Central

Basaruddin, T.

2016-01-01

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

Ontology-based knowledge management for personalized adverse drug events detection.

PubMed

Cao, Feng; Sun, Xingzhi; Wang, Xiaoyuan; Li, Bo; Li, Jing; Pan, Yue

2011-01-01

Since Adverse Drug Event (ADE) has become a leading cause of death around the world, there arises high demand for helping clinicians or patients to identify possible hazards from drug effects. Motivated by this, we present a personalized ADE detection system, with the focus on applying ontology-based knowledge management techniques to enhance ADE detection services. The development of electronic health records makes it possible to automate the personalized ADE detection, i.e., to take patient clinical conditions into account during ADE detection. Specifically, we define the ADE ontology to uniformly manage the ADE knowledge from multiple sources. We take advantage of the rich semantics from the terminology SNOMED-CT and apply it to ADE detection via the semantic query and reasoning.

PharmacoGx: an R package for analysis of large pharmacogenomic datasets.

PubMed

Smirnov, Petr; Safikhani, Zhaleh; El-Hachem, Nehme; Wang, Dong; She, Adrian; Olsen, Catharina; Freeman, Mark; Selby, Heather; Gendoo, Deena M A; Grossmann, Patrick; Beck, Andrew H; Aerts, Hugo J W L; Lupien, Mathieu; Goldenberg, Anna; Haibe-Kains, Benjamin

2016-04-15

Pharmacogenomics holds great promise for the development of biomarkers of drug response and the design of new therapeutic options, which are key challenges in precision medicine. However, such data are scattered and lack standards for efficient access and analysis, consequently preventing the realization of the full potential of pharmacogenomics. To address these issues, we implemented PharmacoGx, an easy-to-use, open source package for integrative analysis of multiple pharmacogenomic datasets. We demonstrate the utility of our package in comparing large drug sensitivity datasets, such as the Genomics of Drug Sensitivity in Cancer and the Cancer Cell Line Encyclopedia. Moreover, we show how to use our package to easily perform Connectivity Map analysis. With increasing availability of drug-related data, our package will open new avenues of research for meta-analysis of pharmacogenomic data. PharmacoGx is implemented in R and can be easily installed on any system. The package is available from CRAN and its source code is available from GitHub. bhaibeka@uhnresearch.ca or benjamin.haibe.kains@utoronto.ca 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.

Assessing the drug-likeness of lamellarins, a marine-derived natural product class with diverse oncological activities.

PubMed

Chittchang, Montakarn; Gleeson, M Paul; Ploypradith, Poonsakdi; Ruchirawat, Somsak

2010-06-01

Natural products currently represent an underutilized source of leads for the pharmaceutical industry, especially when one considers that almost 50% of all drugs were either derived from such sources or are very closely related. Lamellarins are a class of natural products with diverse biological activities and have entered into preclinical development for the treatment of multidrug-resistant tumors. Although these compounds demonstrated good cell penetration, as observed by their low microM activity in whole cell models, they have not been extensively profiled from a physicochemical point of view, and this is the goal of this study. For this study, we have determined the experimental logP values of a set of 25 lamellarins, given it is the single most important parameter in determining multiple ADMET parameters. We also discuss the relationship between this natural product class, natural product derivatives in development and on the market, oral marketed drugs, as well as drug molecules in development, using a range of physicochemical parameters in conjunction with principal components analysis (PCA). The impact of this systematic analysis on our ongoing medicinal chemistry strategy is also discussed. Copyright (c) 2010 Elsevier Masson SAS. All rights reserved.

Adverse Drug Event Causality Analysis (ADECA): A Process for Evaluating Evidence and Assigning Drugs to Risk Categories for Sudden Death.

PubMed

Woosley, Raymond L; Romero, Klaus; Heise, Craig W; Gallo, Tyler; Tate, Jared; Woosley, Raymond David; Ward, Sophie

2017-06-01

Growing evidence indicates that many drugs have the ability to cause a potentially lethal cardiac arrhythmia, torsades de pointes (TdP). This necessitates the development of a compilation of drugs that have this potential toxicity. Such a list is helpful in identifying the etiology of TdP in patients taking multiple drugs and assists decision making by those caring for patients at high risk of TdP. The Arizona Center for Education and Research on Therapeutics (AZCERT) has developed a process to standardize the identification of drugs and place them in risk categories for their clinical ability to cause TdP and QT prolongation. AZCERT's Adverse Drug Event Causality Analysis (ADECA) utilizes 16 types of data drawn from four sources to compile an open-source knowledge base, QTdrugs, which is maintained on the CredibleMeds.org website. Because the evidence for most drugs is incomplete, the ADECA process is used to place drugs into one of three categories that represent different levels of certainty: known TdP risk, possible TdP risk, and conditional TdP risk. Each category has strict evidentiary requirements for clinical evidence of TdP and/or QT prolongation. These are described in this paper. Because evidence can evolve over time, the ADECA process includes the continuous gathering and analysis of newly emerging evidence to revise the lists. The QTdrugs lists have proven to be a valued, readily available, commercial influence-free resource for healthcare providers, patients, researchers, and authors of consensus guidelines for the safe use of medicines.

Generics Substitution, Bioequivalence Standards, and International Oversight: Complex Issues Facing the FDA.

PubMed

Bate, Roger; Mathur, Aparna; Lever, Harry M; Thakur, Dinesh; Graedon, Joe; Cooperman, Tod; Mason, Preston; Fox, Erin R

2016-03-01

The regulations for assessing the quality of generic drugs and their bioequivalence to innovator products are outdated and need to be substantially modernized. There are multiple reasons why these changes are needed, including: (i) the regulations remain largely unchanged since the passage of the Hatch-Waxman Act in 1984; (ii) medication therapies have become substantially more complex over the three decades since the passage of the Act; (iii) a switch from an innovator drug to a generic drug, or switching from one generic to another, is not a benign process - there is substantial clinical professional judgment involved and in some instances these decisions should be better informed; and (iv) pharmaceutical ingredients for finished products, whether innovator or generic, are from multiple sources of supply, adding variability in their production, and which may not be accounted for in specification tolerances. When these elements are viewed together, they clearly suggest that more transparency of responsible manufacturers in product labels and updated standards for bioequivalence are required. Copyright © 2015 Elsevier Ltd. All rights reserved.

Literacy demands of product information intended to supplement television direct-to-consumer prescription drug advertisements.

PubMed

Kaphingst, Kimberly A; Rudd, Rima E; DeJong, William; Daltroy, Lawren H

2004-11-01

The US Food and Drug Administration (FDA) allows television direct-to-consumer (DTC) prescription drug advertisements that do not fully disclose drug risks if the ads include "adequate provision" for dissemination of the drug's approved labeling. This requirement can be met in part by referring consumers to multiple text sources of product labeling. This study was designed to assess the materials to which consumers were referred in 23 DTC television advertisements. SMOG assessments showed that the average reading grade levels were in the high school range for the main body sections of the materials and college-level range for the brief summary sections. The Suitability Assessment of Materials (SAM) instrument identified specific difficulties with the materials, including content, graphics, layout, and typography features. Stronger plain language requirements are recommended. Health care providers should be aware that patients who ask about an advertised drug might not have the full information required to make an informed decision.

Drug Target Prediction and Repositioning Using an Integrated Network-Based Approach

PubMed Central

Emig, Dorothea; Ivliev, Alexander; Pustovalova, Olga; Lancashire, Lee; Bureeva, Svetlana; Nikolsky, Yuri; Bessarabova, Marina

2013-01-01

The discovery of novel drug targets is a significant challenge in drug development. Although the human genome comprises approximately 30,000 genes, proteins encoded by fewer than 400 are used as drug targets in the treatment of diseases. Therefore, novel drug targets are extremely valuable as the source for first in class drugs. On the other hand, many of the currently known drug targets are functionally pleiotropic and involved in multiple pathologies. Several of them are exploited for treating multiple diseases, which highlights the need for methods to reliably reposition drug targets to new indications. Network-based methods have been successfully applied to prioritize novel disease-associated genes. In recent years, several such algorithms have been developed, some focusing on local network properties only, and others taking the complete network topology into account. Common to all approaches is the understanding that novel disease-associated candidates are in close overall proximity to known disease genes. However, the relevance of these methods to the prediction of novel drug targets has not yet been assessed. Here, we present a network-based approach for the prediction of drug targets for a given disease. The method allows both repositioning drug targets known for other diseases to the given disease and the prediction of unexploited drug targets which are not used for treatment of any disease. Our approach takes as input a disease gene expression signature and a high-quality interaction network and outputs a prioritized list of drug targets. We demonstrate the high performance of our method and highlight the usefulness of the predictions in three case studies. We present novel drug targets for scleroderma and different types of cancer with their underlying biological processes. Furthermore, we demonstrate the ability of our method to identify non-suspected repositioning candidates using diabetes type 1 as an example. PMID:23593264

Open innovation for phenotypic drug discovery: The PD2 assay panel.

PubMed

Lee, Jonathan A; Chu, Shaoyou; Willard, Francis S; Cox, Karen L; Sells Galvin, Rachelle J; Peery, Robert B; Oliver, Sarah E; Oler, Jennifer; Meredith, Tamika D; Heidler, Steven A; Gough, Wendy H; Husain, Saba; Palkowitz, Alan D; Moxham, Christopher M

2011-07-01

Phenotypic lead generation strategies seek to identify compounds that modulate complex, physiologically relevant systems, an approach that is complementary to traditional, target-directed strategies. Unlike gene-specific assays, phenotypic assays interrogate multiple molecular targets and signaling pathways in a target "agnostic" fashion, which may reveal novel functions for well-studied proteins and discover new pathways of therapeutic value. Significantly, existing compound libraries may not have sufficient chemical diversity to fully leverage a phenotypic strategy. To address this issue, Eli Lilly and Company launched the Phenotypic Drug Discovery Initiative (PD(2)), a model of open innovation whereby external research groups can submit compounds for testing in a panel of Lilly phenotypic assays. This communication describes the statistical validation, operations, and initial screening results from the first PD(2) assay panel. Analysis of PD(2) submissions indicates that chemical diversity from open source collaborations complements internal sources. Screening results for the first 4691 compounds submitted to PD(2) have confirmed hit rates from 1.6% to 10%, with the majority of active compounds exhibiting acceptable potency and selectivity. Phenotypic lead generation strategies, in conjunction with novel chemical diversity obtained via open-source initiatives such as PD(2), may provide a means to identify compounds that modulate biology by novel mechanisms and expand the innovation potential of drug discovery.

GERIREX - growing a second generation medical expert system

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

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

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

Factors associated with prescribing restriction on oncology formulary drugs in Malaysia.

PubMed

Fatokun, Omotayo; Olawepo, Michael N

2016-10-01

Background Drugs listed on formularies are often subjected to a variety of utilization restriction measures. However, the degree of restriction is influenced by multiple factors, including the characteristics and attributes of the listed drugs. Objective To identify the factors that are associated with the levels of prescribing restriction on oncology formulary drugs in Malaysia. Setting Oncology formulary in Malaysia. Method The Malaysia Drug Code assigned to each of the drug products on the Malaysia Ministry of Health (MOH) drug formulary was used to identify oncology drugs belonging to WHO ATC class L (antineoplastic and immunomodulating agents). Main outcome measures Categories of prescribing restrictions, therapeutic class, drug type, administration mode, number of sources and the post-approval use period. Results Oncology drugs having a shorter post-approval use period (p < 0.001), biologic oncology drugs (p = 0.01) and oncology drugs belonging to immunosuppressant therapeutic class (p = 0.03) were all significantly associated with a greater likelihood of being subjected to a higher level of prescribing restriction. Conclusion This study suggests that safety concerns, costs and potentials for inappropriate use were the important considerations influencing a higher level of prescribing restriction placement on oncology drugs in the Malaysia MOH drug formulary.

Association of authorized generic marketing with prescription drug spending on antidepressants from 2000 to 2011.

PubMed

Cheng, Ning; Banerjee, Tannista; Qian, Jingjing; Hansen, Richard A

Prior research suggests that authorized generic drugs increase competition and decrease prices, but little empirical evidence supports this conclusion. This study evaluated the impact of authorized generic marketing on brand and generic prices. Longitudinal analysis of the household component of the Medical Expenditure Panel Survey. Interview panels over 12 years, with a new panel each year. For each panel, 5 rounds of household interviews were conducted over 30 months. Nationally representative sample of the U.S. civilian noninstitutionalized population, focusing on people using 1 of 5 antidepressant drugs that became generically available between 2000 to 2011. Drugs and dose/formulations with versus without an authorized generic drug marketed. Multiple linear regression models with lagged variables evaluated the effect of an authorized generic on average inflation-adjusted brand and generic price, adjusting for payment sources, generic entry time, competitor price, and year. During 2000-2011, annual brand antidepressant utilization decreased from 51.47 to 7.52 million prescriptions, and generic antidepressant utilization increased from 0 to 88.83 million prescriptions. Over time, payment per prescription for brand prescriptions increased 25% overall, and generic payments decreased 70% for all payer types. With unadjusted data, after generic entry the average brand price decreased $0.59 per year with and $3.62 per year without an authorized generic in the market. Average generic prices decreased $10.30 per year with and $8.47 per year without an authorized generic in the market. In multiple regression models with lagged variables adjusted for heteroscedasticity, payer source, time since generic entry, competitor price, and year, authorized generics significantly reduced average payment for generic (-$3.03) and brand (-$60.64) prescriptions, and over time this price change slowly diminished. Availability of an authorized generic was associated with reduced average generic and brand price in the antidepressant market, supporting prior evidences. Copyright © 2017 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

ChEMBL web services: streamlining access to drug discovery data and utilities

PubMed Central

Davies, Mark; Nowotka, Michał; Papadatos, George; Dedman, Nathan; Gaulton, Anna; Atkinson, Francis; Bellis, Louisa; Overington, John P.

2015-01-01

ChEMBL is now a well-established resource in the fields of drug discovery and medicinal chemistry research. The ChEMBL database curates and stores standardized bioactivity, molecule, target and drug data extracted from multiple sources, including the primary medicinal chemistry literature. Programmatic access to ChEMBL data has been improved by a recent update to the ChEMBL web services (version 2.0.x, https://www.ebi.ac.uk/chembl/api/data/docs), which exposes significantly more data from the underlying database and introduces new functionality. To complement the data-focused services, a utility service (version 1.0.x, https://www.ebi.ac.uk/chembl/api/utils/docs), which provides RESTful access to commonly used cheminformatics methods, has also been concurrently developed. The ChEMBL web services can be used together or independently to build applications and data processing workflows relevant to drug discovery and chemical biology. PMID:25883136

Public voices in pharmaceutical deliberations: negotiating "clinical benefit" in the FDA's Avastin Hearing.

PubMed

Teston, Christa B; Graham, S Scott; Baldwinson, Raquel; Li, Andria; Swift, Jessamyn

2014-06-01

This article offers a hybrid rhetorical-qualitative discourse analysis of the FDA's 2011 Avastin Hearing, which considered the revocation of the breast cancer indication for the popular cancer drug Avastin. We explore the multiplicity of stakeholders, the questions that motivated deliberations, and the kinds of evidence presented during the hearing. Pairing our findings with contemporary scholarship in rhetorical stasis theory, Mol's (2002) construct of multiple ontologies, and Callon, Lascoumes, and Barthe's (2011) "hybrid forums," we demonstrate that the FDA's deliberative procedures elides various sources of evidence and the potential multiplicity of definitions for "clinical benefit." Our findings suggest that while the FDA invited multiple stakeholders to offer testimony, there are ways that the FDA might have more meaningfully incorporated public voices in the deliberative process. We conclude with suggestions for how a true hybrid forum might be deployed.

Targetting the hemozoin synthesis pathway for antimalarial drug and detected by TEM (Transmission electron microscope)

NASA Astrophysics Data System (ADS)

Abbas, Jamilah; Artanti, Nina; Sundowo, Andini; Dewijanti, Indah Dwiatmi; Hanafi, Muhammad; Lisa, Syafrudin, Din

2017-11-01

Malaria is a major public health problem mainly due to the development of resistance by the most lethal causative parasite species, the alarming spread of drug resistance and limited number of effective drug available now. Therefore it is important to discover new antimalarial drug. Malaria is caused by a singlecelled parasite from the genus Plasmodium. Plasmodium falciparum parasite infect red blood cells, ingesting and degradation hemoglobin in the acidic food vacuola trough a sequential metabolic process involving multiple proteases. During these process, hemoglobin is utilized as the predominant source of nutrition. Proteolysis of hemoglobin yields amino acid for protein synthesis as well as toxic heme. Massive degradation of hemoglobin generates large amount of toxic heme. Malaria parasite has evolved a distinct mechanism for detoxification of heme through conversion into insoluble crystalline pigment, known as hemozoin (β hematoin). Hemozoin synthesis is an indispensable process for the parasite and is the target for action of several known antimalarial drug. TEM (Transmission Electron Microscope) technology for hemozoin formation in vitro assay was done in this research. Calophyllum aerophyllum Lauterb as medicinal plants was used as a source of antimalarial drug. Acetone extracts of C. lowii showed growth inhibition against parasite P. falciparum with IC50 = 5.2 µg/mL. Whereas from hexane, acetone and methanol fraction of C. aerophyllum showed growth inhibition with IC50 = 0.054, 0.055 and 0.0054 µg/mL respectively. New drug from Calophyllum might have potential compounds that have unique structures and mechanism of action which required to develop new drug for treatment of sensitive and drug resistant strain of malaria.

SuperTarget goes quantitative: update on drug–target interactions

PubMed Central

Hecker, Nikolai; Ahmed, Jessica; von Eichborn, Joachim; Dunkel, Mathias; Macha, Karel; Eckert, Andreas; Gilson, Michael K.; Bourne, Philip E.; Preissner, Robert

2012-01-01

There are at least two good reasons for the on-going interest in drug–target interactions: first, drug-effects can only be fully understood by considering a complex network of interactions to multiple targets (so-called off-target effects) including metabolic and signaling pathways; second, it is crucial to consider drug-target-pathway relations for the identification of novel targets for drug development. To address this on-going need, we have developed a web-based data warehouse named SuperTarget, which integrates drug-related information associated with medical indications, adverse drug effects, drug metabolism, pathways and Gene Ontology (GO) terms for target proteins. At present, the updated database contains >6000 target proteins, which are annotated with >330 000 relations to 196 000 compounds (including approved drugs); the vast majority of interactions include binding affinities and pointers to the respective literature sources. The user interface provides tools for drug screening and target similarity inclusion. A query interface enables the user to pose complex queries, for example, to find drugs that target a certain pathway, interacting drugs that are metabolized by the same cytochrome P450 or drugs that target proteins within a certain affinity range. SuperTarget is available at http://bioinformatics.charite.de/supertarget. PMID:22067455

Drug/Cell-line Browser: interactive canvas visualization of cancer drug/cell-line viability assay datasets.

PubMed

Duan, Qiaonan; Wang, Zichen; Fernandez, Nicolas F; Rouillard, Andrew D; Tan, Christopher M; Benes, Cyril H; Ma'ayan, Avi

2014-11-15

Recently, several high profile studies collected cell viability data from panels of cancer cell lines treated with many drugs applied at different concentrations. Such drug sensitivity data for cancer cell lines provide suggestive treatments for different types and subtypes of cancer. Visualization of these datasets can reveal patterns that may not be obvious by examining the data without such efforts. Here we introduce Drug/Cell-line Browser (DCB), an online interactive HTML5 data visualization tool for interacting with three of the recently published datasets of cancer cell lines/drug-viability studies. DCB uses clustering and canvas visualization of the drugs and the cell lines, as well as a bar graph that summarizes drug effectiveness for the tissue of origin or the cancer subtypes for single or multiple drugs. DCB can help in understanding drug response patterns and prioritizing drug/cancer cell line interactions by tissue of origin or cancer subtype. DCB is an open source Web-based tool that is freely available at: http://www.maayanlab.net/LINCS/DCB CONTACT: avi.maayan@mssm.edu Supplementary data are available at Bioinformatics online. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Dissecting Impulsivity and its Relationships to Drug Addictions

PubMed Central

Ashenhurst, James R.; Cervantes, M. Catalina; James, Alexander S.; Groman, Stephanie M.; Pennington, Zachary T.

2015-01-01

Addictions are often characterized as forms of impulsive behavior. That said, it is often noted that impulsivity is a multidimensional construct, spanning several psychological domains. This review describes the relationship between varieties of impulsivity and addiction-related behaviors, the nature of the causal relationship between the two and the underlying neurobiological mechanisms that promote impulsive behaviors. We conclude that the available data strongly supports the notion that impulsivity is both a risk factor for, and a consequence of, drug and alcohol consumption. While the evidence indicating that subtypes of impulsive behavior are uniquely informative – either biologically or with respect to their relationships to addictions – is convincing, multiple lines of study link “distinct” subtypes of impulsivity to low dopamine D2 receptor function and perturbed serotonergic transmission, revealing shared mechanisms between the subtypes. Therefore, a common biological framework involving monoaminergic transmitters in key frontostriatal circuits may link multiple forms of impulsivity to drug self-administration and addiction-related behaviors. Further dissection of these relationships is needed before the next phase of genetic and genomic discovery will be able to reveal the biological sources of the vulnerability for addiction indexed by impulsivity. PMID:24654857

Mixed Approach Retrospective Analyses of Suicide and Suicidal Ideation for Brand Compared with Generic Central Nervous System Drugs.

PubMed

Cheng, Ning; Rahman, Md Motiur; Alatawi, Yasser; Qian, Jingjing; Peissig, Peggy L; Berg, Richard L; Page, C David; Hansen, Richard A

2018-04-01

Several different types of drugs acting on the central nervous system (CNS) have previously been associated with an increased risk of suicide and suicidal ideation (broadly referred to as suicide). However, a differential association between brand and generic CNS drugs and suicide has not been reported. This study compares suicide adverse event rates for brand versus generic CNS drugs using multiple sources of data. Selected examples of CNS drugs (sertraline, gabapentin, zolpidem, and methylphenidate) were evaluated via the US FDA Adverse Event Reporting System (FAERS) for a hypothesis-generating study, and then via administrative claims and electronic health record (EHR) data for a more rigorous retrospective cohort study. Disproportionality analyses with reporting odds ratios and 95% confidence intervals (CIs) were used in the FAERS analyses to quantify the association between each drug and reported suicide. For the cohort studies, Cox proportional hazards models were used, controlling for demographic and clinical characteristics as well as the background risk of suicide in the insured population. The FAERS analyses found significantly lower suicide reporting rates for brands compared with generics for all four studied products (Breslow-Day P < 0.05). In the claims- and EHR-based cohort study, the adjusted hazard ratio (HR) was statistically significant only for sertraline (HR 0.58; 95% CI 0.38-0.88). Suicide reporting rates were disproportionately larger for generic than for brand CNS drugs in FAERS and adjusted retrospective cohort analyses remained significant only for sertraline. However, even for sertraline, temporal confounding related to the close proximity of black box warnings and generic availability is possible. Additional analyses in larger data sources with additional drugs are needed.

Patient centric drug product design in modern drug delivery as an opportunity to increase safety and effectiveness.

PubMed

Stegemann, Sven

2018-06-01

The advances in drug delivery technologies have enabled pharmaceutical scientists to deliver a drug through various administration routes and optimize the drug release and absorption. The wide range of drug delivery systems and dosage forms represent a toolbox of technology for the development of pharmaceutical drug products but might also be a source of medication errors and nonadherence. Patient centric drug product development is being suggested as an important factor to increase therapeutic outcomes. Areas covered: Patients have impaired health and potentially disabilities and they are not medical or pharmaceutical experts but are requested to manage complex therapeutic regimens. As such the application of technology should also serve to reduce complexity, build on patients' intuition and ease of use. Patients form distinct populations based on the targeted disease, disease cluster or age group with specific characteristics or therapeutic contexts. Expert opinion: Establishing a target product and patient profile is essential to guide drug product design development. Including the targeted patient populations in the process is a prerequisite to achieve patient-centric pharmaceutical drug product design. Addressing the needs early on in the product design process, will create more universal design, avoiding the necessity for multiple product presentations to cover the different patient populations.

Simultaneous screening for 238 drugs in blood by liquid chromatography-ion spray tandem mass spectrometry with multiple-reaction monitoring.

PubMed

Gergov, M; Ojanperä, I; Vuori, E

2003-09-25

A liquid chromatography-tandem mass spectrometry (LC-MS-MS) method is presented for the qualitative screening for 238 drugs in blood samples, which is considerably more than in previous methods. After a two-step liquid-liquid extraction and C(18) chromatography, the compounds were introduced into a triple quadrupole mass spectrometer equipped with a turbo ion spray ion source operating in the positive ionization mode. Identification was based on the compound's absolute retention time, protonated molecular ion, and one representative fragment ion obtained by multiple reaction monitoring (MRM) at an individually selected collision energy of 20, 35, or 50 eV. The limit of detection (LOD) for the majority of the compounds (80%) was < or = 0.05 mg/l, ranging from 0.002 mg/l (e.g., antihistamines) to 5 mg/l (acidic compounds), and for malathion it was 10 mg/l. The LOD values were sufficiently low to allow the majority of compounds to be detected at therapeutic concentrations in the blood.

Mining integrated semantic networks for drug repositioning opportunities

PubMed Central

Mullen, Joseph; Tipney, Hannah

2016-01-01

Current research and development approaches to drug discovery have become less fruitful and more costly. One alternative paradigm is that of drug repositioning. Many marketed examples of repositioned drugs have been identified through serendipitous or rational observations, highlighting the need for more systematic methodologies to tackle the problem. Systems level approaches have the potential to enable the development of novel methods to understand the action of therapeutic compounds, but requires an integrative approach to biological data. Integrated networks can facilitate systems level analyses by combining multiple sources of evidence to provide a rich description of drugs, their targets and their interactions. Classically, such networks can be mined manually where a skilled person is able to identify portions of the graph (semantic subgraphs) that are indicative of relationships between drugs and highlight possible repositioning opportunities. However, this approach is not scalable. Automated approaches are required to systematically mine integrated networks for these subgraphs and bring them to the attention of the user. We introduce a formal framework for the definition of integrated networks and their associated semantic subgraphs for drug interaction analysis and describe DReSMin, an algorithm for mining semantically-rich networks for occurrences of a given semantic subgraph. This algorithm allows instances of complex semantic subgraphs that contain data about putative drug repositioning opportunities to be identified in a computationally tractable fashion, scaling close to linearly with network data. We demonstrate the utility of our approach by mining an integrated drug interaction network built from 11 sources. This work identified and ranked 9,643,061 putative drug-target interactions, showing a strong correlation between highly scored associations and those supported by literature. We discuss the 20 top ranked associations in more detail, of which 14 are novel and 6 are supported by the literature. We also show that our approach better prioritizes known drug-target interactions, than other state-of-the art approaches for predicting such interactions. PMID:26844016

ClinicalTrials.gov and Drugs@FDA: A Comparison of Results Reporting for New Drug Approval Trials.

PubMed

Schwartz, Lisa M; Woloshin, Steven; Zheng, Eugene; Tse, Tony; Zarin, Deborah A

2016-09-20

Pharmaceutical companies and other trial sponsors must submit certain trial results to ClinicalTrials.gov. The validity of these results is unclear. To validate results posted on ClinicalTrials.gov against publicly available U.S. Food and Drug Administration (FDA) reviews on Drugs@FDA. ClinicalTrials.gov (registry and results database) and Drugs@FDA (medical and statistical reviews). 100 parallel-group, randomized trials for new drug approvals (January 2013 to July 2014) with results posted on ClinicalTrials.gov (15 March 2015). 2 assessors extracted, and another verified, the trial design, primary and secondary outcomes, adverse events, and deaths. Most trials were phase 3 (90%), double-blind (92%), and placebo-controlled (73%) and involved 32 drugs from 24 companies. Of 137 primary outcomes identified from ClinicalTrials.gov, 134 (98%) had corresponding data at Drugs@FDA, 130 (95%) had concordant definitions, and 107 (78%) had concordant results. Most differences were nominal (that is, relative difference <10%). Primary outcome results in 14 trials could not be validated. Of 1927 secondary outcomes from ClinicalTrials.gov, Drugs@FDA mentioned 1061 (55%) and included results data for 367 (19%). Of 96 trials with 1 or more serious adverse events in either source, 14 could be compared and 7 had discordant numbers of persons experiencing the adverse events. Of 62 trials with 1 or more deaths in either source, 25 could be compared and 17 were discordant. Unknown generalizability to uncontrolled or crossover trial results. Primary outcome definitions and results were largely concordant between ClinicalTrials.gov and Drugs@FDA. Half the secondary outcomes, as well as serious events and deaths, could not be validated because Drugs@FDA includes only "key outcomes" for regulatory decision making and frequently includes only adverse event results aggregated across multiple trials. National Library of Medicine.

Drugs Approved for Multiple Myeloma

Cancer.gov

This page lists cancer drugs approved by the Food and Drug Administration (FDA) for multiple myeloma and other plasma cell neoplasms. The list includes generic names, brand names, and common drug combinations, which are shown in capital letters. The drug names link to NCI's Cancer Drug Information summaries.

Content and Usability Evaluation of Patient Oriented Drug-Drug Interaction Websites.

PubMed

Adam, Terrence J; Vang, Joseph

Drug-Drug Interactions (DDI) are an important source of preventable adverse drug events and a common reason for hospitalization among patients on multiple drug therapy regimens. DDI information systems are important patient safety tools with the capacity to identify and warn health professionals of clinically significant DDI risk. While substantial research has been completed on DDI information systems in professional settings such as community, hospital, and independent pharmacies; there has been limited research on DDI systems offered through online websites directly for use by ambulatory patients. The focus of this project is to test patient oriented website capacity to correctly identify drug interactions among well established and clinically significant medication combinations and convey clinical risk data to patients. The patient education capability was assessed by evaluating website Information Capacity, Patient Usability and Readability. The study results indicate that the majority of websites identified which met the inclusion and exclusion criteria operated similarly, but vary in risk severity assessment and are not optimally patient oriented to effectively deliver risk information. The limited quality of information and complex medical term content complicate DDI risk data conveyance and the sites may not provide optimal information delivery to allow medication consumers to understand and manage their medication regimens.

Pharmacokinetics-on-a-Chip Using Label-Free SERS Technique for Programmable Dual-Drug Analysis.

PubMed

Fei, Jiayuan; Wu, Lei; Zhang, Yizhi; Zong, Shenfei; Wang, Zhuyuan; Cui, Yiping

2017-06-23

Synergistic effects of dual or multiple drugs have attracted great attention in medical fields, especially in cancer therapies. We provide a programmable microfluidic platform for pharmacokinetic detection of multiple drugs in multiple cells. The well-designed microfluidic platform includes two 2 × 3 microarrays of cell chambers, two gradient generators, and several pneumatic valves. Through the combined use of valves and gradient generators, each chamber can be controlled to infuse different kinds of living cells and drugs with specific concentrations as needed. In our experiments, 6-mercaptopurine (6MP) and methimazole (MMI) were chosen as two drug models and their pharmacokinetic parameters in different living cells were monitored through intracellular SERS spectra, which reflected the molecular structure of these drugs. The dynamic change of SERS fingerprints from 6MP and MMI molecules were recorded during drug metabolism in living cells. The results indicated that both 6MP and MMI molecules were diffused into the cells within 4 min and excreted out after 36 h. Moreover, the intracellular distribution of these drugs was monitored through SERS mapping. Thus, our microfluidic platform simultaneously accomplishes the functions to monitor pharmacokinetic action, distribution, and fingerprint of multiple drugs in multiple cells. Owing to its real-time, rapid-speed, high-precision, and programmable capability of multiple-drug and multicell analysis, such a microfluidic platform has great potential in drug design and development.

Inhibition of HIV-1 Replication by Secondary Metabolites From Endophytic Fungi of Desert Plants

PubMed Central

Wellensiek, Brian P.; Ramakrishnan, Rajesh; Bashyal, Bharat P.; Eason, Yvette; Gunatilaka, A. A. Leslie; Ahmad, Nafees

2013-01-01

Most antiretroviral drugs currently in use to treat an HIV-1 infection are chemically synthesized and lead to the development of viral resistance, as well as cause severe toxicities. However, a largely unexplored source for HIV-1 drug discovery is endophytic fungi that live in a symbiotic relationship with plants. These fungi produce biologically active secondary metabolites, which are natural products that are beneficial to the host. We prepared several hundred extracts from endophytic fungi of desert plants and evaluated the inhibitory effects on HIV-1 replication of those extracts that showed less than 30% cytotoxicity in T-lymphocytes. Those extracts that inhibited viral replication were fractionated in order to isolate the compounds responsible for activity. Multiple rounds of fractionation and antiviral evaluation lead to the identification of four compounds, which almost completely impede HIV-1 replication. These studies demonstrate that metabolites from endophytic fungi of desert plants can serve as a viable source for identifying potent inhibitors of HIV-1 replication. PMID:23961302

OpenSource lab-on-a-chip physiometer for accelerated zebrafish embryo biotests.

PubMed

Akagi, Jin; Hall, Chris J; Crosier, Kathryn E; Cooper, Jonathan M; Crosier, Philip S; Wlodkowic, Donald

2014-01-02

Zebrafish (Danio rerio) embryo assays have recently come into the spotlight as convenient experimental models in both biomedicine and ecotoxicology. As a small aquatic model organism, zebrafish embryo assays allow for rapid physiological, embryo-, and genotoxic tests of drugs and environmental toxins that can be simply dissolved in water. This protocol describes prototyping and application of an innovative, miniaturized, and polymeric chip-based device capable of immobilizing a large number of living fish embryos for real-time and/or time-lapse microscopic examination. The device provides a physical address designation to each embryo during analysis, continuous perfusion of medium, and post-analysis specimen recovery. Miniaturized embryo array is a new concept of immobilization and real-time drug perfusion of multiple individual and developing zebrafish embryos inside the mesofluidic device. The OpenSource device presented in this protocol is particularly suitable to perform accelerated fish embryo biotests in ecotoxicology and phenotype-based pharmaceutical screening. Copyright © 2014 John Wiley & Sons, Inc.

ChEMBL web services: streamlining access to drug discovery data and utilities.

PubMed

Davies, Mark; Nowotka, Michał; Papadatos, George; Dedman, Nathan; Gaulton, Anna; Atkinson, Francis; Bellis, Louisa; Overington, John P

2015-07-01

ChEMBL is now a well-established resource in the fields of drug discovery and medicinal chemistry research. The ChEMBL database curates and stores standardized bioactivity, molecule, target and drug data extracted from multiple sources, including the primary medicinal chemistry literature. Programmatic access to ChEMBL data has been improved by a recent update to the ChEMBL web services (version 2.0.x, https://www.ebi.ac.uk/chembl/api/data/docs), which exposes significantly more data from the underlying database and introduces new functionality. To complement the data-focused services, a utility service (version 1.0.x, https://www.ebi.ac.uk/chembl/api/utils/docs), which provides RESTful access to commonly used cheminformatics methods, has also been concurrently developed. The ChEMBL web services can be used together or independently to build applications and data processing workflows relevant to drug discovery and chemical biology. © The Author(s) 2015. Published by Oxford University Press on behalf of Nucleic Acids Research.

Drug-Induced Psychosis: How to Avoid Star Gazing in Schizophrenia Research by Looking at More Obvious Sources of Light

PubMed Central

Paparelli, Alessandra; Di Forti, Marta; Morrison, Paul D.; Murray, Robin M.

2010-01-01

The prevalent view today is that schizophrenia is a syndrome rather than a specific disease. Liability to schizophrenia is highly heritable. It appears that multiple genetic and environmental factors operate together to push individuals over a threshold into expressing the characteristic clinical picture. One environmental factor which has been curiously neglected is the evidence that certain drugs can induce schizophrenia-like psychosis. In the last 60 years, improved understanding of the relationship between drug abuse and psychosis has contributed substantially to our modern view of the disorder suggesting that liability to psychosis in general, and to schizophrenia in particular, is distributed trough the general population in a similar continuous way to liability to medical disorders such as hypertension and diabetes. In this review we examine the main hypotheses resulting from the link observed between the most common psychotomimetic drugs (lysergic acid diethylamide, amphetamines, cannabis, phencyclidine) and schizophrenia. PMID:21267359

Advancing tuberculosis drug regimen development through innovative quantitative translational pharmacology methods and approaches.

PubMed

Hanna, Debra; Romero, Klaus; Schito, Marco

2017-03-01

The development of novel tuberculosis (TB) multi-drug regimens that are more efficacious and of shorter duration requires a robust drug development pipeline. Advances in quantitative modeling and simulation can be used to maximize the utility of patient-level data from prior and contemporary clinical trials, thus optimizing study design for anti-TB regimens. This perspective article highlights the work of seven project teams developing first-in-class translational and quantitative methodologies that aim to inform drug development decision-making, dose selection, trial design, and safety assessments, in order to achieve shorter and safer therapies for patients in need. These tools offer the opportunity to evaluate multiple hypotheses and provide a means to identify, quantify, and understand relevant sources of variability, to optimize translation and clinical trial design. When incorporated into the broader regulatory sciences framework, these efforts have the potential to transform the development paradigm for TB combination development, as well as other areas of global health. Copyright © 2016. Published by Elsevier Ltd.

Inference of vessel intent and behaviour for maritime security operations

NASA Astrophysics Data System (ADS)

van den Broek, Bert; Smith, Arthur; den Breejen, Eric; van de Voorde, Imelda

2014-10-01

Coastguard and Navy assets are increasingly involved in Maritime Security Operations (MSO) for countering piracy, weapons and drugs smuggling, terrorism and illegal trafficking. Persistent tracking of vessels in interrupted time series over long distances and the modelling of intent and behaviour from multiple data sources are key enablers for Situation Assessment in MSO. Results of situation assessment are presented for AIS/VTS observations in the Dutch North Sea and for simulated scenarios in the Gulf of Oman.

Combining Evidence of Preferential Gene-Tissue Relationships from Multiple Sources

PubMed Central

Guo, Jing; Hammar, Mårten; Öberg, Lisa; Padmanabhuni, Shanmukha S.; Bjäreland, Marcus; Dalevi, Daniel

2013-01-01

An important challenge in drug discovery and disease prognosis is to predict genes that are preferentially expressed in one or a few tissues, i.e. showing a considerably higher expression in one tissue(s) compared to the others. Although several data sources and methods have been published explicitly for this purpose, they often disagree and it is not evident how to retrieve these genes and how to distinguish true biological findings from those that are due to choice-of-method and/or experimental settings. In this work we have developed a computational approach that combines results from multiple methods and datasets with the aim to eliminate method/study-specific biases and to improve the predictability of preferentially expressed human genes. A rule-based score is used to merge and assign support to the results. Five sets of genes with known tissue specificity were used for parameter pruning and cross-validation. In total we identify 3434 tissue-specific genes. We compare the genes of highest scores with the public databases: PaGenBase (microarray), TiGER (EST) and HPA (protein expression data). The results have 85% overlap to PaGenBase, 71% to TiGER and only 28% to HPA. 99% of our predictions have support from at least one of these databases. Our approach also performs better than any of the databases on identifying drug targets and biomarkers with known tissue-specificity. PMID:23950964

Personal digital assistant-based drug information sources: potential to improve medication safety.

PubMed

Galt, Kimberly A; Rule, Ann M; Houghton, Bruce; Young, Daniel O; Remington, Gina

2005-04-01

This study compared the potential for personal digital assistant (PDA)-based drug information sources to minimize potential medication errors dependent on accurate and complete drug information at the point of care. A quality and safety framework for drug information resources was developed to evaluate 11 PDA-based drug information sources. Three drug information sources met the criteria of the framework: Eprocrates Rx Pro, Lexi-Drugs, and mobileMICROMEDEX. Medication error types related to drug information at the point of care were then determined. Forty-seven questions were developed to test the potential of the sources to prevent these error types. Pharmacists and physician experts from Creighton University created these questions based on the most common types of questions asked by primary care providers. Three physicians evaluated the drug information sources, rating the source for each question: 1=no information available, 2=some information available, or 3 = adequate amount of information available. The mean ratings for the drug information sources were: 2.0 (Eprocrates Rx Pro), 2.5 (Lexi-Drugs), and 2.03 (mobileMICROMEDEX). Lexi-Drugs was significantly better (mobileMICROMEDEX t test; P=0.05; Eprocrates Rx Pro t test; P=0.01). Lexi-Drugs was found to be the most specific and complete PDA resource available to optimize medication safety by reducing potential errors associated with drug information. No resource was sufficient to address the patient safety information needs for all cases.

Reverse translation of adverse event reports paves the way for de-risking preclinical off-targets.

PubMed

Maciejewski, Mateusz; Lounkine, Eugen; Whitebread, Steven; Farmer, Pierre; DuMouchel, William; Shoichet, Brian K; Urban, Laszlo

2017-08-08

The Food and Drug Administration Adverse Event Reporting System (FAERS) remains the primary source for post-marketing pharmacovigilance. The system is largely un-curated, unstandardized, and lacks a method for linking drugs to the chemical structures of their active ingredients, increasing noise and artefactual trends. To address these problems, we mapped drugs to their ingredients and used natural language processing to classify and correlate drug events. Our analysis exposed key idiosyncrasies in FAERS, for example reports of thalidomide causing a deadly ADR when used against myeloma, a likely result of the disease itself; multiplications of the same report, unjustifiably increasing its importance; correlation of reported ADRs with public events, regulatory announcements, and with publications. Comparing the pharmacological, pharmacokinetic, and clinical ADR profiles of methylphenidate, aripiprazole, and risperidone, and of kinase drugs targeting the VEGF receptor, demonstrates how underlying molecular mechanisms can emerge from ADR co-analysis. The precautions and methods we describe may enable investigators to avoid confounding chemistry-based associations and reporting biases in FAERS, and illustrate how comparative analysis of ADRs can reveal underlying mechanisms.

Programmable release of multiple protein drugs from aptamer-functionalized hydrogels via nucleic acid hybridization.

PubMed

Battig, Mark R; Soontornworajit, Boonchoy; Wang, Yong

2012-08-01

Polymeric delivery systems have been extensively studied to achieve localized and controlled release of protein drugs. However, it is still challenging to control the release of multiple protein drugs in distinct stages according to the progress of disease or treatment. This study successfully demonstrates that multiple protein drugs can be released from aptamer-functionalized hydrogels with adjustable release rates at predetermined time points using complementary sequences (CSs) as biomolecular triggers. Because both aptamer-protein interactions and aptamer-CS hybridization are sequence-specific, aptamer-functionalized hydrogels constitute a promising polymeric delivery system for the programmable release of multiple protein drugs to treat complex human diseases.

Endophytic fungi: a reservoir of antibacterials

PubMed Central

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

2015-01-01

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

Promise and Peril: Dissemination of Findings from Studies of Drugs Used in Pregnancy and Their Association with Birth Defects

PubMed Central

Patrick, Stephen W.; Cooper, William O.

2015-01-01

When and how to publish birth defects research can be complex, especially in the context of drugs used in pregnancy. Such research frequently involves multiple stakeholders, including regulatory agencies. Researchers must balance the potential peril of an unnecessarily panicked populace versus the benefit of protecting the public's health. We use a case presentation and contemporary literature to highlight the potential tradeoffs that researchers must consider. We highlight important considerations including the public health impact, examining the likelihood of causality, understanding common considerations when using large data sources, the role of peer review and working in partnership with regulatory agencies. We suggest that plans for analyses, dissemination and risk communication are done best a priori and not post hoc. Rigorous research evaluating the impact of drugs used in pregnancy, coupled with effective dissemination strategies, has the potential improve outcomes for mothers and their infants for generations. PMID:26153150

Multiphase flow microfluidics for the production of single or multiple emulsions for drug delivery.

PubMed

Zhao, Chun-Xia

2013-11-01

Considerable effort has been directed towards developing novel drug delivery systems. Microfluidics, capable of generating monodisperse single and multiple emulsion droplets, executing precise control and operations on these droplets, is a powerful tool for fabricating complex systems (microparticles, microcapsules, microgels) with uniform size, narrow size distribution and desired properties, which have great potential in drug delivery applications. This review presents an overview of the state-of-the-art multiphase flow microfluidics for the production of single emulsions or multiple emulsions for drug delivery. The review starts with a brief introduction of the approaches for making single and multiple emulsions, followed by presentation of some potential drug delivery systems (microparticles, microcapsules and microgels) fabricated in microfluidic devices using single or multiple emulsions as templates. The design principles, manufacturing processes and properties of these drug delivery systems are also discussed and compared. Furthermore, drug encapsulation and drug release (including passive and active controlled release) are provided and compared highlighting some key findings and insights. Finally, site-targeting delivery using multiphase flow microfluidics is also briefly introduced. Copyright © 2013 Elsevier B.V. All rights reserved.

Qualitative analysis of seized synthetic cannabinoids and synthetic cathinones by gas chromatography triple quadrupole tandem mass spectrometry.

PubMed

Gwak, Seongshin; Arroyo-Mora, Luis E; Almirall, José R

2015-02-01

Designer drugs are analogues or derivatives of illicit drugs with a modification of their chemical structure in order to circumvent current legislation for controlled substances. Designer drugs of abuse have increased dramatically in popularity all over the world for the past couple of years. Currently, the qualitative seized-drug analysis is mainly performed by gas chromatography-electron ionization-mass spectrometry (GC-EI-MS) in which most of these emerging designer drug derivatives are extensively fragmented not presenting a molecular ion in their mass spectra. The absence of molecular ion and/or similar fragmentation pattern among these derivatives may cause the equivocal identification of unknown seized-substances. In this study, the qualitative identification of 34 designer drugs, mainly synthetic cannabinoids and synthetic cathinones, were performed by gas chromatography-triple quadrupole-tandem mass spectrometry with two different ionization techniques, including electron ionization (EI) and chemical ionization (CI) only focusing on qualitative seized-drug analysis, not from the toxicological point of view. The implementation of CI source facilitates the determination of molecular mass and the identification of seized designer drugs. Developed multiple reaction monitoring (MRM) mode may increase sensitivity and selectivity in the analysis of seized designer drugs. In addition, CI mass spectra and MRM mass spectra of these designer drug derivatives can be used as a potential supplemental database along with EI mass spectral database. Copyright © 2014 John Wiley & Sons, Ltd.

A survey of current trends in computational drug repositioning.

PubMed

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.

DDR: efficient computational method to predict drug-target interactions using graph mining and machine learning approaches.

PubMed

Olayan, Rawan S; Ashoor, Haitham; Bajic, Vladimir B

2018-04-01

Finding computationally drug-target interactions (DTIs) is a convenient strategy to identify new DTIs at low cost with reasonable accuracy. However, the current DTI prediction methods suffer the high false positive prediction rate. We developed DDR, a novel method that improves the DTI prediction accuracy. DDR is based on the use of a heterogeneous graph that contains known DTIs with multiple similarities between drugs and multiple similarities between target proteins. DDR applies non-linear similarity fusion method to combine different similarities. Before fusion, DDR performs a pre-processing step where a subset of similarities is selected in a heuristic process to obtain an optimized combination of similarities. Then, DDR applies a random forest model using different graph-based features extracted from the DTI heterogeneous graph. Using 5-repeats of 10-fold cross-validation, three testing setups, and the weighted average of area under the precision-recall curve (AUPR) scores, we show that DDR significantly reduces the AUPR score error relative to the next best start-of-the-art method for predicting DTIs by 34% when the drugs are new, by 23% when targets are new and by 34% when the drugs and the targets are known but not all DTIs between them are not known. Using independent sources of evidence, we verify as correct 22 out of the top 25 DDR novel predictions. This suggests that DDR can be used as an efficient method to identify correct DTIs. The data and code are provided at https://bitbucket.org/RSO24/ddr/. vladimir.bajic@kaust.edu.sa. Supplementary data are available at Bioinformatics online.

Opportunities and Challenges for Niosomes as Drug Delivery Systems.

PubMed

Thakkar, Miloni; Brijesh, S

2016-01-01

With the increase in drug resistance observed in most infectious diseases as well as some forms of cancer, and with the chances of development of new drug molecules to address this issue looking bleak, one of the most plausible ways to disease treatment is combination therapy. Combination therapy would ensure delay in drug resistance, if utilized rationally. However, the biggest difficulty in employing combination therapy are adverse effects due to potential drug-drug interactions and patient compliance due to multiple routes of administration or multiple dosing that may be required. To overcome these issues, researchers have utilized nanoparticle-based systems that can hold multiple drugs in a single carrier. There are several nanocarrier systems available for such purposes. However, the focus of this review will be non-ionic surfactant-based systems (niosomes) for delivery of multiple therapeutic agents. Niosomes are artificially prepared drug delivery carriers. They are structurally similar to liposomes albeit more stable than them. Literature pertaining to combination drug delivery and various drug delivery systems was reviewed. It was conceptualized that many of the methods used to prepare various types of carriers for combination delivery of drugs may be used for niosomal systems as well. We envisage that niosomes may effectively be utilized to package older drugs in newer ways. The review will thus focus on techniques that may be used for the formulation of niosomes, ways to encapsulate multiple-drug moieties, and challenges associated in preparing and optimizing such systems.

Establishment of an In Vitro Assay for Assessing the Effects of Drugs on the Liver Stages of Plasmodium vivax Malaria

DTIC Science & Technology

2010-06-01

Materials and Methods Pv spz A chimpanzee at the Yerkes Primate Center, Emory University, Atlanta, GA was infected with Pv (India VII strain) in order to have...a source of Pv gametocytes. This strain of Pv was earlier adapted to infect and grow in various new world monkeys and chimpanzees [23]. Multiple...batches of Anopheles dirus mosquitoes were fed on blood from the infected chimpanzee , and it was documented at Center for Disease Control & Prevention

Overlooked Short Toxin-Like Proteins: A Shortcut to Drug Design

PubMed Central

Linial, Michal

2017-01-01

Short stable peptides have huge potential for novel therapies and biosimilars. Cysteine-rich short proteins are characterized by multiple disulfide bridges in a compact structure. Many of these metazoan proteins are processed, folded, and secreted as soluble stable folds. These properties are shared by both marine and terrestrial animal toxins. These stable short proteins are promising sources for new drug development. We developed ClanTox (classifier of animal toxins) to identify toxin-like proteins (TOLIPs) using machine learning models trained on a large-scale proteomic database. Insects proteomes provide a rich source for protein innovations. Therefore, we seek overlooked toxin-like proteins from insects (coined iTOLIPs). Out of 4180 short (<75 amino acids) secreted proteins, 379 were predicted as iTOLIPs with high confidence, with as many as 30% of the genes marked as uncharacterized. Based on bioinformatics, structure modeling, and data-mining methods, we found that the most significant group of predicted iTOLIPs carry antimicrobial activity. Among the top predicted sequences were 120 termicin genes from termites with antifungal properties. Structural variations of insect antimicrobial peptides illustrate the similarity to a short version of the defensin fold with antifungal specificity. We also identified 9 proteins that strongly resemble ion channel inhibitors from scorpion and conus toxins. Furthermore, we assigned functional fold to numerous uncharacterized iTOLIPs. We conclude that a systematic approach for finding iTOLIPs provides a rich source of peptides for drug design and innovative therapeutic discoveries. PMID:29109389

Novel paths towards neural cellular products for neurological disorders.

PubMed

Daadi, Marcel M

2011-11-01

The prospect of using neural cells derived from stem cells or from reprogrammed adult somatic cells provides a unique opportunity in cell therapy and drug discovery for developing novel strategies for brain repair. Cell-based therapeutic approaches for treating CNS afflictions caused by disease or injury aim to promote structural repair of the injured or diseased neural tissue, an outcome currently not achieved by drug therapy. Preclinical research in animal models of various diseases or injuries report that grafts of neural cells enhance endogenous repair, provide neurotrophic support to neurons undergoing degeneration and replace lost neural cells. In recent years, the sources of neural cells for treating neurological disorders have been rapidly expanding and in addition to offering therapeutic potential, neural cell products hold promise for disease modeling and drug discovery use. Specific neural cell types have been derived from adult or fetal brain, from human embryonic stem cells, from induced pluripotent stem cells and directly transdifferentiated from adult somatic cells, such as skin cells. It is yet to be determined if the latter approach will evolve into a paradigm shift in the fields of stem cell research and regenerative medicine. These multiple sources of neural cells cover a wide spectrum of safety that needs to be balanced with efficacy to determine the viability of the cellular product. In this article, we will review novel sources of neural cells and discuss current obstacles to developing them into viable cellular products for treating neurological disorders.

Regulatory issues with multiplicity in drug approval: Principles and controversies in a changing landscape.

PubMed

Benda, Norbert; Brandt, Andreas

2018-01-01

Recently, new draft guidelines on multiplicity issues in clinical trials have been issued by European Medicine Agency (EMA) and Food and Drug Administration (FDA), respectively. Multiplicity is an issue in clinical trials, if the probability of a false-positive decision is increased by insufficiently accounting for testing multiple hypotheses. We outline the regulatory principles related to multiplicity issues in confirmatory clinical trials intended to support a marketing authorization application in the EU, describe the reasons for an increasing complexity regarding multiple hypotheses testing and discuss the specific multiplicity issues emerging within the regulatory context and being relevant for drug approval.

Abuse of Methylamphetamine

PubMed Central

Hawks, David; Mitcheson, Martin; Ogborne, Alan; Edwards, Griffith

1969-01-01

Seventy-four regular users of methylamphetamine injections were interviewed in four settings by use of a relatively structured standardized questionary. All but two had injected methylamphetamine within the previous 48 hours and had on average been using methylamphetamine continuously for 19 months. Significant features found in those interviewed were British nationality, single status, under 25 years of age, and a history of parental separation, absence, or bereavement. Educational standards were poor and a history of consistent truancy from secondary school was frequently reported. Comparison of their best and present occupations showed that downward drift had occurred. Forty-one per cent. of the sample had some definite or tentative evidence of neurotic disturbance in childhood. Twenty-three per cent. had been sentenced to detention centre, approved school, or Borstal training, and 20% had been sentenced to prison. Sixty-five per cent. had been charged with offences of one sort and 24% had been convicted of both drug and non-drug offences. A significant number had been heavy drinkers in the past, while most had been, and in many cases still were, multiple-drug users who had first started to use drugs between the ages of 16 and 20 years. They tended to have obtained methylamphetamine initially from people they knew or from sellers. While the majority were currently getting methylamphetamine from doctors, the fact that 40% gave non-medical agents as their major source of drugs suggests that a significant number were supplementing their supplies from illicit sources. More than one-half were rated as being continually involved in the “drug scene.” Most of those interviewed accepted frequent psychotic episodes as a side-effect of their use of methylamphetamine. Malnutrition, weight loss, and sleep disturbance were frequent. PMID:5786759

Incidental retinal phototoxicity associated with ingestion of photosensitizing drugs.

PubMed

Mauget-Faÿsse, M; Quaranta, M; Francoz, N; BenEzra, D; Mauget-Fa, M

2001-07-01

to report on the possible correlation between incident retinal phototoxicity and the use of photosensitizing drugs. four patients were examined because of scotomas and visual loss after an incidental exposure to a strong light source. One patient (two eyes) was exposed to standard camera flash; one patient (one eye) had a brief exposure to welding light; one patient (two eyes) underwent uncomplicated phacoemulsifications with intraocular lens implantation. The fourth patient had a severe retinal phototoxicity following a secondary intraocular lens implantation. All four patients underwent a thorough assessment including history of systemic drug use. These patients had ophthalmologic evaluation including: best corrected visual acuity (ETDRS charts), fundus examination, fluorescein and indocyanine green angiographies and were followed for 1 year. on presentation, the mean visual acuity was 7.5/20 (range: 20/400-20/20). Fundus examination disclosed yellow-gray sub-retinal lesions in all affected eyes. Early phase fluorescein angiography showed one or multiple hypofluorescent spots surrounded by a halo of hyperfluorescent window defect. In the late phase, some of these spots leaked the fluorescein dye. Indocyanine green angiography demonstrated hypofluorescent spots throughout with ill-defined borders of hyperfluorescence observed during the late stages. The common finding in these four patients was the fact that they were all taking one or more photosensitizing drugs (hydrochlorothiazide, furosemide, allopurinol, and benzodiazepines). Three of the patients had a full visual recovery a few months after the phototoxicity. The fourth patient remained with a visual acuity of 20/60 12 months after the light exposure. Despite the visual recovery, non-homogeneous retinal pigment epithelial disturbances persisted in all affected eyes. phototoxicity following incidental light exposure may occur in patients taking drugs of photosensitizing potential. Therefore, the thorough history of systemic drug ingestion should be obtained if patients have exposure to strong light sources.

Use of Natural Products as Chemical Library for Drug Discovery and Network Pharmacology

PubMed Central

Gu, Jiangyong; Gui, Yuanshen; Chen, Lirong; Yuan, Gu; Lu, Hui-Zhe; Xu, Xiaojie

2013-01-01

Background Natural products have been an important source of lead compounds for drug discovery. How to find and evaluate bioactive natural products is critical to the achievement of drug/lead discovery from natural products. Methodology We collected 19,7201 natural products structures, reported biological activities and virtual screening results. Principal component analysis was employed to explore the chemical space, and we found that there was a large portion of overlap between natural products and FDA-approved drugs in the chemical space, which indicated that natural products had large quantity of potential lead compounds. We also explored the network properties of natural product-target networks and found that polypharmacology was greatly enriched to those compounds with large degree and high betweenness centrality. In order to make up for a lack of experimental data, high throughput virtual screening was employed. All natural products were docked to 332 target proteins of FDA-approved drugs. The most potential natural products for drug discovery and their indications were predicted based on a docking score-weighted prediction model. Conclusions Analysis of molecular descriptors, distribution in chemical space and biological activities of natural products was conducted in this article. Natural products have vast chemical diversity, good drug-like properties and can interact with multiple cellular target proteins. PMID:23638153

Data integration to prioritize drugs using genomics and curated data.

PubMed

Louhimo, Riku; Laakso, Marko; Belitskin, Denis; Klefström, Juha; Lehtonen, Rainer; Hautaniemi, Sampsa

2016-01-01

Genomic alterations affecting drug target proteins occur in several tumor types and are prime candidates for patient-specific tailored treatments. Increasingly, patients likely to benefit from targeted cancer therapy are selected based on molecular alterations. The selection of a precision therapy benefiting most patients is challenging but can be enhanced with integration of multiple types of molecular data. Data integration approaches for drug prioritization have successfully integrated diverse molecular data but do not take full advantage of existing data and literature. We have built a knowledge-base which connects data from public databases with molecular results from over 2200 tumors, signaling pathways and drug-target databases. Moreover, we have developed a data mining algorithm to effectively utilize this heterogeneous knowledge-base. Our algorithm is designed to facilitate retargeting of existing drugs by stratifying samples and prioritizing drug targets. We analyzed 797 primary tumors from The Cancer Genome Atlas breast and ovarian cancer cohorts using our framework. FGFR, CDK and HER2 inhibitors were prioritized in breast and ovarian data sets. Estrogen receptor positive breast tumors showed potential sensitivity to targeted inhibitors of FGFR due to activation of FGFR3. Our results suggest that computational sample stratification selects potentially sensitive samples for targeted therapies and can aid in precision medicine drug repositioning. Source code is available from http://csblcanges.fimm.fi/GOPredict/.

Dose critical in-vivo detection of anti-cancer drug levels in blood

DOEpatents

Miller, Holly H.; Hirschfeld, deceased, Tomas B.

1991-01-01

A method and apparatus are disclosed for the in vivo and in vitro detection and measurement of dose critical levels of DNA-binding anti-cancer drug levels in biological fluids. The apparatus comprises a laser based fiber optic sensor (optrode) which utilizes the secondary interactions between the drug and an intercalating fluorochrome bound to a probe DNA, which in turn is attached to the fiber tip at one end thereof. The other end of the optical fiber is attached to an illumination source, detector and recorder. The fluorescence intensity is measured as a function of the drug concentration and its binding constant to the probe DNA. Anticancer drugs which lend themselves to analysis by the use of the method and the optrode of the present invention include doxorubicin, daunorubicin, carminomycin, aclacinomycin, chlorambucil, cyclophosphamide, methotrexate, 5-uracil, arabinosyl cytosine, mitomycin, cis-platinum 11 diamine dichloride procarbazine, vinblastine vincristine and the like. The present method and device are suitable for the continuous monitoring of the levels of these and other anticancer drugs in biological fluids such as blood, serum, urine and the like. The optrode of the instant invention also enables the measurement of the levels of these drugs from a remote location and from multiple samples.

Combining automatic table classification and relationship extraction in extracting anticancer drug-side effect pairs from full-text articles.

PubMed

Xu, Rong; Wang, QuanQiu

2015-02-01

Anticancer drug-associated side effect knowledge often exists in multiple heterogeneous and complementary data sources. A comprehensive anticancer drug-side effect (drug-SE) relationship knowledge base is important for computation-based drug target discovery, drug toxicity predication and drug repositioning. In this study, we present a two-step approach by combining table classification and relationship extraction to extract drug-SE pairs from a large number of high-profile oncological full-text articles. The data consists of 31,255 tables downloaded from the Journal of Oncology (JCO). We first trained a statistical classifier to classify tables into SE-related and -unrelated categories. We then extracted drug-SE pairs from SE-related tables. We compared drug side effect knowledge extracted from JCO tables to that derived from FDA drug labels. Finally, we systematically analyzed relationships between anti-cancer drug-associated side effects and drug-associated gene targets, metabolism genes, and disease indications. The statistical table classifier is effective in classifying tables into SE-related and -unrelated (precision: 0.711; recall: 0.941; F1: 0.810). We extracted a total of 26,918 drug-SE pairs from SE-related tables with a precision of 0.605, a recall of 0.460, and a F1 of 0.520. Drug-SE pairs extracted from JCO tables is largely complementary to those derived from FDA drug labels; as many as 84.7% of the pairs extracted from JCO tables have not been included a side effect database constructed from FDA drug labels. Side effects associated with anticancer drugs positively correlate with drug target genes, drug metabolism genes, and disease indications. Copyright © 2014 Elsevier Inc. All rights reserved.

Anti-tubercular peptides: A quest of future therapeutic weapon to combat tuberculosis.

PubMed

Khusro, Ameer; Aarti, Chirom; Agastian, Paul

2016-11-01

Tuberculosis (TB) is a symbolic menace to mankind, infecting almost one third of the world's populace and causing over a million mortalities annually. Mycobacterium tuberculosis (Mtb) is the key pathogen of TB that invades and replicates inside the host's macrophage. With the emerging dilemma of multi-drug resistant tuberculosis (MDR-TB) and extensively-drug resistant tuberculosis (XDR-TB), the exigency for developing new TB drugs is an obligation now for worldwide researchers. Among the propitious antimycobacterial agents examined in last few decades, anti-tubercular peptides have been substantiated to be persuasive with multiple advantages such as low immunogenicity, selective affinity to bacterial negatively charged cell envelopes and most importantly divergent mechanisms of action. In this review, we epitomized the current advances in the anti-tubercular peptides, focusing the sources and highlighting the mycobactericidal mechanisms of promising peptides. The review investigates the current anti-tubercular peptides exploited not only from human immune cells, human non-immune cells, bacteria and fungi but also from venoms, cyanobacteria, bacteriophages and several other unplumbed sources. The anti-tubercular peptides of those origins are also known to have unique second non-membrane targets within Mtb. The present context also describes the several cases that manifested the severe side effects of extant anti-TB drugs. The downfall, failure to reach clinical trial phases, inept to MDR- or XDR-TB and severe complications of the currently available anti-tubercular drugs accentuate the imperative necessity to develop efficacious drugs from adequate anti-tubercular peptides. Keeping in view of the emerging trends of drug resistant Mtb globally and unexampled mycobactericidal characteristics of peptides, the anti-tubercular peptides of varied origins can be used as a potential weapon to eradicate TB in future by developing new therapeutic drugs. Copyright © 2016 Hainan Medical University. Production and hosting by Elsevier B.V. All rights reserved.

Adverse Drug Reaction Identification and Extraction in Social Media: A Scoping Review

PubMed Central

Bellet, Florelle; Asfari, Hadyl; Souvignet, Julien; Texier, Nathalie; Jaulent, Marie-Christine; Beyens, Marie-Noëlle; Burgun, Anita; Bousquet, Cédric

2015-01-01

Background The underreporting of adverse drug reactions (ADRs) through traditional reporting channels is a limitation in the efficiency of the current pharmacovigilance system. Patients’ experiences with drugs that they report on social media represent a new source of data that may have some value in postmarketing safety surveillance. Objective A scoping review was undertaken to explore the breadth of evidence about the use of social media as a new source of knowledge for pharmacovigilance. Methods Daubt et al’s recommendations for scoping reviews were followed. The research questions were as follows: How can social media be used as a data source for postmarketing drug surveillance? What are the available methods for extracting data? What are the different ways to use these data? We queried PubMed, Embase, and Google Scholar to extract relevant articles that were published before June 2014 and with no lower date limit. Two pairs of reviewers independently screened the selected studies and proposed two themes of review: manual ADR identification (theme 1) and automated ADR extraction from social media (theme 2). Descriptive characteristics were collected from the publications to create a database for themes 1 and 2. Results Of the 1032 citations from PubMed and Embase, 11 were relevant to the research question. An additional 13 citations were added after further research on the Internet and in reference lists. Themes 1 and 2 explored 11 and 13 articles, respectively. Ways of approaching the use of social media as a pharmacovigilance data source were identified. Conclusions This scoping review noted multiple methods for identifying target data, extracting them, and evaluating the quality of medical information from social media. It also showed some remaining gaps in the field. Studies related to the identification theme usually failed to accurately assess the completeness, quality, and reliability of the data that were analyzed from social media. Regarding extraction, no study proposed a generic approach to easily adding a new site or data source. Additional studies are required to precisely determine the role of social media in the pharmacovigilance system. PMID:26163365

Adverse Drug Reaction Identification and Extraction in Social Media: A Scoping Review.

PubMed

Lardon, Jérémy; Abdellaoui, Redhouane; Bellet, Florelle; Asfari, Hadyl; Souvignet, Julien; Texier, Nathalie; Jaulent, Marie-Christine; Beyens, Marie-Noëlle; Burgun, Anita; Bousquet, Cédric

2015-07-10

The underreporting of adverse drug reactions (ADRs) through traditional reporting channels is a limitation in the efficiency of the current pharmacovigilance system. Patients' experiences with drugs that they report on social media represent a new source of data that may have some value in postmarketing safety surveillance. A scoping review was undertaken to explore the breadth of evidence about the use of social media as a new source of knowledge for pharmacovigilance. Daubt et al's recommendations for scoping reviews were followed. The research questions were as follows: How can social media be used as a data source for postmarketing drug surveillance? What are the available methods for extracting data? What are the different ways to use these data? We queried PubMed, Embase, and Google Scholar to extract relevant articles that were published before June 2014 and with no lower date limit. Two pairs of reviewers independently screened the selected studies and proposed two themes of review: manual ADR identification (theme 1) and automated ADR extraction from social media (theme 2). Descriptive characteristics were collected from the publications to create a database for themes 1 and 2. Of the 1032 citations from PubMed and Embase, 11 were relevant to the research question. An additional 13 citations were added after further research on the Internet and in reference lists. Themes 1 and 2 explored 11 and 13 articles, respectively. Ways of approaching the use of social media as a pharmacovigilance data source were identified. This scoping review noted multiple methods for identifying target data, extracting them, and evaluating the quality of medical information from social media. It also showed some remaining gaps in the field. Studies related to the identification theme usually failed to accurately assess the completeness, quality, and reliability of the data that were analyzed from social media. Regarding extraction, no study proposed a generic approach to easily adding a new site or data source. Additional studies are required to precisely determine the role of social media in the pharmacovigilance system.

The Association Between Stimulant, Opioid, and Multiple Drug Use on Behavioral Health Care Utilization in a Safety-Net Health System.

PubMed

Calcaterra, Susan L; Keniston, Angela; Blum, Joshua; Crume, Tessa; Binswanger, Ingrid A

2015-01-01

Prior studies show an association between drug use and health care utilization. The relationship between specific drug type and emergent/urgent, inpatient, outpatient, and behavioral health care utilization has not been examined. We aimed to determine if multiple drug use was associated with increased utilization of behavioral health care. To assess health care utilization, we conducted a retrospective cohort study of patients who accessed health care at a safety-net medical center and affiliated clinics. Using electronic health records, we categorized patients who used stimulants, opioids, or multiple drugs based on urine toxicology screening tests and/or International Classification of Diseases, 9th Revision (ICD-9). Remaining patients were categorized as patients without identified drug use. Health care utilization by drug use group and visit type was determined using a negative binomial regression model. Associations were reported as incidence rate ratios. Utilization was described by rates of health care-related visits for inpatient, emergent/urgent, outpatient, and behavioral health care among patients who used drugs, categorized by drug types, compared with patients without identified drug use. Of 95,198 index visits, 4.6% (n=4340) were by patients who used drugs. Opioid and multiple drug users had significantly higher rates of behavioral health care visits than patients without identified drug use (opioid incidence rate ratio [IRR]=7.2; 95% confidence interval [CI]: 3.8-13.8; multiple drug use IRR=5.6, 95% CI: 3.3-9.7). Patients who used stimulants were less likely to use behavioral health services (IRR=1.3, 95% CI: 0.9-2.0) when compared with opioid and multiple drug users, but were more likely to use inpatient (IRR=1.6, 95% CI: 1.4-1.8) and emergent/urgent care (IRR=1.4, 95% CI: 1.3-1.5) services as compared with patients without identified drug use. Integrated medical and mental health care and drug treatment may reduce utilization of costly health care services and improve patient outcomes. How to capture and deliver primary care and behavioral health care to patients who use stimulants needs further investigation.

Impact of treatment heterogeneity on drug resistance and supply chain costs☆

PubMed Central

Spiliotopoulou, Eirini; Boni, Maciej F.; Yadav, Prashant

2013-01-01

The efficacy of scarce drugs for many infectious diseases is threatened by the emergence and spread of resistance. Multiple studies show that available drugs should be used in a socially optimal way to contain drug resistance. This paper studies the tradeoff between risk of drug resistance and operational costs when using multiple drugs for a specific disease. Using a model for disease transmission and resistance spread, we show that treatment with multiple drugs, on a population level, results in better resistance-related health outcomes, but more interestingly, the marginal benefit decreases as the number of drugs used increases. We compare this benefit with the corresponding change in procurement and safety stock holding costs that result from higher drug variety in the supply chain. Using a large-scale simulation based on malaria transmission dynamics, we show that disease prevalence seems to be a less important factor when deciding the optimal width of drug assortment, compared to the duration of one episode of the disease and the price of the drug(s) used. Our analysis shows that under a wide variety of scenarios for disease prevalence and drug cost, it is optimal to simultaneously deploy multiple drugs in the population. If the drug price is high, large volume purchasing discounts are available, and disease prevalence is high, it may be optimal to use only one drug. Our model lends insights to policy makers into the socially optimal size of drug assortment for a given context. PMID:25843982

Impact of treatment heterogeneity on drug resistance and supply chain costs.

PubMed

Spiliotopoulou, Eirini; Boni, Maciej F; Yadav, Prashant

2013-09-01

The efficacy of scarce drugs for many infectious diseases is threatened by the emergence and spread of resistance. Multiple studies show that available drugs should be used in a socially optimal way to contain drug resistance. This paper studies the tradeoff between risk of drug resistance and operational costs when using multiple drugs for a specific disease. Using a model for disease transmission and resistance spread, we show that treatment with multiple drugs, on a population level, results in better resistance-related health outcomes, but more interestingly, the marginal benefit decreases as the number of drugs used increases. We compare this benefit with the corresponding change in procurement and safety stock holding costs that result from higher drug variety in the supply chain. Using a large-scale simulation based on malaria transmission dynamics, we show that disease prevalence seems to be a less important factor when deciding the optimal width of drug assortment, compared to the duration of one episode of the disease and the price of the drug(s) used. Our analysis shows that under a wide variety of scenarios for disease prevalence and drug cost, it is optimal to simultaneously deploy multiple drugs in the population. If the drug price is high, large volume purchasing discounts are available, and disease prevalence is high, it may be optimal to use only one drug. Our model lends insights to policy makers into the socially optimal size of drug assortment for a given context.

Identifying Drug-Target Interactions with Decision Templates.

PubMed

Yan, Xiao-Ying; Zhang, Shao-Wu

2018-01-01

During the development process of new drugs, identification of the drug-target interactions wins primary concerns. However, the chemical or biological experiments bear the limitation in coverage as well as the huge cost of both time and money. Based on drug similarity and target similarity, chemogenomic methods can be able to predict potential drug-target interactions (DTIs) on a large scale and have no luxurious need about target structures or ligand entries. In order to reflect the cases that the drugs having variant structures interact with common targets and the targets having dissimilar sequences interact with same drugs. In addition, though several other similarity metrics have been developed to predict DTIs, the combination of multiple similarity metrics (especially heterogeneous similarities) is too naïve to sufficiently explore the multiple similarities. In this paper, based on Gene Ontology and pathway annotation, we introduce two novel target similarity metrics to address above issues. More importantly, we propose a more effective strategy via decision template to integrate multiple classifiers designed with multiple similarity metrics. In the scenarios that predict existing targets for new drugs and predict approved drugs for new protein targets, the results on the DTI benchmark datasets show that our target similarity metrics are able to enhance the predictive accuracies in two scenarios. And the elaborate fusion strategy of multiple classifiers has better predictive power than the naïve combination of multiple similarity metrics. Compared with other two state-of-the-art approaches on the four popular benchmark datasets of binary drug-target interactions, our method achieves the best results in terms of AUC and AUPR for predicting available targets for new drugs (S2), and predicting approved drugs for new protein targets (S3).These results demonstrate that our method can effectively predict the drug-target interactions. The software package can freely available at https://github.com/NwpuSY/DT_all.git for academic users. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

The Impact of Drug Use in Social Networks of Patients with Substance Use and Bipolar Disorders

PubMed Central

McDonald, Leah J.; Griffin, Margaret L.; Kolodziej, Monika E.; Fitzmaurice, Garrett M.; Weiss, Roger D.

2011-01-01

In this exploratory analysis, we assessed the effect of drug use among social network members on recovery from drug dependence in patients with co-occurring bipolar disorder. Patients (n=57) enrolled in a group therapy study completed assessments over 15 months. Patients with 0–1 drug users in their social networks at intake had few days of drug use during treatment and follow-up, whereas those with ≥ 2 drug users had significantly more days of drug use. Multivariate analysis showed that patients who consistently named multiple drug users in their social networks had a marked increase in drug use over 15 months, while those who never or occasionally named multiple drug users had a small decline in drug use over time. Multiple drug users in social networks of treatment-seeking drug dependent patients with co-occurring bipolar disorder may indicate poor drug use outcomes; efforts to reduce the association with drug users may be useful. This clinical trial has been registered in a public trials registry at clinicaltrials.gov (identifier is NCT00227838). PMID:21314751

Intermittent Drug Dosing Intervals Guided by the Operational Multiple Dosing Half Lives for Predictable Plasma Accumulation and Fluctuation

PubMed Central

Grover, Anita; Benet, Leslie Z.

2013-01-01

Intermittent drug dosing intervals are usually initially guided by the terminal pharmacokinetic half life and are dependent on drug formulation. For chronic multiple dosing and for extended release dosage forms, the terminal half life often does not predict the plasma drug accumulation or fluctuation observed. We define and advance applications for the operational multiple dosing half lives for drug accumulation and fluctuation after multiple oral dosing at steady-state. Using Monte Carlo simulation, our results predict a way to maximize the operational multiple dosing half lives relative to the terminal half life by using a first-order absorption rate constant close to the terminal elimination rate constant in the design of extended release dosage forms. In this way, drugs that may be eliminated early in the development pipeline due to a relatively short half life can be formulated to be dosed at intervals three times the terminal half life, maximizing compliance, while maintaining tight plasma concentration accumulation and fluctuation ranges. We also present situations in which the operational multiple dosing half lives will be especially relevant in the determination of dosing intervals, including for drugs that follow a direct PKPD model and have a narrow therapeutic index, as the rate of concentration decrease after chronic multiple dosing (that is not the terminal half life) can be determined via simulation. These principles are illustrated with case studies on valproic acid, diazepam, and anti-hypertensives. PMID:21499748

Isolation and characterization of multiple drug resistance bacterial pathogens from waste water in hospital and non-hospital environments, Northwest Ethiopia

PubMed Central

2014-01-01

Background The importance of bacterial isolates from waste water environment as a reservoir of antibiotic resistance and a potential source of novel resistance genes to clinical pathogens is underestimated. This study is aimed at to isolate and characterize public health important bacteria from waste water in hospital and non- hospital environments and evaluate the distribution of multiple drug resistance bacteria in the study area. Methods A cross-sectional study was conducted at Gondar from January-June 2012. The hospital waste water was taken from different sections of the Gondar University Teaching Hospital. Non- hospital environment samples were taken at different sites of the university campuses, Gondar College of Teachers education, and soft drink factory in Gondar. Samples were aseptically collected, transported and processed with in two hours following standard procedure. Identified organisms were assessed for different antibiotics following Kirby-Bauer disk diffusion method. All data was registered and entered in to SPSS version 16 computer program. P-values less than 0.05 were taken as statistically significant. Result A total of 60 waste water samples were processed for the presence of drug resistance pathogens. Among the total samples 113 bacterial isolates were recovered and of these 65 (57.5%) were from hospital environment and 48 (42.5%) were from non-hospital environment. The most frequently identified bacterium was Klebsiella spp. 30 (26.6%) followed by Pseudomonas spp. 19(16.8%), E. coli (11.5%) and Citrobacter spp (11.5%), and Staphylococcus aureus (8.2%). The over all prevalence of multiple drug resistance (MDR) in this study was 79/113 (69.9%). MDR in hospital environment was found to be 53/68 (81.5%) while in non hospital environment was found to be 26/48 (54.2%). Conclusions Multiple drug resistance to the commonly used antibiotics is high in the study area. The contamination of waste water by antibiotics or other pollutants lead to the rise of resistance due to selection pressure. The presence of antibiotic resistance organisms in this waste water should not be overlooked. Since this organisms may be vital to the safety and well-being of patients who are hospitalized and individual susceptible to infection. Therefore, proper waste water treatment plant should be established and improved sanitary measure should be practice. PMID:24708553

Isolation and characterization of multiple drug resistance bacterial pathogens from waste water in hospital and non-hospital environments, Northwest Ethiopia.

PubMed

Moges, Feleke; Endris, Mengistu; Belyhun, Yeshambel; Worku, Walelegn

2014-04-05

The importance of bacterial isolates from waste water environment as a reservoir of antibiotic resistance and a potential source of novel resistance genes to clinical pathogens is underestimated. This study is aimed at to isolate and characterize public health important bacteria from waste water in hospital and non- hospital environments and evaluate the distribution of multiple drug resistance bacteria in the study area. A cross-sectional study was conducted at Gondar from January-June 2012. The hospital waste water was taken from different sections of the Gondar University Teaching Hospital. Non- hospital environment samples were taken at different sites of the university campuses, Gondar College of Teachers education, and soft drink factory in Gondar. Samples were aseptically collected, transported and processed with in two hours following standard procedure. Identified organisms were assessed for different antibiotics following Kirby-Bauer disk diffusion method. All data was registered and entered in to SPSS version 16 computer program. P-values less than 0.05 were taken as statistically significant. A total of 60 waste water samples were processed for the presence of drug resistance pathogens. Among the total samples 113 bacterial isolates were recovered and of these 65 (57.5%) were from hospital environment and 48 (42.5%) were from non-hospital environment. The most frequently identified bacterium was Klebsiella spp. 30 (26.6%) followed by Pseudomonas spp. 19(16.8%), E. coli (11.5%) and Citrobacter spp (11.5%), and Staphylococcus aureus (8.2%). The over all prevalence of multiple drug resistance (MDR) in this study was 79/113 (69.9%). MDR in hospital environment was found to be 53/68 (81.5%) while in non hospital environment was found to be 26/48 (54.2%). Multiple drug resistance to the commonly used antibiotics is high in the study area. The contamination of waste water by antibiotics or other pollutants lead to the rise of resistance due to selection pressure. The presence of antibiotic resistance organisms in this waste water should not be overlooked. Since this organisms may be vital to the safety and well-being of patients who are hospitalized and individual susceptible to infection. Therefore, proper waste water treatment plant should be established and improved sanitary measure should be practice.

Reverse translation of adverse event reports paves the way for de-risking preclinical off-targets

PubMed Central

Maciejewski, Mateusz; Lounkine, Eugen; Whitebread, Steven; Farmer, Pierre; DuMouchel, William; Shoichet, Brian K; Urban, Laszlo

2017-01-01

The Food and Drug Administration Adverse Event Reporting System (FAERS) remains the primary source for post-marketing pharmacovigilance. The system is largely un-curated, unstandardized, and lacks a method for linking drugs to the chemical structures of their active ingredients, increasing noise and artefactual trends. To address these problems, we mapped drugs to their ingredients and used natural language processing to classify and correlate drug events. Our analysis exposed key idiosyncrasies in FAERS, for example reports of thalidomide causing a deadly ADR when used against myeloma, a likely result of the disease itself; multiplications of the same report, unjustifiably increasing its importance; correlation of reported ADRs with public events, regulatory announcements, and with publications. Comparing the pharmacological, pharmacokinetic, and clinical ADR profiles of methylphenidate, aripiprazole, and risperidone, and of kinase drugs targeting the VEGF receptor, demonstrates how underlying molecular mechanisms can emerge from ADR co-analysis. The precautions and methods we describe may enable investigators to avoid confounding chemistry-based associations and reporting biases in FAERS, and illustrate how comparative analysis of ADRs can reveal underlying mechanisms. DOI: http://dx.doi.org/10.7554/eLife.25818.001 PMID:28786378

The role of acetylcholine in cocaine addiction.

PubMed

Williams, Mark J; Adinoff, Bryon

2008-07-01

Central nervous system cholinergic neurons arise from several discrete sources, project to multiple brain regions, and exert specific effects on reward, learning, and memory. These processes are critical for the development and persistence of addictive disorders. Although other neurotransmitters, including dopamine, glutamate, and serotonin, have been the primary focus of drug research to date, a growing preclinical literature reveals a critical role of acetylcholine (ACh) in the experience and progression of drug use. This review will present and integrate the findings regarding the role of ACh in drug dependence, with a primary focus on cocaine and the muscarinic ACh system. Mesostriatal ACh appears to mediate reinforcement through its effect on reward, satiation, and aversion, and chronic cocaine administration produces neuroadaptive changes in the striatum. ACh is further involved in the acquisition of conditional associations that underlie cocaine self-administration and context-dependent sensitization, the acquisition of associations in conditioned learning, and drug procurement through its effects on arousal and attention. Long-term cocaine use may induce neuronal alterations in the brain that affect the ACh system and impair executive function, possibly contributing to the disruptions in decision making that characterize this population. These primarily preclinical studies suggest that ACh exerts a myriad of effects on the addictive process and that persistent changes to the ACh system following chronic drug use may exacerbate the risk of relapse during recovery. Ultimately, ACh modulation may be a potential target for pharmacological treatment interventions in cocaine-addicted subjects. However, the complicated neurocircuitry of the cholinergic system, the multiple ACh receptor subtypes, the confluence of excitatory and inhibitory ACh inputs, and the unique properties of the striatal cholinergic interneurons suggest that a precise target of cholinergic manipulation will be required to impact substance use in the clinical population.

Equitable Prices of Single-Source Drugs in Thailand.

PubMed

Ngorsuraches, Surachat; Chaiyakan, Kanokkan

2015-08-01

In Thailand, total drug expenditure has grown rapidly. Recently, the Thai government has addressed the issue of drug pricing, but the prices of single-source drugs remain a major challenge. To examine equitable prices of single-source drugs in Thailand. A total of 98 single-source and high-expenditure drugs were examined. Unit prices from the Drug and Medical Supplies Information Center (DMSIC) and National Average Drug Acquisition Cost (NADAC) were used to represent drug prices at the provider level in Thailand and the U.S., respectively. Data for measuring drug affordability, e.g., dose and poverty line, were obtained from Micromedex online and the National Statistical Office (NSO). The U.S. drug prices were adjusted by the Human Development Index (HDI) to be equitable prices for Thailand. Purchasing Power Parity (PPP) was used to convert US currency into Thai baht. All prices in this study were based on the year 2012. Catastrophic, Impoverishment, and WHO/Health Action International (HAI) approaches were used to determine Thai citizens' ability to afford the study drugs. Finally, uncertainty analyses were conducted. From all study drugs, 55 single-source drugs were priced higher than their equitable prices, ranging from 0.38 to 422.36% higher. Among these, 28 items were antineoplastic drugs. The prices of drugs outside the National List of Essential Medicines (NLEM), as well as the country's newer drugs, tended to be higher than their calculated equitable prices. The majority of drugs in Thailand priced higher than equitable prices were unaffordable for most Thai citizens. The uncertainty analyses revealed that almost all results were relatively robust. Most single-source drug prices in Thailand were higher than their equitable prices, and were likely to be unaffordable to Thai citizens.

Influence of commercial information on prescription quantity in primary care.

PubMed

Caamaño, Francisco; Figueiras, Adolfo; Gestal-Otero, Juan Jesus

2002-09-01

In the last few years we have witnessed many publicly-financed health services reaching a crisis point. Thus, drug expenditure is nowadays one of the main concerns of health managers, and its containment one of the first goals of health authorities in western countries. The objective of this study is to identify the effect of the perceived quality stated in commercial information, its uses, and how physicians perceive the influence it has on prescription amounts. A cross-sectional study of 405 primary care physicians was conducted in Galicia (north-west Spain). The independent variables physician's education and speciality, physician's perception of the quality of available drug information sources, type of practice, and number of patients were collected, through a postal questionnaire. Environmental characteristics of the practice were obtained from secondary sources. Multiple regression models were constructed using as dependent variables two indicators of prescription volume. The response rate was 75.2%. Prescription amounts was found to be associated with perceived credibility of information provided by medical visitors, regulated physician training, and environmental characteristics of the practice (primary care team practice, urban environment). The study results suggest that in order to decrease prescription amounts it is necessary to limit the role of pharmaceutical companies in physician training, improve physician education and training, and emphasize more objective sources of information.

Drug-Induced Nephrotoxicity and Dose Adjustment Recommendations: Agreement Among Four Drug Information Sources.

PubMed

Bicalho, Millena Drumond; Soares, Danielly Botelho; Botoni, Fernando Antonio; Reis, Adriano Max Moreira; Martins, Maria Auxiliadora Parreiras

2015-09-09

: Hospitalized patients require the use of a variety of drugs, many of which individually or in combination have the potential to cause kidney damage. The use of potentially nephrotoxic drugs is often unavoidable, and the need for dose adjustment should be evaluated. This study is aimed at assessing concordance in information on drug-induced nephrotoxicity and dose adjustment recommendations by comparing four drug information sources (DRUGDEX(®), UpToDate(®), Medscape(®) and the Brazilian Therapeutic Formulary) using the formulary of a Brazilian public hospital. A total of 218 drugs were investigated. The global Fleiss' kappa coefficient was 0.265 for nephrotoxicity (p < 0.001; CI 95%, 0.211-0.319) and 0.346 for recommendations (p < 0.001; CI 95%, 0.292-0.401), indicating fair concordance among the sources. Anti-infectives and anti-hypertensives were the main drugs cited as nephrotoxic by the different sources. There were no clear definitions for qualitative data or quantitative values for dose adjustments among the four information sources. There was no advice for dosing for a large number of the drugs in the international databases. The National Therapeutic Formulary offered imprecise dose adjustment recommendations for many nephrotoxic drugs. Discrepancies among information sources may have a clinical impact on patient care and contribute to drug-related morbidity and mortality.

An investigation into the characteristics and drug release properties of multiple W/O/W emulsion systems containing low concentration of lipophilic polymeric emulsifier.

PubMed

Vasiljevic, Dragana; Parojcic, Jelena; Primorac, Marija; Vuleta, Gordana

2006-02-17

Multiple W/O/W emulsions with high content of inner phase (Phi1=Phi2=0.8) were prepared using relatively low concentrations of lipophilic polymeric primary emulsifier, PEG 30-dipolyhydroxystearate, and diclofenac diethylamine (DDA) as a model drug. The investigated formulations were characterized and their stability over the time was evaluated by dynamic and oscillatory rheological measurements, microscopic analysis and in vitro drug release study. In vitro release profiles of the selected model drug were evaluated in terms of the effective diffusion coefficients and flux of the released drug. The multiple emulsion samples exhibited good stability during the ageing time. Concentration of the lipophilic primary emulsifier markedly affected rheological behaviour as well as the droplet size and in vitro drug release kinetics of the investigated systems. The multiple emulsion systems with highest concentration (2.4%, w/w) of the primary emulsifier had the lowest droplet size and the highest apparent viscosity and highest elastic characteristics. Drug release data indicated predominately diffusional drug release mechanism with sustained and prolonged drug release accomplished with 2.4% (w/w) of lipophilic emulsifier employed.

Indicators of Methamphetamine Use and Abuse in San Diego County, California: 2001–2005†

PubMed Central

Pollini, Robin A.; Strathdee, Steffanie A.

2013-01-01

San Diego County, California, is a major distribution center for methamphetamine entering the U.S. from Mexico. All available indicators suggest that the use and abuse of methamphetamine increased between 2001 and 2005. Drug treatment admissions for primary methamphetamine use accounted for 49% of all drug treatment admissions in 2005, up from 37% in 2001, with trends showing smaller proportions of female and Hispanic users and a larger proportion of methamphetamine smokers (vs. inhalation or injection). Increases in prevalence of methamphetamine use were documented among arrestees as well; by 2005, 51% of female and 21% of juvenile arrestees tested positive for methamphetamine The proportion of emergency department visits involving illicit drugs in which methamphetamine was reported increased from 32% in 2004 to 40% in 2005, although this change was not statistically significant, and methamphetamine-related deaths increased 48% between 2001 and 2005. Data from non-federal drug seizures in San Diego County documented an increase from 21 % of all drug items analyzed in 2001 to 32% in 2005 In summary, methamphetamine remains the drug of utmost concern in San Diego. The availability of multiple data sources is imperative for constructing valid characterizations of trends in methamphetamine use and abuse and its affect on health. PMID:18284098

Modulating PD-L1 expression in multiple myeloma: an alternative strategy to target the PD-1/PD-L1 pathway.

PubMed

Tremblay-LeMay, Rosemarie; Rastgoo, Nasrin; Chang, Hong

2018-03-27

Even with recent advances in therapy regimen, multiple myeloma patients commonly develop drug resistance and relapse. The relevance of targeting the PD-1/PD-L1 axis has been demonstrated in pre-clinical models. Monotherapy with PD-1 inhibitors produced disappointing results, but combinations with other drugs used in the treatment of multiple myeloma seemed promising, and clinical trials are ongoing. However, there have recently been concerns about the safety of PD-1 and PD-L1 inhibitors combined with immunomodulators in the treatment of multiple myeloma, and several trials have been suspended. There is therefore a need for alternative combinations of drugs or different approaches to target this pathway. Protein expression of PD-L1 on cancer cells, including in multiple myeloma, has been associated with intrinsic aggressive features independent of immune evasion mechanisms, thereby providing a rationale for the adoption of new strategies directly targeting PD-L1 protein expression. Drugs modulating the transcriptional and post-transcriptional regulation of PD-L1 could represent new therapeutic strategies for the treatment of multiple myeloma, help potentiate the action of other drugs or be combined to PD-1/PD-L1 inhibitors in order to avoid the potentially problematic combination with immunomodulators. This review will focus on the pathophysiology of PD-L1 expression in multiple myeloma and drugs that have been shown to modulate this expression.

A Bayesian evidence synthesis approach to estimate disease prevalence in hard-to-reach populations: hepatitis C in New York City.

PubMed

Tan, Sarah; Makela, Susanna; Heller, Daliah; Konty, Kevin; Balter, Sharon; Zheng, Tian; Stark, James H

2018-06-01

Existing methods to estimate the prevalence of chronic hepatitis C (HCV) in New York City (NYC) are limited in scope and fail to assess hard-to-reach subpopulations with highest risk such as injecting drug users (IDUs). To address these limitations, we employ a Bayesian multi-parameter evidence synthesis model to systematically combine multiple sources of data, account for bias in certain data sources, and provide unbiased HCV prevalence estimates with associated uncertainty. Our approach improves on previous estimates by explicitly accounting for injecting drug use and including data from high-risk subpopulations such as the incarcerated, and is more inclusive, utilizing ten NYC data sources. In addition, we derive two new equations to allow age at first injecting drug use data for former and current IDUs to be incorporated into the Bayesian evidence synthesis, a first for this type of model. Our estimated overall HCV prevalence as of 2012 among NYC adults aged 20-59 years is 2.78% (95% CI 2.61-2.94%), which represents between 124,900 and 140,000 chronic HCV cases. These estimates suggest that HCV prevalence in NYC is higher than previously indicated from household surveys (2.2%) and the surveillance system (2.37%), and that HCV transmission is increasing among young injecting adults in NYC. An ancillary benefit from our results is an estimate of current IDUs aged 20-59 in NYC: 0.58% or 27,600 individuals. Copyright © 2018 Elsevier B.V. All rights reserved.

Potential public health significance of faecal contamination and multidrug-resistant Escherichia coli and Salmonella serotypes in a lake in India.

PubMed

Abhirosh, C; Sherin, V; Thomas, A P; Hatha, A A M; Mazumder, A

2011-06-01

To assess the prevalence of faecal coliform bacteria and multiple drug resistance among Escherichia coli and Salmonella serotypes from Vembanadu Lake. Systematic microbiological testing. Monthly collection of water samples were made from ten stations on the southern and northern parts of a salt water regulator constructed in Vembanadu Lake in order to prevent incursion of seawater during certain periods of the year. Density of faecal colifrom bacteria was estimated. E. coli and Salmonella were isolated and their different serotypes were identified. Antibiotic resistance analysis of E. coli and Salmonella serotypes was done and the MAR index of individual isolates was calculated. Density of faecal coliform bacteria ranged from mean MPN value 2900 -7100/100ml. Results showed multiple drug resistance pattern among the bacterial isolates. E. coli showed more than 50% resistance to amickacin, oxytetracycline, streptomycin, tetracycline and kanamycin while Salmonella showed high resistance to oxytetracycline, streptomycin, tetracycline and ampicillin. The MAR indexing of the isolates showed that they have originated from high risk source such as humans, poultry and dairy cows. The high density of faecal coliform bacteria and prevalence of multi drug resistant E. coli and Salmonella serotypes in the lake may pose severe public health risk through related water borne and food borne outbreaks. Copyright © 2011 The Royal Society for Public Health. Published by Elsevier Ltd. All rights reserved.

Natural Compounds As Modulators of Non-apoptotic Cell Death in Cancer Cells

PubMed Central

Guamán-Ortiz, Luis Miguel; Orellana, Maria Isabel Ramirez; Ratovitski, Edward A.

2017-01-01

Cell death is an innate capability of cells to be removed from microenvironment, if and when they are damaged by multiple stresses. Cell death is often regulated by multiple molecular pathways and mechanism, including apoptosis, autophagy, and necroptosis. The molecular network underlying these processes is often intertwined and one pathway can dynamically shift to another one acquiring certain protein components, in particular upon treatment with various drugs. The strategy to treat human cancer ultimately relies on the ability of anticancer therapeutics to induce tumor-specific cell death, while leaving normal adjacent cells undamaged. However, tumor cells often develop the resistance to the drug-induced cell death, thus representing a great challenge for the anticancer approaches. Numerous compounds originated from the natural sources and biopharmaceutical industries are applied today in clinics showing advantageous results. However, some exhibit serious toxic side effects. Thus, novel effective therapeutic approaches in treating cancers are continued to be developed. Natural compounds with anticancer activity have gained a great interest among researchers and clinicians alike since they have shown more favorable safety and efficacy then the synthetic marketed drugs. Numerous studies in vitro and in vivo have found that several natural compounds display promising anticancer potentials. This review underlines certain information regarding the role of natural compounds from plants, microorganisms and sea life forms, which are able to induce non-apoptotic cell death in tumor cells, namely autophagy and necroptosis. PMID:28367073

[Effect of pharmacologic treatment of the nutritional status of neurologic patients].

PubMed

Piñeiro Corrales, Guadalupe; Vázquez López, Cristina; Álvarez Payero, Miriam

2014-01-01

Clinical manifestations accompanying neurological diseases are diverse and affect multiple organs. Nutritional status of patients with certain neurological diseases such as stroke, Alzheimer's disease, Parkinson's disease, Epilepsy and Multiple Sclerosis can be altered because of symptoms associated with disease course, including certain micronutrient deficiency (folic acid, zinc, vitamin B6 and B12, vitamin D, vitamin E and vitamin C), changes in energy expenditure, intake decreased, gastrointestinal disorders and dysfunction of the bone mass. Also, we have to take in account other factors as: advanced age, multiple co morbidities, polypharmacy, the use of herbal products, social habits, diet and pharmacological treatments effect. An assessment of the factors related to neurological treatment that cause alterations in metabolic and nutritional status was performed: side effects of anti-Parkinson drugs, antiepileptic drugs, and multiple sclerosis drugs; drug-nutrient interactions; and nutrient-drug interactions.

Antimicrobial Activities of Methanol, Ethanol and Supercritical CO2 Extracts of Philippine Piper betle L. on Clinical Isolates of Gram Positive and Gram Negative Bacteria with Transferable Multiple Drug Resistance

PubMed Central

Valle, Demetrio L.; Cabrera, Esperanza C.; Puzon, Juliana Janet M.; Rivera, Windell L.

2016-01-01

Piper betle L. has traditionally been used in alternative medicine in different countries for various therapeutic purposes, including as an anti-infective agent. However, studies reported in the literature are mainly on its activities on drug susceptible bacterial strains. This study determined the antimicrobial activities of its ethanol, methanol, and supercritical CO2 extracts on clinical isolates of multiple drug resistant bacteria which have been identified by the Infectious Disease Society of America as among the currently more challenging strains in clinical management. Assay methods included the standard disc diffusion method and the broth microdilution method for the determination of the minimum inhibitory concentration (MIC) and the minimum bactericidal concentrations (MBC) of the extracts for the test microorganisms. This study revealed the bactericidal activities of all the P. betle leaf crude extracts on methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococcus (VRE), extended spectrum β-lactamase-producing Enterobacteriaceae, carbapenem-resistant Enterobacteriaceae, and metallo-β-lactamase-producing Pseudomonas aeruginosa and Acinetobacter baumannii, with minimum bactericidal concentrations that ranged from 19μg/ml to 1250 μg/ml. The extracts proved to be more potent against the Gram positive MRSA and VRE than for the Gram negative test bacteria. VRE isolates were more susceptible to all the extracts than the MRSA isolates. Generally, the ethanol extracts proved to be more potent than the methanol extracts and supercritical CO2 extracts as shown by their lower MICs for both the Gram positive and Gram negative MDRs. MTT cytotoxicity assay showed that the highest concentration (100 μg/ml) of P. betle ethanol extract tested was not toxic to normal human dermal fibroblasts (HDFn). Data from the study firmly established P. betle as an alternative source of anti-infectives against multiple drug resistant bacteria. PMID:26741962

Antimicrobial Activities of Methanol, Ethanol and Supercritical CO2 Extracts of Philippine Piper betle L. on Clinical Isolates of Gram Positive and Gram Negative Bacteria with Transferable Multiple Drug Resistance.

PubMed

Valle, Demetrio L; Cabrera, Esperanza C; Puzon, Juliana Janet M; Rivera, Windell L

2016-01-01

Piper betle L. has traditionally been used in alternative medicine in different countries for various therapeutic purposes, including as an anti-infective agent. However, studies reported in the literature are mainly on its activities on drug susceptible bacterial strains. This study determined the antimicrobial activities of its ethanol, methanol, and supercritical CO2 extracts on clinical isolates of multiple drug resistant bacteria which have been identified by the Infectious Disease Society of America as among the currently more challenging strains in clinical management. Assay methods included the standard disc diffusion method and the broth microdilution method for the determination of the minimum inhibitory concentration (MIC) and the minimum bactericidal concentrations (MBC) of the extracts for the test microorganisms. This study revealed the bactericidal activities of all the P. betle leaf crude extracts on methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococcus (VRE), extended spectrum β-lactamase-producing Enterobacteriaceae, carbapenem-resistant Enterobacteriaceae, and metallo-β-lactamase-producing Pseudomonas aeruginosa and Acinetobacter baumannii, with minimum bactericidal concentrations that ranged from 19μg/ml to 1250 μg/ml. The extracts proved to be more potent against the Gram positive MRSA and VRE than for the Gram negative test bacteria. VRE isolates were more susceptible to all the extracts than the MRSA isolates. Generally, the ethanol extracts proved to be more potent than the methanol extracts and supercritical CO2 extracts as shown by their lower MICs for both the Gram positive and Gram negative MDRs. MTT cytotoxicity assay showed that the highest concentration (100 μg/ml) of P. betle ethanol extract tested was not toxic to normal human dermal fibroblasts (HDFn). Data from the study firmly established P. betle as an alternative source of anti-infectives against multiple drug resistant bacteria.

Pharming Pharmacopoeia: Living Apothecaries from the Sea

NASA Astrophysics Data System (ADS)

Baden, D. G.

2012-12-01

The quest for, and development of, new drugs to treat extant and emerging diseases is an interdisciplinary effort, often requiring isolation of pro-drugs from new organisms, environments, and species followed by activity measurement. Exploitation of cultivated microalgae from marine sources has produced some of the most potent natural biological agents known, with specific receptor-mediated activities in pulmonary medicine, toxicology, cancer chemotherapy, the cardiovascular system, central and peripheral nervous system, and in dermatology. Our recent discovery that one class of marine-derived molecule promotes trans-membrane transport, a second that enhances mucus secretion, and a third which is an inhibitor of inflammation--- all isolated from the same organism, highlights the increasingly broad potential for innovative exploitation of natural products that occur in marine microalgae. Approaches that include interdisciplinary teams, permanent innovation, and disruptive technologies all will be described in the context of discoveries made in the treatment of cystic fibrosis, in the improvement of drug efficacy, and in the development of multiple for translational sciences in the ocean and health arenas.

Promise and peril: Dissemination of findings from studies of drugs used in pregnancy and their association with birth defects.

PubMed

Patrick, Stephen W; Cooper, William O

2015-08-01

When and how to publish birth defects research can be complex, especially in the context of drugs used in pregnancy. Such research frequently involves multiple stakeholders, including regulatory agencies. Researchers must balance the potential peril of an unnecessarily panicked populace versus the benefit of protecting the public's health. We use a case presentation and contemporary literature to highlight the potential tradeoffs that researchers must consider. We highlight important considerations including the public health impact, examining the likelihood of causality, understanding common considerations when using large data sources, the role of peer review and working in partnership with regulatory agencies. We suggest that plans for analyses, dissemination and risk communication are done best a priori and not post hoc. Rigorous research evaluating the impact of drugs used in pregnancy, coupled with effective dissemination strategies, has the potential improve outcomes for mothers and their infants for generations. © 2015 Wiley Periodicals, Inc.

Recollections of sexual socialisation among marginalised heterosexual black men

PubMed Central

Dunlap, Eloise; Benoit, Ellen; Graves, Jennifer L.

2013-01-01

This paper describes the sexual socialisation process of marginalised, drug-using heterosexual black men, focusing primarily on the sources and content of sexual information. Analysing qualitative interview data, we discovered that the men in our sample both learn about sex and become sexually active at an early age. They most often learn about sex from the media and least often learn about sex from family members. The content of sexual information varies in specifics, but overall tends to equate sex with pleasure, encourage sexual activity with multiple partners, and emphasise using protection. Our goal is to use this data to better understand how sexual socialisation contributes to the prevalence of multiple sexual partners and high rates of HIV among heterosexual black men in order to inform future risk-reduction intervention programmes. PMID:24482611

The current evidence base for the feasibility of 48-hour continuous subcutaneous infusions (CSCIs): A systematically-structured review

PubMed Central

Dickman, Andrew; Mason, Stephen; Ellershaw, John

2018-01-01

Background A continuous subcutaneous infusion (CSCI) is an effective method of multiple drug administration commonly encountered in end of life care when the oral route is compromised. At present, current practice is to limit syringe driver infusion time to a maximum of 24 hours as dictated by available chemical stability data. However, the ability to deliver prescribed medication by a CSCI over 48 hours may have numerous benefits in both patient care and health service resource utilisation. Aim To examine and present the current evidence base for the stability of 48-hour multiple-drug CSCIs in current clinical practice. Design A systematically-structured review following PRISMA guidelines. Data sources Three electronic databases and the grey literature were searched with no time limits. Empirical studies reporting data on the chemical stability of continuous subcutaneous infusions or solutions stored in polypropylene syringes were included. Results Twenty-one empirical studies were included in this review reporting chemical compatibility and stability of 32 discrete combinations of twenty-four drugs tested at a variety of different drug concentrations. The majority of combinations reported were assessed as being chemically compatible. The greatest risk of clinically significant chemical degradation was observed with midazolam. Only one study reported the microbiological stability of the solution examined. Conclusions There is currently limited evidence for the physical, chemical and microbiological stability of solutions for continuous subcutaneous infusion over a period of 48 hours. More stability data is required before the use of 48-hour CSCIs can be evaluated for use within clinical practice. PMID:29538455

Common characteristics of open source software development and applicability for drug discovery: a systematic review.

PubMed

Ardal, Christine; Alstadsæter, Annette; Røttingen, John-Arne

2011-09-28

Innovation through an open source model has proven to be successful for software development. This success has led many to speculate if open source can be applied to other industries with similar success. We attempt to provide an understanding of open source software development characteristics for researchers, business leaders and government officials who may be interested in utilizing open source innovation in other contexts and with an emphasis on drug discovery. A systematic review was performed by searching relevant, multidisciplinary databases to extract empirical research regarding the common characteristics and barriers of initiating and maintaining an open source software development project. Common characteristics to open source software development pertinent to open source drug discovery were extracted. The characteristics were then grouped into the areas of participant attraction, management of volunteers, control mechanisms, legal framework and physical constraints. Lastly, their applicability to drug discovery was examined. We believe that the open source model is viable for drug discovery, although it is unlikely that it will exactly follow the form used in software development. Hybrids will likely develop that suit the unique characteristics of drug discovery. We suggest potential motivations for organizations to join an open source drug discovery project. We also examine specific differences between software and medicines, specifically how the need for laboratories and physical goods will impact the model as well as the effect of patents.

Nonsteroidal Anti-Inflammatory Drugs and Analgesics Use by Kidney Transplant Recipients.

PubMed

Mulka-Gierek, Maria; Foroncewicz, Bartosz; Pączek, Leszek; Wawiórko, Elżbieta; Kamińska, Joanna; Kosieradzki, Maciej; Małkowski, Piotr; Małczuk, Bianka; Nazarewski, Sławomir; Mucha, Krzysztof

2018-03-02

BACKGROUND Nonsteroidal anti-inflammatory drugs (NSAIDs) and analgesics are the most commonly used drugs and are increasingly available over-the-counter (OTC). In certain groups of patients, including kidney transplant recipients, their use may be complicated by adverse effects or drug interactions. The aim of our study was to assess the causes and frequency of OTC NSAIDs or analgesics use, as well as the awareness of related side effects. MATERIAL AND METHODS We enrolled 94 randomly selected kidney transplant recipients, who represented 5% of all kidney transplant recipients at our center. An anonymous survey consisting of 23 multiple-choice questions was administered voluntarily and anonymously. RESULTS In all, 63% of study patients confirmed taking the OTC painkillers; 22% of these patients took these drugs at least several times a week, and 4% took these drugs daily. For 38% of the study kidney transplant recipients, NSAIDs or analgesics were reported to be the only way to manage their pain. In addition, 30% of study patients were unaware of the risks associated with these drugs, despite the fact that 89% of the study patients consider physicians the best source of information. CONCLUSIONS Our study found that 63% of kidney transplant recipients regularly took OTC painkillers and 30% were unaware of the potential adverse effects. This necessitates continuous, ongoing education of kidney transplant recipients about the risks of OTC NSAIDs or analgesics use.

Hangover free! The social and material trajectories of PartySmart.

PubMed

Pordié, Laurent

2015-04-01

This paper presents three embedded episodes in the life of a polyherbal drug indicated as a preventative measure for hangovers. Invented and marketed in 2005 by a leading ayurvedic pharmaceutical company in India, PartySmart is a reformulated compound based on ayurvedic, biomedical and phytochemical sources. This creative process has involved multiple translations, resulting in hybrid pharmacological models, including, for instance, ayurvedic post-digestive tastes and biomedical effects on enzymatic activities. These modes of therapeutic action are conceptualizations of an active drug-- i.e., a digested and metabolized drug. A problem arises, however, in the fact that the ingestion of this drug is linked to alcohol consumption in a country where it is widely considered in negative terms. For this reason, PartySmart was seen as an ambivalent presence in the firm's catalogue and thus a series of interventions aiming to uphold the image of this drug transformed both its social inscription and its materiality. This transformation also took a different, global trajectory as the drug gradually developed as a transnational pharmaceutical commodity and became a new object in new latitudes. By focusing on the social and material dimensions of this drug in these contexts, this paper calls upon science studies to expand the scope of pharmaceutical anthropology. It brings together various layers of analysis to offer new perspectives on contemporary herbal formulations as they traverse material cultures, medical epistemologies, sociopolitical borders, legal environments and social practices.

Heroin and fentanyl overdoses in Kentucky: Epidemiology and surveillance.

PubMed

Slavova, Svetla; Costich, Julia F; Bunn, Terry L; Luu, Huong; Singleton, Michael; Hargrove, Sarah L; Triplett, Jeremy S; Quesinberry, Dana; Ralston, William; Ingram, Van

2017-08-01

The study aims to describe recent changes in Kentucky's drug overdose trends related to increased heroin and fentanyl involvement, and to discuss future directions for improved drug overdose surveillance. The study used multiple data sources (death certificates, postmortem toxicology results, emergency department [ED] records, law enforcement drug submissions, and prescription drug monitoring records) to describe temporal, geographic, and demographic changes in drug overdoses in Kentucky. Fentanyl- and heroin-related overdose death rates increased across all age groups from years 2011 to 2015 with the highest rates consistently among 25-34-year-olds. The majority of the heroin and fentanyl overdose decedents had histories of substantial exposures to legally acquired prescription opioids. Law enforcement drug submission data were strongly correlated with drug overdose ED and mortality data. The 2016 crude rate of heroin-related overdose ED visits was 104/100,000, a 68% increase from 2015 (62/100,000). More fentanyl-related overdose deaths were reported between October, 2015, and September, 2016, than ED visits, in striking contrast with the observed ratio of >10 to 1 heroin-related overdose ED visits to deaths. Many fatal fentanyl overdoses were associated with heroin adulterated with fentanyl; <40% of the heroin overdose ED discharge records listed procedure codes for drug screening. The lack of routine ED drug testing likely resulted in underreporting of non-fatal overdoses involving fentanyl and other synthetic drugs. In order to inform coordinated public health and safety responses, drug overdose surveillance must move from a reactive to a proactive mode, utilizing the infrastructure for electronic health records. Copyright © 2017 Elsevier B.V. All rights reserved.

Factors affecting osteoarthritis patients' self-reported goal-directed drug information-seeking behaviors after exposure to direct-to-consumer advertising from physicians and the internet.

PubMed

Liu, Yifei; Farris, Karen B; Doucette, William R

2011-10-01

The objective of this study was to investigate appraisal of means (ie, self-efficacy, outcome expectancy, and affect) in predicting patients' goal-directed behaviors of direct-to-consumer advertising (DTCA)-prompted drug-information search from physicians and the internet. One thousand patients were randomly selected from a nationwide sample frame of 3000 osteoarthritis patients. A self-administered survey assessed exposure to DTCA, drug-information search as goal, self-efficacy, outcome expectancy, affect, and osteoarthritis pain. After 6 weeks, another survey measured the behavior of drug-information search for respondents to the first survey. Study subjects were those who were exposed to DTCA in the previous month, and who set drug-information search as their goal. For each information source, a multiple regression analysis was conducted in which drug-information search was the dependent variable, and self-efficacy, outcome expectancy, affect, and osteoarthritis pain were the independent variables. Among 454 patients who were exposed to DTCA, 174 patients set drug-information search as their goal and were the study subjects. The regression for physicians was not statistically significant. The regression for the internet was significant, accounting for 15% of behavior variance. Self-efficacy was a strong predictor of goal-directed drug-information search from the internet. Appraisal of means was useful to predict the goal-directed behavior of DTCA-prompted drug-information search from the internet. For patients who set drug-information search as a goal, actions to promote drug-information search from the internet need to focus on self-efficacy.

A Critical Examination of the Introduction of Drug Detection Dogs for Policing of Illicit Drugs in New South Wales, Australia Using Kingdon's "Multiple Streams" Heuristic

ERIC Educational Resources Information Center

Lancaster, Kari; Ritter, Alison; Hughes, Caitlin; Hoppe, Robert

2017-01-01

This paper critically analyses the introduction of drug detection dogs as a tool for policing of illicit drugs in New South Wales, Australia. Using Kingdon's "multiple streams" heuristic as a lens for analysis, we identify how the issue of drugs policing became prominent on the policy agenda, and the conditions under which the…

Bioerodible System for Sequential Release of Multiple Drugs

PubMed Central

Sundararaj, Sharath C.; Thomas, Mark V.; Dziubla, Thomas D.; Puleo, David A.

2013-01-01

Because many complex physiological processes are controlled by multiple biomolecules, comprehensive treatment of certain disease conditions may be more effectively achieved by administration of more than one type of drug. Thus, the objective of the present research was to develop a multilayered, polymer-based system for sequential delivery of multiple drugs. The polymers used were cellulose acetate phthalate (CAP) complexed with Pluronic F-127 (P). After evaluating morphology of the resulting CAPP system, in vitro release of small molecule drugs and a model protein was studied from both single and multilayered devices. Drug release from single-layered CAPP films followed zero-order kinetics related to surface erosion of the association polymer. Release studies from multilayered CAPP devices showed the possibility of achieving intermittent release of one type of drug as well as sequential release of more than one type of drug. Mathematical modeling accurately predicted the release profiles for both single layer and multilayered devices. The present CAPP association polymer-based multilayer devices can be used for localized, sequential delivery of multiple drugs for the possible treatment of complex disease conditions, and perhaps for tissue engineering applications, that require delivery of more than one type of biomolecule. PMID:24096151

Stable Isotopic Constraints on the Geographic Sources of Marijuana in Alaska

NASA Astrophysics Data System (ADS)

Booth, A. L.; Wooller, M. J.; Haubenstock, N. A.; Howe, T. A.

2007-12-01

Marijuana in Alaska can have numerous sources. Confiscated plants are known to originate either from within the state (e.g., Fairbanks and the Matanuska-Susitna Valley) or from numerous areas outside the state (e.g., Latin America, Canada and the contiguous United States). Latin America reportedly supplies a large percentage of the marijuana currently distributed in the lower 48 states of the U.S.A. However, in more remote areas of the country such as Fairbanks, Alaska, the supply proportions from different geographic areas are not well known. This is due to an insufficient ability to trace source regions from which confiscated marijuana was originally grown. As such, we have analyzed multiple stable isotopes (C, N, O and H) preserved in marijuana samples to identify the likely geographic source from which the marijuana originated (Drug Enforcement Agency license # RW0324551). These samples were confiscated in Fairbanks, Alaska and supplied to us by the University of Alaska Fairbanks (UAF) Police Department. Among 36 marijuana plant samples, we found an unexpectedly large range in the stable carbon isotope compositions (‰13C = -62.2‰ to -24.4‰), with twelve of the 36 samples exhibiting exceedingly low δ13C (-36.1‰ to -62.2‰) relative to typical δ13C of other C3 plants. Interior growing conditions (e.g., hydroponics and/or greenhouses) and a variety of CO2 sources (e.g., CO2 from tanks and fermentation CO2 generators) frequently supplied to growing marijuana to improve yields may account for these exceptionally low δ13C values. Stable oxygen and hydrogen isotope compositions (δ18O and δD vs. V-SMOW) of the marijuana samples were found to range from 10.0‰ to 27.6‰ and -197.1‰ to -134.9‰ respectively. The large range of values suggests that the samples originated from multiple sources ranging from low to high latitudes. δ15N of the marijuana samples also exhibited a large range (-7.0‰ to 14.8‰). This project has implications for the improvement of forensic technology in relatively remote areas such as Alaska. Officers for the Alaska Bureau of Drug and Alcohol Enforcement spend a significant amount of time controlling the production and distribution of marijuana, while the resources allocated for law enforcement must be utilized over a wide geographic area.

Club drug use among young men who have sex with men in NYC: a preliminary epidemiological profile.

PubMed

Clatts, Michael C; Goldsamt, Lloyd A; Yi, Huso

2005-01-01

This paper describes findings from a study of young men who have sex with men (YMSM) in New York City. Using a cross-sectional design and a community-based targeted sampling approach, a total of 569 YMSM were recruited during 2000 and 2001 for a structured survey interview. High rates of lifetime exposure to a variety of club drugs (including methamphetamine, ketamine, and MDMA) are observed in the overall sample. Among those who use club drugs on a chronic basis (N=145), we found high rates of a prior suicide attempt (including high rates of multiple suicide attempts), high rates of lifetime exposure to multiple types of drugs, high rates of current poly drug use (including multiple types of club drugs), and high rates of current depressive symptoms. Chronic club drug users had a mean CES-D score of 8.5 and nearly two-thirds had a score of 7 or more. Although high rates of condom use are reported in some types of sexual exchanges, data show multiple types of sexual risk among chronic club drug users, including high rates of unprotected anal intercourse (UAI) with most frequent partners and comorbid drug use among both YMSM and their sexual partners.

Club Drug Use Among Young Men Who Have Sex with Men in NYC: A Preliminary Epidemiological Profile

PubMed Central

CLATTS, MICHAEL C.; GOLDSAMT, LLOYD A.; YI, HUSO

2009-01-01

This paper describes findings from a study of young men who have sex with men (YMSM) in New York City. Using a cross-sectional design and a community-based targeted sampling approach, a total of 569 YMSM were recruited during 2000 and 2001 for a structured survey interview. High rates of lifetime exposure to a variety of club drugs (including methamphetamine, ketamine, and MDMA) are observed in the overall sample. Among those who use club drugs on a chronic basis (N = 145), we found high rates of a prior suicide attempt (including high rates of multiple suicide attempts), high rates of lifetime exposure to multiple types of drugs, high rates of current poly drug use (including multiple types of club drugs), and high rates of current depressive symptoms. Chronic club drug users had a mean CES-D score of 8.5 and nearly two-thirds had a score of 7 or more. Although high rates of condom use are reported in some types of sexual exchanges, data show multiple types of sexual risk among chronic club drug users, including high rates of unprotected anal intercourse (UAI) with most frequent partners and comorbid drug use among both YMSM and their sexual partners. PMID:16048819

A Multiple Indicators Multiple Causes (MIMIC) model of internal barriers to drug treatment in China.

PubMed

Qi, Chang; Kelly, Brian C; Liao, Yanhui; He, Haoyu; Luo, Tao; Deng, Huiqiong; Liu, Tieqiao; Hao, Wei; Wang, Jichuan

2015-03-01

Although evidence exists for distinct barriers to drug abuse treatment (BDATs), investigations of their inter-relationships and the effect of individual characteristics on the barrier factors have been sparse, especially in China. A Multiple Indicators Multiple Causes (MIMIC) model is applied for this target. A sample of 262 drug users were recruited from three drug rehabilitation centers in Hunan Province, China. We applied a MIMIC approach to investigate the effect of gender, age, marital status, education, primary substance use, duration of primary drug use, and drug treatment experience on the internal barrier factors: absence of problem (AP), negative social support (NSS), fear of treatment (FT), and privacy concerns (PC). Drug users of various characteristics were found to report different internal barrier factors. Younger participants were more likely to report NSS (-0.19, p=0.038) and PC (-0.31, p<0.001). Compared to other drug users, ice users were more likely to report AP (0.44, p<0.001) and NSS (0.25, p=0.010). Drug treatment experiences related to AP (0.20, p=0.012). In addition, differential item functioning (DIF) occurred in three items when participant from groups with different duration of drug use, ice use, or marital status. Individual characteristics had significant effects on internal barriers to drug treatment. On this basis, BDAT perceived by different individuals could be assessed before tactics were utilized to successfully remove perceived barriers to drug treatment. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Open Source Drug Discovery with the Malaria Box Compound Collection for Neglected Diseases and Beyond

PubMed Central

Van Voorhis, Wesley C.; Adams, John H.; Adelfio, Roberto; Ahyong, Vida; Akabas, Myles H.; Alano, Pietro; Alday, Aintzane; Alemán Resto, Yesmalie; Alsibaee, Aishah; Alzualde, Ainhoa; Andrews, Katherine T.; Avery, Simon V.; Avery, Vicky M.; Ayong, Lawrence; Baker, Mark; Baker, Stephen; Ben Mamoun, Choukri; Bhatia, Sangeeta; Bickle, Quentin; Bounaadja, Lotfi; Bowling, Tana; Bosch, Jürgen; Boucher, Lauren E.; Boyom, Fabrice F.; Brea, Jose; Brennan, Marian; Burton, Audrey; Caffrey, Conor R.; Camarda, Grazia; Carrasquilla, Manuela; Carter, Dee; Belen Cassera, Maria; Chih-Chien Cheng, Ken; Chindaudomsate, Worathad; Chubb, Anthony; Colon, Beatrice L.; Colón-López, Daisy D.; Corbett, Yolanda; Crowther, Gregory J.; Cowan, Noemi; D’Alessandro, Sarah; Le Dang, Na; Delves, Michael; Du, Alan Y.; Duffy, Sandra; Abd El-Salam El-Sayed, Shimaa; Ferdig, Michael T.; Fernández Robledo, José A.; Fidock, David A.; Florent, Isabelle; Fokou, Patrick V. T.; Galstian, Ani; Gamo, Francisco Javier; Gold, Ben; Golub, Todd; Goldgof, Gregory M.; Guha, Rajarshi; Guiguemde, W. Armand; Gural, Nil; Guy, R. Kiplin; Hansen, Michael A. E.; Hanson, Kirsten K.; Hemphill, Andrew; Hooft van Huijsduijnen, Rob; Horii, Takaaki; Horrocks, Paul; Hughes, Tyler B.; Huston, Christopher; Igarashi, Ikuo; Ingram-Sieber, Katrin; Itoe, Maurice A.; Jadhav, Ajit; Naranuntarat Jensen, Amornrat; Jensen, Laran T.; Jiang, Rays H. Y.; Kaiser, Annette; Keiser, Jennifer; Ketas, Thomas; Kicka, Sebastien; Kim, Sunyoung; Kirk, Kiaran; Kumar, Vidya P.; Kyle, Dennis E.; Lafuente, Maria Jose; Landfear, Scott; Lee, Nathan; Lee, Sukjun; Lehane, Adele M.; Li, Fengwu; Little, David; Liu, Liqiong; Llinás, Manuel; Loza, Maria I.; Lubar, Aristea; Lucantoni, Leonardo; Lucet, Isabelle; Maes, Louis; Mancama, Dalu; Mansour, Nuha R.; March, Sandra; McGowan, Sheena; Medina Vera, Iset; Meister, Stephan; Mercer, Luke; Mestres, Jordi; Mfopa, Alvine N.; Misra, Raj N.; Moon, Seunghyun; Moore, John P.; Morais Rodrigues da Costa, Francielly; Müller, Joachim; Muriana, Arantza; Nakazawa Hewitt, Stephen; Nare, Bakela; Nathan, Carl; Narraidoo, Nathalie; Nawaratna, Sujeevi; Ojo, Kayode K.; Ortiz, Diana; Panic, Gordana; Papadatos, George; Parapini, Silvia; Patra, Kailash; Pham, Ngoc; Prats, Sarah; Plouffe, David M.; Poulsen, Sally-Ann; Pradhan, Anupam; Quevedo, Celia; Quinn, Ronald J.; Rice, Christopher A.; Abdo Rizk, Mohamed; Ruecker, Andrea; St. Onge, Robert; Salgado Ferreira, Rafaela; Samra, Jasmeet; Robinett, Natalie G.; Schlecht, Ulrich; Schmitt, Marjorie; Silva Villela, Filipe; Silvestrini, Francesco; Sinden, Robert; Smith, Dennis A.; Soldati, Thierry; Spitzmüller, Andreas; Stamm, Serge Maximilian; Sullivan, David J.; Sullivan, William; Suresh, Sundari; Suzuki, Brian M.; Suzuki, Yo; Swamidass, S. Joshua; Taramelli, Donatella; Tchokouaha, Lauve R. Y.; Theron, Anjo; Thomas, David; Tonissen, Kathryn F.; Townson, Simon; Tripathi, Abhai K.; Trofimov, Valentin; Udenze, Kenneth O.; Ullah, Imran; Vallieres, Cindy; Vigil, Edgar; Vinetz, Joseph M.; Voong Vinh, Phat; Vu, Hoan; Watanabe, Nao-aki; Weatherby, Kate; White, Pamela M.; Wilks, Andrew F.; Winzeler, Elizabeth A.; Wojcik, Edward; Wree, Melanie; Wu, Wesley; Yokoyama, Naoaki; Zollo, Paul H. A.; Abla, Nada; Blasco, Benjamin; Burrows, Jeremy; Laleu, Benoît; Leroy, Didier; Spangenberg, Thomas; Wells, Timothy; Willis, Paul A.

2016-01-01

A major cause of the paucity of new starting points for drug discovery is the lack of interaction between academia and industry. Much of the global resource in biology is present in universities, whereas the focus of medicinal chemistry is still largely within industry. Open source drug discovery, with sharing of information, is clearly a first step towards overcoming this gap. But the interface could especially be bridged through a scale-up of open sharing of physical compounds, which would accelerate the finding of new starting points for drug discovery. The Medicines for Malaria Venture Malaria Box is a collection of over 400 compounds representing families of structures identified in phenotypic screens of pharmaceutical and academic libraries against the Plasmodium falciparum malaria parasite. The set has now been distributed to almost 200 research groups globally in the last two years, with the only stipulation that information from the screens is deposited in the public domain. This paper reports for the first time on 236 screens that have been carried out against the Malaria Box and compares these results with 55 assays that were previously published, in a format that allows a meta-analysis of the combined dataset. The combined biochemical and cellular assays presented here suggest mechanisms of action for 135 (34%) of the compounds active in killing multiple life-cycle stages of the malaria parasite, including asexual blood, liver, gametocyte, gametes and insect ookinete stages. In addition, many compounds demonstrated activity against other pathogens, showing hits in assays with 16 protozoa, 7 helminths, 9 bacterial and mycobacterial species, the dengue fever mosquito vector, and the NCI60 human cancer cell line panel of 60 human tumor cell lines. Toxicological, pharmacokinetic and metabolic properties were collected on all the compounds, assisting in the selection of the most promising candidates for murine proof-of-concept experiments and medicinal chemistry programs. The data for all of these assays are presented and analyzed to show how outstanding leads for many indications can be selected. These results reveal the immense potential for translating the dispersed expertise in biological assays involving human pathogens into drug discovery starting points, by providing open access to new families of molecules, and emphasize how a small additional investment made to help acquire and distribute compounds, and sharing the data, can catalyze drug discovery for dozens of different indications. Another lesson is that when multiple screens from different groups are run on the same library, results can be integrated quickly to select the most valuable starting points for subsequent medicinal chemistry efforts. PMID:27467575

Open Source Drug Discovery with the Malaria Box Compound Collection for Neglected Diseases and Beyond.

PubMed

Van Voorhis, Wesley C; Adams, John H; Adelfio, Roberto; Ahyong, Vida; Akabas, Myles H; Alano, Pietro; Alday, Aintzane; Alemán Resto, Yesmalie; Alsibaee, Aishah; Alzualde, Ainhoa; Andrews, Katherine T; Avery, Simon V; Avery, Vicky M; Ayong, Lawrence; Baker, Mark; Baker, Stephen; Ben Mamoun, Choukri; Bhatia, Sangeeta; Bickle, Quentin; Bounaadja, Lotfi; Bowling, Tana; Bosch, Jürgen; Boucher, Lauren E; Boyom, Fabrice F; Brea, Jose; Brennan, Marian; Burton, Audrey; Caffrey, Conor R; Camarda, Grazia; Carrasquilla, Manuela; Carter, Dee; Belen Cassera, Maria; Chih-Chien Cheng, Ken; Chindaudomsate, Worathad; Chubb, Anthony; Colon, Beatrice L; Colón-López, Daisy D; Corbett, Yolanda; Crowther, Gregory J; Cowan, Noemi; D'Alessandro, Sarah; Le Dang, Na; Delves, Michael; DeRisi, Joseph L; Du, Alan Y; Duffy, Sandra; Abd El-Salam El-Sayed, Shimaa; Ferdig, Michael T; Fernández Robledo, José A; Fidock, David A; Florent, Isabelle; Fokou, Patrick V T; Galstian, Ani; Gamo, Francisco Javier; Gokool, Suzanne; Gold, Ben; Golub, Todd; Goldgof, Gregory M; Guha, Rajarshi; Guiguemde, W Armand; Gural, Nil; Guy, R Kiplin; Hansen, Michael A E; Hanson, Kirsten K; Hemphill, Andrew; Hooft van Huijsduijnen, Rob; Horii, Takaaki; Horrocks, Paul; Hughes, Tyler B; Huston, Christopher; Igarashi, Ikuo; Ingram-Sieber, Katrin; Itoe, Maurice A; Jadhav, Ajit; Naranuntarat Jensen, Amornrat; Jensen, Laran T; Jiang, Rays H Y; Kaiser, Annette; Keiser, Jennifer; Ketas, Thomas; Kicka, Sebastien; Kim, Sunyoung; Kirk, Kiaran; Kumar, Vidya P; Kyle, Dennis E; Lafuente, Maria Jose; Landfear, Scott; Lee, Nathan; Lee, Sukjun; Lehane, Adele M; Li, Fengwu; Little, David; Liu, Liqiong; Llinás, Manuel; Loza, Maria I; Lubar, Aristea; Lucantoni, Leonardo; Lucet, Isabelle; Maes, Louis; Mancama, Dalu; Mansour, Nuha R; March, Sandra; McGowan, Sheena; Medina Vera, Iset; Meister, Stephan; Mercer, Luke; Mestres, Jordi; Mfopa, Alvine N; Misra, Raj N; Moon, Seunghyun; Moore, John P; Morais Rodrigues da Costa, Francielly; Müller, Joachim; Muriana, Arantza; Nakazawa Hewitt, Stephen; Nare, Bakela; Nathan, Carl; Narraidoo, Nathalie; Nawaratna, Sujeevi; Ojo, Kayode K; Ortiz, Diana; Panic, Gordana; Papadatos, George; Parapini, Silvia; Patra, Kailash; Pham, Ngoc; Prats, Sarah; Plouffe, David M; Poulsen, Sally-Ann; Pradhan, Anupam; Quevedo, Celia; Quinn, Ronald J; Rice, Christopher A; Abdo Rizk, Mohamed; Ruecker, Andrea; St Onge, Robert; Salgado Ferreira, Rafaela; Samra, Jasmeet; Robinett, Natalie G; Schlecht, Ulrich; Schmitt, Marjorie; Silva Villela, Filipe; Silvestrini, Francesco; Sinden, Robert; Smith, Dennis A; Soldati, Thierry; Spitzmüller, Andreas; Stamm, Serge Maximilian; Sullivan, David J; Sullivan, William; Suresh, Sundari; Suzuki, Brian M; Suzuki, Yo; Swamidass, S Joshua; Taramelli, Donatella; Tchokouaha, Lauve R Y; Theron, Anjo; Thomas, David; Tonissen, Kathryn F; Townson, Simon; Tripathi, Abhai K; Trofimov, Valentin; Udenze, Kenneth O; Ullah, Imran; Vallieres, Cindy; Vigil, Edgar; Vinetz, Joseph M; Voong Vinh, Phat; Vu, Hoan; Watanabe, Nao-Aki; Weatherby, Kate; White, Pamela M; Wilks, Andrew F; Winzeler, Elizabeth A; Wojcik, Edward; Wree, Melanie; Wu, Wesley; Yokoyama, Naoaki; Zollo, Paul H A; Abla, Nada; Blasco, Benjamin; Burrows, Jeremy; Laleu, Benoît; Leroy, Didier; Spangenberg, Thomas; Wells, Timothy; Willis, Paul A

2016-07-01

A major cause of the paucity of new starting points for drug discovery is the lack of interaction between academia and industry. Much of the global resource in biology is present in universities, whereas the focus of medicinal chemistry is still largely within industry. Open source drug discovery, with sharing of information, is clearly a first step towards overcoming this gap. But the interface could especially be bridged through a scale-up of open sharing of physical compounds, which would accelerate the finding of new starting points for drug discovery. The Medicines for Malaria Venture Malaria Box is a collection of over 400 compounds representing families of structures identified in phenotypic screens of pharmaceutical and academic libraries against the Plasmodium falciparum malaria parasite. The set has now been distributed to almost 200 research groups globally in the last two years, with the only stipulation that information from the screens is deposited in the public domain. This paper reports for the first time on 236 screens that have been carried out against the Malaria Box and compares these results with 55 assays that were previously published, in a format that allows a meta-analysis of the combined dataset. The combined biochemical and cellular assays presented here suggest mechanisms of action for 135 (34%) of the compounds active in killing multiple life-cycle stages of the malaria parasite, including asexual blood, liver, gametocyte, gametes and insect ookinete stages. In addition, many compounds demonstrated activity against other pathogens, showing hits in assays with 16 protozoa, 7 helminths, 9 bacterial and mycobacterial species, the dengue fever mosquito vector, and the NCI60 human cancer cell line panel of 60 human tumor cell lines. Toxicological, pharmacokinetic and metabolic properties were collected on all the compounds, assisting in the selection of the most promising candidates for murine proof-of-concept experiments and medicinal chemistry programs. The data for all of these assays are presented and analyzed to show how outstanding leads for many indications can be selected. These results reveal the immense potential for translating the dispersed expertise in biological assays involving human pathogens into drug discovery starting points, by providing open access to new families of molecules, and emphasize how a small additional investment made to help acquire and distribute compounds, and sharing the data, can catalyze drug discovery for dozens of different indications. Another lesson is that when multiple screens from different groups are run on the same library, results can be integrated quickly to select the most valuable starting points for subsequent medicinal chemistry efforts.

Importance of multi-P450 inhibition in drug-drug interactions: evaluation of incidence, inhibition magnitude and prediction from in vitro data

PubMed Central

Isoherranen, Nina; Lutz, Justin D; Chung, Sophie P; Hachad, Houda; Levy, Rene H; Ragueneau-Majlessi, Isabelle

2012-01-01

Drugs that are mainly cleared by a single enzyme are considered more sensitive to drug-drug interactions (DDIs) than drugs cleared by multiple pathways. However, whether this is true when a drug cleared by multiple pathways is co-administered with an inhibitor of multiple P450 enzymes (multi-P450 inhibition) is not known. Mathematically, simultaneous equipotent inhibition of two elimination pathways that each contributes half of the drug clearance is equal to equipotent inhibition of a single pathway that clears the drug. However, simultaneous strong or moderate inhibition of two pathways by a single inhibitor is perceived as an unlikely scenario. The aim of this study was (i) to identify P450 inhibitors currently in clinical use that can inhibit more than one clearance pathway of an object drug in vivo, and (ii) to evaluate the magnitude and predictability of DDIs caused by these multi-P450 inhibitors. Multi-P450 inhibitors were identified using the Metabolism and Transport Drug Interaction Database™. A total of 38 multi-P450 inhibitors, defined as inhibitors that increased the AUC or decreased the clearance of probes of two or more P450’s, were identified. Seventeen (45 %) multi-P450 inhibitors were strong inhibitors of at least one P450 and an additional 12 (32 %) were moderate inhibitors of one or more P450s. Only one inhibitor (fluvoxamine) was a strong inhibitor of more than one enzyme. Fifteen of the multi-P450 inhibitors also inhibit drug transporters in vivo, but such data are lacking on many of the inhibitors. Inhibition of multiple P450 enzymes by a single inhibitor resulted in significant (>2-fold) clinical DDIs with drugs that are cleared by multiple pathways such as imipramine and diazepam while strong P450 inhibitors resulted in only weak DDIs with these object drugs. The magnitude of the DDIs between multi-P450 inhibitors and diazepam, imipramine and omeprazole could be predicted using in vitro data with similar accuracy as probe substrate studies with the same inhibitors. The results of this study suggest that inhibition of multiple clearance pathways in vivo is clinically relevant and the risk of DDIs with object drugs may be best evaluated in studies using multi-P450 inhibitors. PMID:22823924

THz-wave parametric source and its imaging applications

NASA Astrophysics Data System (ADS)

Kawase, Kodo

2004-08-01

Widely tunable coherent terahertz (THz) wave generation has been demonstrated based on the parametric oscillation using MgO doped LiNbO3 crystal pumped by a Q-switched Nd:YAG laser. This method exhibits multiple advantages like wide tunability, coherency and compactness of its system. We have developed a novel basic technology for terahertz (THz) imaging, which allows detection and identification of chemicals by introducing the component spatial pattern analysis. The spatial distributions of the chemicals were obtained from terahertz multispectral transillumination images, using absorption spectra previously measured with a widely tunable THz-wave parametric oscillator. Further we have applied this technique to the detection and identification of illicit drugs concealed in envelopes. The samples we used were methamphetamine and MDMA, two of the most widely consumed illegal drugs in Japan, and aspirin as a reference.

Biological and nonbiological complex drugs for multiple sclerosis in Latin America: regulations and risk management.

PubMed

Carrá, Adriana; Macías Islas, Miguel Angel; Tarulla, Adriana; Bichuetti, Denis Bernardi; Finkelsztejn, Alessandro; Fragoso, Yara Dadalti; Árcega-Revilla, Raul; Cárcamo Rodríguez, Claudia; Durán, Juan Carlos; Bonitto, Juan García; León, Rosalba; Oehninger Gatti, Carlos; Orozco, Geraldine; Vizcarra Escobar, Darwin

2015-06-01

Biological drugs and nonbiological complex drugs with expired patents are followed by biosimilars and follow-on drugs that are supposedly similar and comparable with the reference product in terms of quality, safety and efficacy. Unlike simple molecules that can be copied and reproduced, biosimilars and follow-on complex drugs are heterogeneous and need specific regulations from health and pharmacovigilance agencies. A panel of 14 Latin American experts on multiple sclerosis from nine different countries met to discuss the recommendations regarding biosimilars and follow-on complex drugs for treating multiple sclerosis. Specific measures relating to manufacturing, therapeutic equivalence assessment and pharmacovigilance reports need to be implemented before commercialization. Physical, chemical, biological and immunogenic characterizations of the new product need to be available before clinical trials start. The new product must maintain the same immunogenicity as the original. Automatic substitution of biological and complex drugs poses unacceptable risks to the patient.

Controlled Substance Prescribing Patterns--Prescription Behavior Surveillance System, Eight States, 2013.

PubMed

Paulozzi, Leonard J; Strickler, Gail K; Kreiner, Peter W; Koris, Caitlin M

2015-10-16

Drug overdose is the leading cause of injury death in the United States. The death rate from drug overdose in the United States more than doubled during 1999-2013, from 6.0 per 100,000 population in 1999 to 13.8 in 2013. The increase in drug overdoses is attributable primarily to the misuse and abuse of prescription drugs, especially opioid analgesics, sedatives/tranquilizers, and stimulants. Such drugs are prescribed widely in the United States, with substantial variation by state. Certain patients obtain drugs for nonmedical use or resale by obtaining overlapping prescriptions from multiple prescribers. The risk for overdose is directly associated with the use of multiple prescribers and daily dosages of >100 morphine milligram equivalents (MMEs) per day. 2013. The Prescription Behavior Surveillance System (PBSS) is a public health surveillance system that allows public health authorities to characterize and quantify the use and misuse of prescribed controlled substances. PBSS began collecting data in 2012 and is funded by CDC and the Food and Drug Administration. PBSS uses standard metrics to measure prescribing rates per 1,000 state residents by demographic variables, drug type, daily dose, and source of payment. Data from the system can be used to calculate rates of misuse by certain behavioral measures such as use of multiple prescribers and pharmacies within specified time periods. This report is based on 2013 de-identified data (most recent available) that represent approximately one fourth of the U.S. Data were submitted quarterly by prescription drug monitoring programs (PDMPs) in eight states (California, Delaware, Florida, Idaho, Louisiana, Maine, Ohio, and West Virginia) that routinely collect data on every prescription for a controlled substance to help law enforcement and health care providers identify misuse or abuse of such drugs. In all eight states, opioid analgesics were prescribed approximately twice as often as stimulants or benzodiazepines. Prescribing rates by drug class varied widely by state: twofold for opioids, fourfold for stimulants, almost twofold for benzodiazepines, and eightfold for carisoprodol, a muscle relaxant. Rates for opioids and benzodiazepines were substantially higher for females than for males in all states. In most states, opioid prescribing rates peaked in either the 45-54 years or the 55-64 years age group. Benzodiazepine prescribing rates increased with age. Louisiana ranked first in opioid prescribing, and Delaware and Maine had relatively high rates of use of long-acting (LA) or extended-release (ER) opioids. Delaware and Maine ranked highest in both mean daily opioid dosage and in the percentage of opioid prescriptions written for >100 MMEs per day. The top 1% of prescribers wrote one in four opioid prescriptions in Delaware, compared with one in eight in Maine. For the five states whose PDMPs collected the method of payment, the percentage of controlled substance prescriptions paid for in cash varied almost threefold, and the percentage paid by Medicaid varied sixfold. In West Virginia, for 1 of every 5 days of treatment with an opioid, the patient also was taking a benzodiazepine. Multiple-provider episode rates were highest in Ohio and lowest in Louisiana. This report presents rates of population-based prescribing and behavioral measures of drug misuse in the general population that have not been available previously for comparison among demographic groups and states. The higher prescribing rates for opioids among women compared with men are consistent with a higher self-reported prevalence of certain common types of pain, such as lower back pain among women. The trend in opioid prescribing rates with age is consistent with an increase in the prevalence of chronic pain with age, but the increasing prescribing rates of benzodiazepines with age is not consistent with the fact that anxiety is most common among persons aged 30-44 years. The variation among states in the type of opioid or benzodiazepine of choice is unexplained. Most opioid prescribing occurs among a small minority of prescribers. Most of the prescriptions by top-decile prescribers probably are written by general, family medicine, internal medicine, and midlevel practitioners. The source of payment varied by state, for reasons that are unclear. Persons who are prescribed opioids also are commonly prescribed benzodiazepine sedatives despite the risk for additive depressant effects. States can use their prescription drug monitoring programs to generate population-based measures for the prescribing of controlled substances and for behaviors that suggest their misuse. Comparing data with other states and tracking changes in these measures over time can be useful in measuring the effect of policies designed to reduce prescription drug misuse.

Amplification of a Gene Related to Mammalian mdr Genes in Drug-Resistant Plasmodium falciparum

NASA Astrophysics Data System (ADS)

Wilson, Craig M.; Serrano, Adelfa E.; Wasley, Annemarie; Bogenschutz, Michael P.; Shankar, Anuraj H.; Wirth, Dyann F.

1989-06-01

The malaria parasite Plasmodium falciparum contains at least two genes related to the mammalian multiple drug resistance genes, and at least one of the P. falciparum genes is expressed at a higher level and is present in higher copy number in a strain that is resistant to multiple drugs than in a strain that is sensitive to the drugs.

An evaluation of the completeness of drug-drug interaction-related information in package inserts.

PubMed

Ng, Giok Qin; Sklar, Grant Edward; Chng, Hui Ting

2017-02-01

The project aimed to evaluate the completeness of drug-drug interaction (DDI)-related information in package inserts (PIs) and develop a systematic approach to conduct the evaluation. DDI-related information in the branded PIs of statins, macrolides, protease inhibitors and selected drugs of narrow therapeutic index (DNTI) were evaluated against the criteria distilled from the Food and Drug Administration (FDA) labelling recommendation guidance document. Decision trees were crafted and employed in the evaluation process. Scores were computed to give each PI an overall completeness score and individual criterion completeness score. The Kruskal-Wallis test and Dunn's multiple comparison test were used to assess the differences in the completeness scores. The mean overall completeness score of the 21 PIs was 35.7 ± 13.4 % (range 12.2-62 %). Eight out of the 11 individual evaluation criterion had a mean completeness score below 50 %. A subclass analysis conducted revealed that PIs from the different drug classes differed in the type of DDI-related information, such that they are more complete or less complete. The completeness score of DDI-related information in the PIs varied extensively amongst and within drug classes. A consensus between the authorities and drug companies on the type and quality of DDI-related information to be included could improve their completeness in PIs and make PIs a valuable source of DDI reference. Decision trees, albeit not validated yet, lay the groundwork for a valuable tool to evaluate DDI-related or other drug information.

Common characteristics of open source software development and applicability for drug discovery: a systematic review

PubMed Central

2011-01-01

Background Innovation through an open source model has proven to be successful for software development. This success has led many to speculate if open source can be applied to other industries with similar success. We attempt to provide an understanding of open source software development characteristics for researchers, business leaders and government officials who may be interested in utilizing open source innovation in other contexts and with an emphasis on drug discovery. Methods A systematic review was performed by searching relevant, multidisciplinary databases to extract empirical research regarding the common characteristics and barriers of initiating and maintaining an open source software development project. Results Common characteristics to open source software development pertinent to open source drug discovery were extracted. The characteristics were then grouped into the areas of participant attraction, management of volunteers, control mechanisms, legal framework and physical constraints. Lastly, their applicability to drug discovery was examined. Conclusions We believe that the open source model is viable for drug discovery, although it is unlikely that it will exactly follow the form used in software development. Hybrids will likely develop that suit the unique characteristics of drug discovery. We suggest potential motivations for organizations to join an open source drug discovery project. We also examine specific differences between software and medicines, specifically how the need for laboratories and physical goods will impact the model as well as the effect of patents. PMID:21955914

Antireward, compulsivity, and addiction: seminal contributions of Dr. Athina Markou to motivational dysregulation in addiction.

PubMed

Koob, George F

2017-05-01

Addiction is defined as a chronically relapsing disorder characterized by compulsive drug seeking that is hypothesized to derive from multiple sources of motivational dysregulation. Dr. Athina Markou made seminal contributions to our understanding of the neurobiology of addiction with her studies on the dysregulation of reward function using animal models with construct validity. Repeated overstimulation of the reward systems with drugs of abuse decreases reward function, characterized by brain stimulation reward and presumbably reflecting dysphoria-like states. The construct of negative reinforcement, defined as drug taking that alleviates a negative emotional state that is created by drug abstinence, is particularly relevant as a driving force in both the withdrawal/negative affect and preoccupation/anticipation stages of the addiction cycle. The negative emotional state that drives such negative reinforcement is hypothesized to derive from the dysregulation of key neurochemical circuits that drive incentive-salience/reward systems (dopamine, opioid peptides) in the ventral striatum and from the recruitment of brain stress systems (corticotropin-releasing factor, dynorphin) within the extended amygdala. As drug taking becomes compulsive-like, the factors that motivate behavior are hypothesized to shift to drug-seeking behavior that is driven not only by positive reinforcement but also by negative reinforcement. This shift in motivation is hypothesized to reflect the allostatic misregulation of hedonic tone such that drug taking makes the hedonic negative emotional state worse during the process of seeking temporary relief with compulsive drug taking.

Unprogrammed Deworming in the Kibera Slum, Nairobi: Implications for Control of Soil-Transmitted Helminthiases

PubMed Central

Harris, Julie R.; Worrell, Caitlin M.; Davis, Stephanie M.; Odero, Kennedy; Mogeni, Ondari D.; Deming, Michael S.; Mohammed, Aden; Montgomery, Joel M.; Njenga, Sammy M.; Fox, LeAnne M.; Addiss, David G.

2015-01-01

Background Programs for control of soil-transmitted helminth (STH) infections are increasingly evaluating national mass drug administration (MDA) interventions. However, “unprogrammed deworming” (receipt of deworming drugs outside of nationally-run STH control programs) occurs frequently. Failure to account for these activities may compromise evaluations of MDA effectiveness. Methods We used a cross-sectional study design to evaluate STH infection and unprogrammed deworming among infants (aged 6–11 months), preschool-aged children (PSAC, aged 1–4 years), and school-aged children (SAC, aged 5–14 years) in Kibera, Kenya, an informal settlement not currently receiving nationally-run MDA for STH. STH infection was assessed by triplicate Kato-Katz. We asked heads of households with randomly-selected children about past-year receipt and source(s) of deworming drugs. Local non-governmental organizations (NGOs) and school staff participating in school-based deworming were interviewed to collect information on drug coverage. Results Of 679 children (18 infants, 184 PSAC, and 477 SAC) evaluated, 377 (55%) reported receiving at least one unprogrammed deworming treatment during the past year. PSAC primarily received treatments from chemists (48.3%) or healthcare centers (37.7%); SAC most commonly received treatments at school (55.0%). Four NGOs reported past-year deworming activities at 47 of >150 schools attended by children in our study area. Past-year deworming was negatively associated with any-STH infection (34.8% vs 45.4%, p = 0.005). SAC whose most recent deworming medication was sourced from a chemist were more often infected with Trichuris (38.0%) than those who received their most recent treatment from a health center (17.3%) or school (23.1%) (p = 0.05). Conclusion Unprogrammed deworming was received by more than half of children in our study area, from multiple sources. Both individual-level treatment and unprogrammed preventive chemotherapy may serve an important public health function, particularly in the absence of programmed deworming; however, they may also lead to an overestimation of programmed MDA effectiveness. A standardized, validated tool is needed to assess unprogrammed deworming. PMID:25763577

Multiple emulsions: an overview.

PubMed

Khan, Azhar Yaqoob; Talegaonkar, Sushama; Iqbal, Zeenat; Ahmed, Farhan Jalees; Khar, Roop Krishan

2006-10-01

Multiple emulsions are complex polydispersed systems where both oil in water and water in oil emulsion exists simultaneously which are stabilized by lipophillic and hydrophilic surfactants respectively. The ratio of these surfactants is important in achieving stable multiple emulsions. Among water-in-oil-in-water (w/o/w) and oil-in-water-in-oil (o/w/o) type multiple emulsions, the former has wider areas of application and hence are studied in great detail. Formulation, preparation techniques and in vitro characterization methods for multiple emulsions are reviewed. Various factors affecting the stability of multiple emulsions and the stabilization approaches with specific reference to w/o/w type multiple emulsions are discussed in detail. Favorable drug release mechanisms and/or rate along with in vivo fate of multiple emulsions make them a versatile carrier. It finds wide range of applications in controlled or sustained drug delivery, targeted delivery, taste masking, bioavailability enhancement, enzyme immobilization, etc. Multiple emulsions have also been employed as intermediate step in the microencapsulation process and are the systems of increasing interest for the oral delivery of hydrophilic drugs, which are unstable in gastrointestinal tract like proteins and peptides. With the advancement in techniques for preparation, stabilization and rheological characterization of multiple emulsions, it will be able to provide a novel carrier system for drugs, cosmetics and pharmaceutical agents. In this review, emphasis is laid down on formulation, stabilization techniques and potential applications of multiple emulsion system.

ANTIBACTERIAL ACTIVITY OF DRACONTOMELON DAO EXTRACTS ON METHICILLIN-RESISTANT S. AUREUS (MRSA) AND E. COLI MULTIPLE DRUG RESISTANCE (MDR).

PubMed

Yuniati, Yuniati; Hasanah, Nurul; Ismail, Sjarif; Anitasari, Silvia; Paramita, Swandari

2018-01-01

Staphylococcus aureus , methicillin-resistant and Escherichia coli , multidrug-resistant included in the list of antibiotic-resistant priority pathogens from WHO. As multidrug-resistant bacteria problem is increasing, it is necessary to probe new sources for identifying antimicrobial compounds. Medicinal plants represent a rich source of antimicrobial agents. One of the potential plants for further examined as antibacterial is Dracontomelon dao (Blanco) Merr. & Rolfe. The present study designed to find the antibacterial activity of D. dao stem bark extracts on Methicillin-resistant S. aureus (MRSA) and E. coli Multiple Drug Resistance (MDR), followed by determined secondary metabolites with antibacterial activity and determined the value of MIC (minimum inhibitory concentration) and MBC (minimum bactericidal concentration). D. dao stem bark extracted using 60% ethanol. Disc diffusion test methods used to find the antibacterial activity, following by microdilution methods to find the value of MIC and MBC. Secondary metabolites with antibacterial activity determined by bioautography using TLC (thin layer chromatography) methods. D. dao stem bark extracts are sensitive to MSSA, MRSA and E.coli MDR bacteria. The inhibition zone is 16.0 mm in MSSA, 11.7 mm in MRSA and 10.7 mm in E. coli MDR. The entire MBC/MIC ratios for MSSA, MRSA and E.coli MDR is lower than 4. The ratio showed bactericidal effects of D. dao stem bark extracts. In TLC results, colorless bands found to be secondary metabolites with antibacterial activity. D. dao stem bark extracts are potential to develop as antibacterial agent especially against MRSA and E. coli MDR strain.

21 CFR 892.5740 - Radionuclide teletherapy source.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Radionuclide teletherapy source. 892.5740 Section 892.5740 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES RADIOLOGY DEVICES Therapeutic Devices § 892.5740 Radionuclide teletherapy source...

Impact of economic sanctions on access to noncommunicable diseases medicines in the Islamic Republic of Iran.

PubMed

Kheirandish, Mehrnaz; Varahrami, Vida; Kebriaeezade, Abbas; Cheraghali, Abdol Majid

2018-04-05

It has been argued that economic sanctions and the economic crisis have adversely affected access to drugs. To assess the impact of economic sanctions on the Iranian banking system in 2011 and Central Bank in 2012 on access to and use of drugs for noncommunicable diseases (NCDs). An interrupted time series study assessed the effects of sanctions on drugs for diabetes (5 drug groups), asthma (5 drug groups), cancer (14 drugs) and multiple sclerosis (2 drugs). We extracted data from national reference databases on the list of drugs on the Iranian pharmaceutical market before 2011 for each selected NCD and their monthly sales. For cancer drugs, we used stratified random sampling by volume and value of sales, and source of supply (domestic or imported). Data were analysed monthly from 2008 to 2013. Market availability of 13 of 26 drugs was significantly reduced. Ten other drugs showed nonsignificant reductions in their market availability. Interferon α2b usage reduced from 0.014 defined daily doses per 1000 inhabitants per day (DID) in 2010 to 0.008 in 2013; and cytarabine from 1.40 mg per 1000 population per day in 2010 to 0.96 in 2013. Selective β2-adrenoreceptor agonists usage reduced from 8.4 to 6.8 DID in the same time period. There is strong evidence that sanctions have had a negative effect on access to drugs, particularly those that depended on the import of their raw material or finished products. Copyright © World Health Organization (WHO) 2018. Some rights reserved. This work is available under the CC BY-NC-SA 3.0 IGO license (https://creativecommons.org/licenses/by-nc-sa/3.0/igo).

Work-related injuries in a state trauma registry: relationship between industry and drug screening.

PubMed

Bunn, Terry L; Slavova, Svetla; Bernard, Andrew C

2014-08-01

Work-related injuries exert a great financial and economic burden on the US population. The study objectives were to identify the industries and occupations associated with worker injuries and to determine the predictors for injured worker drug screening in trauma centers. Work-related injury cases were selected using three criteria (expected payer source of workers' compensation, industry-related e-codes, and work-related indicator) from the Kentucky Trauma Registry data set for years 2008 to 2012. Descriptive analyses and multiple logistic regression were performed on the work-related injury cases. The "other services" and construction industry sectors accounted for the highest number of work-related cases. Drugs were detected in 55% of all drug-screened work-related trauma cases. Higher percentages of injured workers tested positive for drugs in the natural resources and mining, transportation and public utilities, and construction industries. In comparison, higher percentages of injured workers in the other services as well as transportation and public utilities industries were drug screened. Treatment at Level I trauma centers and Glasgow Coma Scale (GCS) scores indicating a coma or severe brain injury were both significant independent predictors for being screened for drugs; industry was not a significant predictor for being drug screened. The injured worker was more likely to be drug screened if the worker had a greater than mild injury, regardless of whether the worker was an interfacility transfer. These findings indicate that there may be elevated drug use or abuse in natural resources and mining, transportation and public utilities, as well as construction industry workers; improved identification of the specific drug types in positive drug screen results of injured workers is needed to better target prevention efforts. Epidemiologic study, level III.

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

PubMed

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

2014-09-01

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

Feasibility and utility of applications of the common data model to multiple, disparate observational health databases

PubMed Central

Makadia, Rupa; Matcho, Amy; Ma, Qianli; Knoll, Chris; Schuemie, Martijn; DeFalco, Frank J; Londhe, Ajit; Zhu, Vivienne; Ryan, Patrick B

2015-01-01

Objectives To evaluate the utility of applying the Observational Medical Outcomes Partnership (OMOP) Common Data Model (CDM) across multiple observational databases within an organization and to apply standardized analytics tools for conducting observational research. Materials and methods Six deidentified patient-level datasets were transformed to the OMOP CDM. We evaluated the extent of information loss that occurred through the standardization process. We developed a standardized analytic tool to replicate the cohort construction process from a published epidemiology protocol and applied the analysis to all 6 databases to assess time-to-execution and comparability of results. Results Transformation to the CDM resulted in minimal information loss across all 6 databases. Patients and observations excluded were due to identified data quality issues in the source system, 96% to 99% of condition records and 90% to 99% of drug records were successfully mapped into the CDM using the standard vocabulary. The full cohort replication and descriptive baseline summary was executed for 2 cohorts in 6 databases in less than 1 hour. Discussion The standardization process improved data quality, increased efficiency, and facilitated cross-database comparisons to support a more systematic approach to observational research. Comparisons across data sources showed consistency in the impact of inclusion criteria, using the protocol and identified differences in patient characteristics and coding practices across databases. Conclusion Standardizing data structure (through a CDM), content (through a standard vocabulary with source code mappings), and analytics can enable an institution to apply a network-based approach to observational research across multiple, disparate observational health databases. PMID:25670757

Advertisements promoting human papillomavirus vaccine for adolescent boys: does source matter?

PubMed

Pepper, Jessica K; Reiter, Paul L; McRee, Annie-Laurie; Brewer, Noel T

2012-06-01

Many parents recall hearing of human papillomavirus (HPV) vaccine through drug company advertisements. This study sought to examine whether parents accurately recall the source (ie, sponsor) of advertisements promoting HPV vaccine and the impact of drug company advertisements. A U.S. national sample of 544 parents of adolescent boys aged 11-17 participated in an online between-subjects experiment. Parents viewed an advertisement encouraging HPV vaccination for boys with a logo from a randomly assigned source. Parents rated trust, likability and motivation for vaccination while viewing the advertisement and later indicated who they believed sponsored it. Nearly half (43%) of parents who viewed a hypothetical advertisement containing a logo incorrectly identified the advertisement source. More parents correctly identified the source of drug company advertisements than advertisement from other sources (62% vs. 25%, OR 4.93, 95% CI 3.26 to 7.46). The majority of parents who saw a logo-free advertisement believed a drug company created it (60%). Among parents who correctly identified the advertisement source, drug company advertisements decreased motivation to vaccinate their sons, an association mediated by reduced liking of and trust in the advertisements. Parents were more accurate in identifying drug company advertisements, primarily because they tended to assume any advertisement was from a drug company. Public health organisations may need to take special measures to ensure their messages are not perceived as sponsored by drug companies.

Direct-injection screening for acidic drugs in plasma and neutral drugs in equine urine by differential-gradient LC-LC coupled MS/MS.

PubMed

Stanley, Shawn M R; Wee, Wei Khee; Lim, Boon Huat; Foo, Hsiao Ching

2007-04-01

Direct-injection LC-LC hybrid tandem MS methods have been developed for undertaking broad-based screening for acidic drugs in protein-precipitated plasma and neutral doping agents in equine urine. In both analyses, analytes present in the matrix were trapped using a HLB extraction column before being refocused and separated on a Chromolith RP-18e monolithic analytical column using a controlled differential gradient generated by proportional dilution of the first column's eluent with water. Each method has been optimised by the adoption of a mobile phase and gradient that was tailored to enhance ionisation in the MS source while maintaining good chromatographic behaviour for the majority of the target drugs. The analytical column eluent was fed into the heated nebulizer (HN) part of the Duospray interface attached to a 4000 QTRAP mass spectrometer. Information dependent acquisition (IDA) with dynamic background subtraction (DBS) was configured to trigger a sensitive enhanced product ion (EPI) scan when a multiple reaction monitoring (MRM) survey scan signal exceeded the defined criteria. Ninety-one percent of acidic drugs in protein-precipitated plasma and 80% of the neutral compounds in equine urine were detected when spiked at 10 ng/ml.

Challenges for Detecting Valproic Acid in a Nontargeted Urine Drug Screening Method.

PubMed

Pope, Jeffrey D; Black, Marion J; Drummer, Olaf H; Schneider, Hans G

2017-08-01

Valproic acid (VPA) is a widely prescribed medicine, and acute toxicity is possible. As such, it should be included in any nontargeted urine drug screening method. In many published liquid chromatography-electrospray ionization-mass spectrometry (LC-ESI-MS/MS) methods, VPA is usually measured using a pseudo-multiple reaction monitoring (MRM) transition. We investigate a simple ultra-high-performance liquid chromatography-quadrupole time-of-flight (QTof) approach to detect the presence of VPA with more confidence. Three commercially sourced VPA metabolites were characterized and added to a nontargeted high-resolution MS urine drug screening method. All analyses were performed on a Waters Xevo G2-XS LC-QTof in negative electrospray ionization mode. The mass detector was operated in MS mode, and data were processed with UNIFI software. Sixty-eight patient urine samples, which were previously identified by a well-established gas chromatography-MS method as containing VPA, were analyzed on the Waters Xevo G2-XS LC-QTof, to validate this approach. VPA metabolite standards were characterized, and their detection data were added to the broad drug screening library. VPA metabolites were readily detectable in the urine of patients taking VPA. The inclusion of characterized VPA metabolites provides a simple and reliable method enabling the detection of VPA in nontargeted urine drug screening.

A novel integrated framework and improved methodology of computer-aided drug design.

PubMed

Chen, Calvin Yu-Chian

2013-01-01

Computer-aided drug design (CADD) is a critical initiating step of drug development, but a single model capable of covering all designing aspects remains to be elucidated. Hence, we developed a drug design modeling framework that integrates multiple approaches, including machine learning based quantitative structure-activity relationship (QSAR) analysis, 3D-QSAR, Bayesian network, pharmacophore modeling, and structure-based docking algorithm. Restrictions for each model were defined for improved individual and overall accuracy. An integration method was applied to join the results from each model to minimize bias and errors. In addition, the integrated model adopts both static and dynamic analysis to validate the intermolecular stabilities of the receptor-ligand conformation. The proposed protocol was applied to identifying HER2 inhibitors from traditional Chinese medicine (TCM) as an example for validating our new protocol. Eight potent leads were identified from six TCM sources. A joint validation system comprised of comparative molecular field analysis, comparative molecular similarity indices analysis, and molecular dynamics simulation further characterized the candidates into three potential binding conformations and validated the binding stability of each protein-ligand complex. The ligand pathway was also performed to predict the ligand "in" and "exit" from the binding site. In summary, we propose a novel systematic CADD methodology for the identification, analysis, and characterization of drug-like candidates.

Individual and couple-level risk factors for hepatitis C infection among heterosexual drug users: a multilevel dyadic analysis.

PubMed

McMahon, James M; Pouget, Enrique R; Tortu, Stephanie

2007-06-01

Hepatitis C virus (HCV) is the most common bloodborne pathogen in the United States and is a leading cause of liver-related morbidity and mortality. Although it is known that HCV is most commonly transmitted among injection drug users, the role of sexual transmission in the spread of HCV remains controversial because of inconsistent findings across studies involving heterosexual couples. A novel multilevel modeling technique designed to overcome the limitations of previous research was performed to assess multiple risk factors for HCV while partitioning the source of risk at the individual and couple level. The analysis was performed on risk exposure and HCV screening data obtained from 265 drug-using couples in East Harlem, New York City. In multivariable analysis, significant individual risk factors for HCV included a history of injection drug use, tattooing, and older age. At the couple level, HCV infection tended to cluster within couples, and this interdependence was accounted for by couples' drug-injection behavior. Individual and couple-level sexual behavior was not associated with HCV infection. Our results are consistent with prior research indicating that sexual contact plays little role in HCV transmission. Rather, couples' injection behavior appears to account for the clustering of HCV within heterosexual dyads.

Drug Use and Multiple Sex Partners among Homeless Ex-Offenders: Secondary Findings from an Experimental Study

PubMed Central

Nyamathi, Adeline M.; Zhang, Sheldon; Wall, Sarah; Hall, Elizabeth A.; Salem, Benissa E.; Farabee, David; Faucette, Mark; Yadav, Kartik

2016-01-01

Background Transitioning into society after release from incarceration presents real challenges for male offenders; in California, up to 60% return to prison within three years following release. The risk for ongoing drug use and having sex with multiple sex partners is a significant challenge for ex-offenders preparing to enter the community. Objectives The aims are to describe drug use and sexual behavior (sex with multiple partners) prior to incarceration and six and 12 months following study enrollment using data obtained as part of a randomized controlled trial (RCT). Methods This is a planned secondary analysis of data obtained as part of an RCT designed to study the effects of intensive peer coaching and nurse case management, intensive peer coaching, and brief nurse counseling on hepatitis A and B vaccination adherence compared to a usual care control treatment that also included brief peer coaching and brief nurse counseling. Self-report data from subjects enrolled at one residential drug treatment facility in Los Angeles were captured at three time points: baseline, and six- and 12-month follow up. Results Findings showed substantive and significant reductions in drug use and engaging in sex with multiple partners six months following enrollment into the study compared to the baseline data, but results did not differ by study condition. At 12-month follow up, drug use and sex with multiple partners increased, but remained less than at baseline levels. Discussion Sustaining reductions in drug use and engaging in sex with multiple partners remains a challenge following incarceration. PMID:27124254

Comparison of drug treatment histories of single and multiple drug abusers in detox.

PubMed

Greberman, S B; Jasinski, D

2001-01-01

This study was undertaken to determine differences in previous treatment patterns in individuals currently using different numbers of substances. Medical records of 1198 inpatient detoxification (detox) admissions were analyzed. Numbers of past admissions to completed detox, methadone, or other types of drug abuse treatment were totaled and ranked to determine most frequent type. Within gender, treatment histories of single and multiple drug abusers usually do not differ. The one exception is male multiple drug abusers ages 26-30, who show increased admissions. Possible explanations are that men do not seek treatment before developing medical complications of addiction or until external factors influence admission. There were differences in treatment histories between genders in multiple drug abusers only. Before age 30, women reported increased treatment of certain types. Possible explanations are that treatment priority is given to women who are, or may be, pregnant. Also, younger men may not enter or complete treatment. Previous treatment history may influence many behaviors. The results of this study delineate several valuable indicators for assessing past history.

Network-based drug discovery by integrating systems biology and computational technologies

PubMed Central

Leung, Elaine L.; Cao, Zhi-Wei; Jiang, Zhi-Hong; Zhou, Hua

2013-01-01

Network-based intervention has been a trend of curing systemic diseases, but it relies on regimen optimization and valid multi-target actions of the drugs. The complex multi-component nature of medicinal herbs may serve as valuable resources for network-based multi-target drug discovery due to its potential treatment effects by synergy. Recently, robustness of multiple systems biology platforms shows powerful to uncover molecular mechanisms and connections between the drugs and their targeting dynamic network. However, optimization methods of drug combination are insufficient, owning to lacking of tighter integration across multiple ‘-omics’ databases. The newly developed algorithm- or network-based computational models can tightly integrate ‘-omics’ databases and optimize combinational regimens of drug development, which encourage using medicinal herbs to develop into new wave of network-based multi-target drugs. However, challenges on further integration across the databases of medicinal herbs with multiple system biology platforms for multi-target drug optimization remain to the uncertain reliability of individual data sets, width and depth and degree of standardization of herbal medicine. Standardization of the methodology and terminology of multiple system biology and herbal database would facilitate the integration. Enhance public accessible databases and the number of research using system biology platform on herbal medicine would be helpful. Further integration across various ‘-omics’ platforms and computational tools would accelerate development of network-based drug discovery and network medicine. PMID:22877768

Current approaches toward production of secondary plant metabolites

PubMed Central

Hussain, Md. Sarfaraj; Fareed, Sheeba; Ansari, Saba; Rahman, Md. Akhlaquer; Ahmad, Iffat Zareen; Saeed, Mohd.

2012-01-01

Plants are the tremendous source for the discovery of new products with medicinal importance in drug development. Today several distinct chemicals derived from plants are important drugs, which are currently used in one or more countries in the world. Secondary metabolites are economically important as drugs, flavor and fragrances, dye and pigments, pesticides, and food additives. Many of the drugs sold today are simple synthetic modifications or copies of the naturally obtained substances. The evolving commercial importance of secondary metabolites has in recent years resulted in a great interest in secondary metabolism, particularly in the possibility of altering the production of bioactive plant metabolites by means of tissue culture technology. Plant cell and tissue culture technologies can be established routinely under sterile conditions from explants, such as plant leaves, stems, roots, and meristems for both the ways for multiplication and extraction of secondary metabolites. In vitro production of secondary metabolite in plant cell suspension cultures has been reported from various medicinal plants, and bioreactors are the key step for their commercial production. Based on this lime light, the present review is aimed to cover phytotherapeutic application and recent advancement for the production of some important plant pharmaceuticals. PMID:22368394

Human hepatocytes derived from pluripotent stem cells: a promising cell model for drug hepatotoxicity screening.

PubMed

Gómez-Lechón, María José; Tolosa, Laia

2016-09-01

Drug-induced liver injury (DILI) is a frequent cause of failure in both clinical and post-approval stages of drug development, and poses a key challenge to the pharmaceutical industry. Current animal models offer poor prediction of human DILI. Although several human cell-based models have been proposed for the detection of human DILI, human primary hepatocytes remain the gold standard for preclinical toxicological screening. However, their use is hindered by their limited availability, variability and phenotypic instability. In contrast, pluripotent stem cells, which include embryonic and induced pluripotent stem cells (iPSCs), proliferate extensively in vitro and can be differentiated into hepatocytes by the addition of soluble factors. This provides a stable source of hepatocytes for multiple applications, including early preclinical hepatotoxicity screening. In addition, iPSCs also have the potential to establish genotype-specific cells from different individuals, which would increase the predictivity of toxicity assays allowing more successful clinical trials. Therefore, the generation of human hepatocyte-like cells derived from pluripotent stem cells seems to be promising for overcoming limitations of hepatocyte preparations, and it is expected to have a substantial repercussion in preclinical hepatotoxicity risk assessment in early drug development stages.

Drug-resistant tuberculosis in Mumbai, India: An agenda for operations research

PubMed Central

Mistry, Nerges; Tolani, Monica; Osrin, David

2012-01-01

Operations research (OR) is well established in India and is also a prominent feature of the global and local agendas for tuberculosis (TB) control. India accounts for a quarter of the global burden of TB and of new cases. Multidrug-resistant TB is a significant problem in Mumbai, India’s most populous city, and there have been recent reports of totally resistant TB. Much thought has been given to the role of OR in addressing programmatic challenges, by both international partnerships and India’s Revised National TB Control Programme. We attempt to summarize the major challenges to TB control in Mumbai, with an emphasis on drug resistance. Specific challenges include diagnosis of TB and defining cure, detecting drug resistant TB, multiple sources of health care in the private, public and informal sectors, co-infection with human immunodeficiency virus (HIV) and a concurrent epidemic of non-communicable diseases, suboptimal prescribing practices, and infection control. We propose a local agenda for OR: modeling the effects of newer technologies, active case detection, and changes in timing of activities, and mapping hotspots and contact networks; modeling the effects of drug control, changing the balance of ambulatory and inpatient care, and adverse drug reactions; modeling the effects of integration of TB and HIV diagnosis and management, and preventive drug therapy; and modeling the effects of initiatives to improve infection control. PMID:24501697

Benefits and limitations of drug studies in temperament research: biochemical responses as indicators of temperament.

PubMed

Netter, Petra

2018-04-19

This paper presents a discussion of principles and problems of neurotransmitter challenge tests using examples of experiments, most of which were performed in the author's laboratory. Drugs targeting synthesis, release, receptors or reuptake of dopamine, serotonin and noradrenergic transmitter (TM) systems were used for characterizing or discriminating certain temperament or personality traits and their sub-factors. Any personality or temperament trait is characterized by multiple TM responses, thus constellations of hormone responses to drugs acting on different TM systems or on different sources of TM activity were investigated within individuals in crossover designs. The major conclusions are: (i) intra-individual patterns of hormone responses to different TM-related drugs, or to agonists and antagonists, can help to discriminate subtypes of temperament dimensions, and (ii) the latency and shape of response curves may help specify processes of biological responses related to psychological dimensions and reveal common TM sensitivities in clusters of traits. TM sensitivity, defined by hormone responses, does not always correspond to accompanying behavioural indicators, but may provide more specific information on underlying mechanisms. Additional consideration of drug doses and experimental induction of stressors may serve to identify temperament-related susceptibilities to certain drugs. Limitations of the challenge approach and recommendations for future research are discussed.This article is part of the theme issue 'Diverse perspectives on diversity: multi-disciplinary approaches to taxonomies of individual differences'. © 2018 The Author(s).

Insulin sparing action of adenovirus 36 and its E4orf1 protein.

PubMed

Dhurandhar, Nikhil V

2013-01-01

Additional drugs are required to effectively manage diabetes and its complications. Recent studies have revealed protective effects of Ad36, a human adenovirus, and its E4orf1 protein on glucose disposal, which may be creatively harnessed to develop novel anti-diabetic agents. Experimental Ad36 infection improves hyperglycemia in animal models and natural Ad36 infection in humans is associated with better glycemic control. Available data indicate distinctive advantages for a drug that may mimic the action of Ad36/E4orf1. The key features of such a potential drug include the ability to increase glucose uptake by adipose tissue and skeletal muscle, to reduce hepatic glucose output independent of proximal insulin signaling, and to up-regulate adiponectin and its hepatic action. The effect of Ad36/E4orf1 on hepatocyte metabolism suggests a role for treating hepatic steatosis. Despite these potential advantages, considerable research is required before such a drug is developed. The in vivo efficacy and safety of E4orf1 in improving hyperglycemia remain unknown, and an appropriate drug delivery system is required. Nonetheless, Ad36 E4orf1 offers a research opportunity to develop a new anti-diabetic agent with multiple potential advantages and conceptually advances the use of a rather unconventional source, microbial proteins, for anti-diabetic drug development. Copyright © 2013 Elsevier Inc. All rights reserved.

The drinking water treatment process as a potential source of affecting the bacterial antibiotic resistance.

PubMed

Bai, Xiaohui; Ma, Xiaolin; Xu, Fengming; Li, Jing; Zhang, Hang; Xiao, Xiang

2015-11-15

Two waterworks, with source water derived from the Huangpu or Yangtze River in Shanghai, were investigated, and the effluents were plate-screened for antibiotic-resistant bacteria (ARB) using five antibiotics: ampicillin (AMP), kanamycin (KAN), rifampicin (RFP), chloramphenicol (CM) and streptomycin (STR). The influence of water treatment procedures on the bacterial antibiotic resistance rate and the changes that bacteria underwent when exposed to the five antibiotics at concentration levels ranging from 1 to 100 μg/mL were studied. Multi-drug resistance was also analyzed using drug sensitivity tests. The results indicated that bacteria derived from water treatment plant effluent that used the Huangpu River rather than the Yangtze River as source water exhibited higher antibiotic resistance rates against AMP, STR, RFP and CM but lower antibiotic resistance rates against KAN. When the antibiotic concentration levels ranged from 1 to 10 μg/mL, the antibiotic resistance rates of the bacteria in the water increased as water treatment progressed. Biological activated carbon (BAC) filtration played a key role in increasing the antibiotic resistance rate of bacteria. Chloramine disinfection can enhance antibiotic resistance. Among the isolated ARB, 75% were resistant to multiple antibiotics. Ozone oxidation, BAC filtration and chloramine disinfection can greatly affect the relative abundance of bacteria in the community. Copyright © 2015 Elsevier B.V. All rights reserved.

Initiation into Prescription Opioid Misuse among Young Injection Drug Users

PubMed Central

Lankenau, Stephen E.; Teti, Michelle; Silva, Karol; Bloom, Jennifer Jackson; Harocopos, Alex; Treese, Meghan

2011-01-01

Background Prescription opioids are the most frequently misused class of prescription drugs among young adults. Initiation into prescription opioid misuse is an important public health concern since opioids are increasingly associated with drug dependence and fatal overdose. Descriptive data about initiation into prescription opioid misuse among young injection drug users (IDUs) are scarce. Methods An exploratory qualitative study was undertaken to describe patterns of initiation into prescription opioid misuse among IDUs aged 16 to 25 years. Those young IDUs who had misused a prescription drug at least three times in the past three months were recruited during 2008 and 2009 in Los Angeles (n=25) and New York (n=25). Informed by an ethno-epidemiological approach, descriptive data from a semi-structured interview guide were analysed both quantitatively and qualitatively. Results Initiation into prescription opioid misuse was facilitated by easy access to opioids via participant’s own prescription, family, or friends, and occurred earlier than misuse of other illicit drugs, such as heroin. Nearly all transitioned into sniffing opioids, most injected opioids, and many initiated injection drug use with an opioid. Motives for transitions to sniffing and injecting opioids included obtaining a more potent high and/or substituting for heroin; access to multiple sources of opioids was common among those who progressed to sniffing and injecting opioids. Conclusion Prescription opioid misuse was a key feature of trajectories into injection drug use and/or heroin use among this sample of young IDUs. A new pattern of drug use may be emerging whereby IDUs initiate prescription opioid misuse before using heroin. PMID:21689917

[Pharmacological treatment conciliation methodology in patients with multiple conditions].

PubMed

Alfaro-Lara, Eva Rocío; Vega-Coca, María Dolores; Galván-Banqueri, Mercedes; Nieto-Martín, María Dolores; Pérez-Guerrero, Concepción; Santos-Ramos, Bernardo

2014-02-01

To carry out a bibliographic review in order to identify the different methodologies used along the reconciliation process of drug therapy applicable to polypathological patients. We performed a literature review. Data sources The bibliographic review (February 2012) included the following databases: Pubmed, EMBASE, CINAHL, PsycINFO and Spanish Medical Index (IME). The different methodologies, identified on those databases, to measure the conciliation process in polypathological patients, or otherwise elderly patients or polypharmacy, were studied. Study selection Two hundred and seventy three articles were retrieved, of which 25 were selected. Data extraction Specifically: the level of care, the sources of information, the use of registration forms, the established time, the medical professional in charge and the registered variables such as errors of reconciliation. Most of studies selected when the patient was admitted into the hospital and after the hospital discharge of the patient. The main sources of information to be highlighted are: the interview and the medical history of the patient. An established time is not explicitly stated on most of them, nor the registration form is used. The main professional in charge is the clinical pharmacologist. Apart from the home medication, the habits of self-medication and phytotherapy are also identified. The common errors of reconciliation vary from the omission of drugs to different forms of interaction with other medicinal products (drugs interactions). There is a large heterogeneity of methodologies used for reconciliation. There is not any work done on the specific figure of the polypathological patient, which precisely requires a standardized methodology due to its complexity and its susceptibility to errors of reconciliation. Copyright © 2012 Elsevier España, S.L. All rights reserved.

Anesthesia in the patient with multiple drug allergies: are all allergies the same?

PubMed

Dewachter, Pascale; Mouton-Faivre, Claudie; Castells, Mariana C; Hepner, David L

2011-06-01

During the preoperative evaluation, patients frequently indicate 'multiple drug allergies', most of which have not been validated. Potential allergic cross-reactivity between drugs and foods is frequently considered as a risk factor for perioperative hypersensitivity. The aim of this review is to facilitate the recognition of risk factors for perioperative anaphylaxis and help the management of patients with 'multiple drug allergies' during the perioperative period. Neuromuscular blocking agents (NMBAs) and antibiotics are the most common drugs triggering perioperative anaphylaxis. Quaternary ammonium ions have been suggested to be the allergenic determinant of NMBAs. Even though the 'pholcodine hypothesis' has been suggested to explain the occurrence of NMBA-induced allergy, this concept remains unclear. Although many practitioners believe that certain food allergies present an issue with the use of propofol, there is no role to contraindicate propofol in egg-allergic, soy-allergic or peanut-allergic patients. IgE-mediated hypersensitivity has been reported with seafood and iodinated drugs, IgE-mediated hypersensitivity has been reported with seafood and iodinated drugs, but there is no cross-reactivity between them. The allergenic determinants have been characterized for fish, shellfish and povidone iodine and remain unknown for contrast agents. There are many false assumptions regarding drug allergies. The main goal of this article is to review the potential cross-reactivity among specific families of drugs and foods in order to facilitate the anesthetic management of patients with 'multiple drug allergies'.

Multiple emulsions as effective platforms for controlled anti-cancer drug delivery.

PubMed

Dluska, Ewa; Markowska-Radomska, Agnieszka; Metera, Agata; Tudek, Barbara; Kosicki, Konrad

2017-09-01

Developing pH-responsive multiple emulsion platforms for effective glioblastoma multiforme therapy with reduced toxicity, a drug release study and modeling. Cancer cell line: U87 MG, multiple emulsions with pH-responsive biopolymer and encapsulated doxorubicin (DOX); preparation of multiple emulsions in a Couette-Taylor flow biocontactor, in vitro release study of DOX (fluorescence intensity analysis), in vitro cytotoxicity study (alamarBlue cell viability assay) and numerical simulation of DOX release rates. The multiple emulsions offered a high DOX encapsulation efficiency (97.4 ± 1%) and pH modulated release rates of a drug. Multiple emulsions with a low concentration of DOX (0.02 μM) exhibited broadly advanced cell (U87 MG) cytotoxicity than free DOX solution used at the same concentration. Emulsion platforms could be explored for potential delivery of chemotherapeutics in glioblastoma multiforme therapy.

Marine actinomycetes: a new source of compounds against the human malaria parasite.

PubMed

Prudhomme, Jacques; McDaniel, Eric; Ponts, Nadia; Bertani, Stéphane; Fenical, William; Jensen, Paul; Le Roch, Karine

2008-06-04

Malaria continues to be a devastating parasitic disease that causes the death of 2 million individuals annually. The increase in multi-drug resistance together with the absence of an efficient vaccine hastens the need for speedy and comprehensive antimalarial drug discovery and development. Throughout history, traditional herbal remedies or natural products have been a reliable source of antimalarial agents, e.g. quinine and artemisinin. Today, one emerging source of small molecule drug leads is the world's oceans. Included among the source of marine natural products are marine microorganisms such as the recently described actinomycete. Members of the genus Salinispora have yielded a wealth of new secondary metabolites including salinosporamide A, a molecule currently advancing through clinical trials as an anticancer agent. Because of the biological activity of metabolites being isolated from marine microorganisms, our group became interested in exploring the potential efficacy of these compounds against the malaria parasite. We screened 80 bacterial crude extracts for their activity against malaria growth. We established that the pure compound, salinosporamide A, produced by the marine actinomycete, Salinispora tropica, shows strong inhibitory activity against the erythrocytic stages of the parasite cycle. Biochemical experiments support the likely inhibition of the parasite 20S proteasome. Crystal structure modeling of salinosporamide A and the parasite catalytic 20S subunit further confirm this hypothesis. Ultimately we showed that salinosporamide A protected mice against deadly malaria infection when administered at an extremely low dosage. These findings underline the potential of secondary metabolites, derived from marine microorganisms, to inhibit Plasmodium growth. More specifically, we highlight the effect of proteasome inhibitors such as salinosporamide A on in vitro and in vivo parasite development. Salinosporamide A (NPI-0052) now being advanced to phase I trials for the treatment of refractory multiple myeloma will need to be further explored to evaluate the safety profile for its use against malaria.

Multi-target drugs to address multiple checkpoints in complex inflammatory pathologies: evolutionary cues for novel "first-in-class" anti-inflammatory drug candidates: a reviewer's perspective.

PubMed

Mathew, Geetha; Unnikrishnan, M K

2015-10-01

Inflammation is a complex, metabolically expensive process involving multiple signaling pathways and regulatory mechanisms which have evolved over evolutionary timescale. Addressing multiple targets of inflammation holistically, in moderation, is probably a more evolutionarily viable strategy, as compared to current therapy which addresses drug targets in isolation. Polypharmacology, addressing multiple targets, is commonly used in complex ailments, suggesting the superior safety and efficacy profile of multi-target (MT) drugs. Phenotypic drug discovery, which generated successful MT and first-in-class drugs in the past, is now re-emerging. A multi-pronged approach, which modulates the evolutionarily conserved, robust and pervasive cellular mechanisms of tissue repair, with AMPK at the helm, regulating the complex metabolic/immune/redox pathways underlying inflammation, is perhaps a more viable strategy than addressing single targets in isolation. Molecules that modulate multiple molecular mechanisms of inflammation in moderation (modulating TH cells toward the anti-inflammatory phenotype, activating AMPK, stimulating Nrf2 and inhibiting NFκB) might serve as a model for a novel Darwinian "first-in-class" therapeutic category that holistically addresses immune, redox and metabolic processes associated with inflammatory repair. Such a multimodal biological activity is supported by the fact that several non-calorific pleiotropic natural products with anti-inflammatory action have been incorporated into diet (chiefly guided by the adaptive development of olfacto-gustatory preferences over evolutionary timescales) rendering such molecules, endowed with evolutionarily privileged molecular scaffolds, naturally oriented toward multiple targets.

Multiple and substitute addictions involving prescription drugs misuse among 12th graders: gateway theory revisited with Market Basket Analysis.

PubMed

Jayawardene, Wasantha Parakrama; YoussefAgha, Ahmed Hassan

2014-01-01

This study aimed to identify the sequential patterns of drug use initiation, which included prescription drugs misuse (PDM), among 12th-grade students in Indiana. The study also tested the suitability of the data mining method Market Basket Analysis (MBA) to detect common drug use initiation sequences in large-scale surveys. Data from 2007 to 2009 Annual Surveys of Alcohol, Tobacco, and Other Drug Use by Indiana Children and Adolescents were used for this study. A close-ended, self-administered questionnaire was used to ask adolescents about the use of 21 substance categories and the age of first use. "Support%" and "confidence%" statistics of Market Basket Analysis detected multiple and substitute addictions, respectively. The lifetime prevalence of using any addictive substance was 73.3%, and it has been decreasing during past few years. Although the lifetime prevalence of PDM was 19.2%, it has been increasing. Males and whites were more likely to use drugs and engage in multiple addictions. Market Basket Analysis identified common drug use initiation sequences that involved 11 drugs. High levels of support existed for associations among alcohol, cigarettes, and marijuana, whereas associations that included prescription drugs had medium levels of support. Market Basket Analysis is useful for the detection of common substance use initiation sequences in large-scale surveys. Before initiation of prescription drugs, physicians should consider the adolescents' risk of addiction. Prevention programs should address multiple addictions, substitute addictions, common sequences in drug use initiation, sex and racial differences in PDM, and normative beliefs of parents and adolescents in relation to PDM.

Impact of Multiple Pharmacy Use on Medication Adherence and Drug-drug Interactions in Older Adults with Medicare Part D

PubMed Central

Marcum, Zachary A.; Driessen, Julia; Thorpe, Carolyn T.; Gellad, Walid F.; Donohue, Julie M.

2014-01-01

Objective To assess the association between multiple pharmacy use and medication adherence and potential drug-drug interactions (DDIs) among older adults. Design, Setting, and Participants Cross-sectional propensity score-weighted analysis of 2009 claims data from a nationally representative sample of 926,956 Medicare Part D beneficiaries aged >65 continuously enrolled in fee-for-service Medicare and Part D that year, and filled >1 prescription at a community/retail or mail order pharmacy. Multiple pharmacy use was defined as concurrent (overlapping time periods) or sequential use (non-overlapping time periods) of >2 pharmacies in the year. Measurements Medication adherence was calculated using a proportion of days covered ≥0.80 for eight therapeutic categories (β-blockers, renin angiotensin system antagonists, calcium channel blockers, statins, sulfonylureas, biguanides [i.e., metformin], thiazolidinediones, and dipeptidyl peptidase-IV inhibitors). Potential DDIs arising from use of certain drugs across a broad set of classes were defined as the concurrent filling of two interacting drugs. Results Overall, 38.1% of the sample used multiple pharmacies. Those using multiple pharmacies (both concurrently and sequentially) consistently had higher adjusted odds of non-adherence (ranging from 1.10 to 1.31, p<0.001) across all chronic medication classes assessed after controlling for socio-demographic, health status and access to care factors, compared to single pharmacy users. The adjusted predicted probability of exposure to a DDI was also slightly higher for those using multiple pharmacies concurrently (3.6%) compared to single pharmacy users (3.2%, AOR 1.11, 95% CI 1.08–1.15) but lower in individuals using multiple pharmacies sequentially (2.8%, AOR 0.85, 95% CI 0.81–0.91). Conclusions Filling prescriptions at multiple pharmacies was associated with lower medication adherence across multiple chronic medications, and a small but statistically significant increase in DDIs among concurrent pharmacy users. PMID:24521363

Antibiotics and bioactive natural products in treatment of methicillin resistant Staphylococcus aureus: A brief review

PubMed Central

Kali, Arunava

2015-01-01

Infections caused by Staphylococcus aureus strains with Methicillin resistance are associated with increased mortality and morbidity, aggressive course, multiple drug resistance and hospital outbreaks. Several first and second line antibiotics are rapidly becoming ineffective for treatment due to emergence of resistance. Extracts of medicinal plants are rich source of unique phytochemicals. Plants used in traditional medicine have been reported to have significant anti-MRSA activity. The objective of this review is to provide a brief overview of antibiotics as well as anti-MRSA natural products and their future prospect. PMID:26009690

Designer phenethylamines routinely found in human urine: 2-ethylamino-1-phenylbutane and 2-amino-1-phenylbutane.

PubMed

Uralets, Victor; App, Mike; Rana, Sumandeep; Morgan, Stewart; Ross, Wayne

2014-03-01

2-Ethylamino-1-phenylbutane (EAPB) and 2-amino-1-phenylbutane (APB) were identified by gas chromatography-mass spectrometry in multiple urine samples submitted for stimulant drug testing and screened positive for amphetamines by enzyme immunoassay. Forty-two samples from all over the USA were found, containing both analytes during a 3-month period May-July 2013. A sports dietary supplement 'CRAZE' has been determined to be one of the sources of EAPB supply. EAPB along with its suggested metabolite APB were detected in a urine sample, obtained from a person known to use 'CRAZE'.

Antibiotics and bioactive natural products in treatment of methicillin resistant Staphylococcus aureus: A brief review.

PubMed

Kali, Arunava

2015-01-01

Infections caused by Staphylococcus aureus strains with Methicillin resistance are associated with increased mortality and morbidity, aggressive course, multiple drug resistance and hospital outbreaks. Several first and second line antibiotics are rapidly becoming ineffective for treatment due to emergence of resistance. Extracts of medicinal plants are rich source of unique phytochemicals. Plants used in traditional medicine have been reported to have significant anti-MRSA activity. The objective of this review is to provide a brief overview of antibiotics as well as anti-MRSA natural products and their future prospect.

21 CFR 123.28 - Source controls.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 21 Food and Drugs 2 2010-04-01 2010-04-01 false Source controls. 123.28 Section 123.28 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) FOOD FOR HUMAN CONSUMPTION FISH AND FISHERY PRODUCTS Raw Molluscan Shellfish § 123.28 Source controls. (a) In order to meet...

21 CFR 352.71 - Light source (solar simulator).

Code of Federal Regulations, 2014 CFR

2014-04-01

... 21 Food and Drugs 5 2014-04-01 2014-04-01 false Light source (solar simulator). 352.71 Section 352.71 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED... Procedures § 352.71 Light source (solar simulator). A solar simulator used for determining the SPF of a...

21 CFR 352.71 - Light source (solar simulator).

Code of Federal Regulations, 2012 CFR

2012-04-01

... 21 Food and Drugs 5 2012-04-01 2012-04-01 false Light source (solar simulator). 352.71 Section 352.71 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED... Procedures § 352.71 Light source (solar simulator). A solar simulator used for determining the SPF of a...

Quantitative and Systems Pharmacology. 1. In Silico Prediction of Drug-Target Interactions of Natural Products Enables New Targeted Cancer Therapy.

PubMed

Fang, Jiansong; Wu, Zengrui; Cai, Chuipu; Wang, Qi; Tang, Yun; Cheng, Feixiong

2017-11-27

Natural products with diverse chemical scaffolds have been recognized as an invaluable source of compounds in drug discovery and development. However, systematic identification of drug targets for natural products at the human proteome level via various experimental assays is highly expensive and time-consuming. In this study, we proposed a systems pharmacology infrastructure to predict new drug targets and anticancer indications of natural products. Specifically, we reconstructed a global drug-target network with 7,314 interactions connecting 751 targets and 2,388 natural products and built predictive network models via a balanced substructure-drug-target network-based inference approach. A high area under receiver operating characteristic curve of 0.96 was yielded for predicting new targets of natural products during cross-validation. The newly predicted targets of natural products (e.g., resveratrol, genistein, and kaempferol) with high scores were validated by various literature studies. We further built the statistical network models for identification of new anticancer indications of natural products through integration of both experimentally validated and computationally predicted drug-target interactions of natural products with known cancer proteins. We showed that the significantly predicted anticancer indications of multiple natural products (e.g., naringenin, disulfiram, and metformin) with new mechanism-of-action were validated by various published experimental evidence. In summary, this study offers powerful computational systems pharmacology approaches and tools for the development of novel targeted cancer therapies by exploiting the polypharmacology of natural products.

Advice on drug safety in pregnancy: are there differences between commonly used sources of information?

PubMed

Frost Widnes, Sofia K; Schjøtt, Jan

2008-01-01

Safety regarding use in pregnancy is not established for many drugs. Inconsistencies between sources providing drug information can give rise to confusion with possible therapeutic consequences. Therefore, it is important to measure clinically important differences between drug information sources. The objective of this study was to compare two easily accessible Norwegian sources providing advice on drug safety in pregnancy - the product monographs in the Felleskatalog (FK), published by the pharmaceutical companies, and the five regional Drug Information Centres (DICs) in Norway - in addition to assessing the frequency of questions regarding drug safety in pregnancy made to the DICs according to the Anatomical Therapeutic Chemical (ATC) classification system. Advice on drug use in pregnancy provided by the DICs in 2003 and 2005 were compared with advice in the product monographs for the respective drugs in the FK. Comparison of advice was based on categorization to one of four categories: can be used, benefit-risk assessment, should not be used, or no available information. A total of 443 drug advice were categorized. Seven out of ten of drugs frequently enquired about, according to the ATC system, were drugs acting on the nervous system (group N). For 208 (47%) of the drugs, advice differed between the DICs and FK. Advice from the FK was significantly (p < 0.01) more restrictive than advice from the DICs. There were no differences in the level of consistency of advice between drugs that were newly introduced and those that had been on the market for a longer time, advice regarding use of drugs in the first trimester and advice regarding use of drugs in the second or third trimester, or between advice provided during 2003 and during 2005. The results of this study show considerable differences between two Norwegian sources providing advice on the use of drugs in pregnancy. Based on the knowledge that healthcare providers choose sources of information in a random manner, our results may be of clinical importance. We believe that the problem with heterogeneous drug information on this subject is not confined to Norway and that our results should be of international interest.

Multiple Measures of Outcome in Assessing a Prison-Based Drug Treatment Program

ERIC Educational Resources Information Center

Prendergast, Michael L.; Hall, Elizabeth A.; Wexler, Harry K.

2003-01-01

Evaluations of prison-based drug treatment programs typically focus on one or two dichotomous outcome variables related to recidivism. In contrast, this paper uses multiple measures of outcomes related to crime and drug use to examine the impact of prison treatment. Crime variables included self-report data of time to first illegal activity,…

Assessing website pharmacy drug quality: safer than you think?

PubMed

Bate, Roger; Hess, Kimberly

2010-08-13

Internet-sourced drugs are often considered suspect. The World Health Organization reports that drugs from websites that conceal their physical address are counterfeit in over 50 percent of cases; the U.S. Food and Drug Administration (FDA) works with the National Association of Boards of Pharmacy (NABP) to regularly update a list of websites likely to sell drugs that are illegal or of questionable quality. This study examines drug purchasing over the Internet, by comparing the sales of five popular drugs from a selection of websites stratified by NABP or other ratings. The drugs were assessed for price, conditions of purchase, and basic quality. Prices and conditions of purchase varied widely. Some websites advertised single pills while others only permitted the purchase of large quantities. Not all websites delivered the exact drugs ordered, some delivered no drugs at all; many websites shipped from multiple international locations, and from locations that were different from those advertised on the websites. All drug samples were tested against approved U.S. brand formulations using Raman spectrometry. Many (17) websites substituted drugs, often in different formulations from the brands requested. These drugs, some of which were probably generics or perhaps non-bioequivalent copy versions, could not be assessed accurately. Of those drugs that could be assessed, none failed from "approved", "legally compliant" or "not recommended" websites (0 out of 86), whereas 8.6% (3 out of 35) failed from "highly not recommended" and unidentifiable websites. Of those drugs that could be assessed, all except Viagra(R) passed spectrometry testing. Of those that failed, few could be identified either by a country of manufacture listed on the packaging, or by the physical location of the website pharmacy. If confirmed by future studies on other drug samples, then U.S. consumers should be able to reduce their risk by relying on credentialing agencies recommended lists and by using common sense when examining packaging and pills.

Assessment of gastrointestinal nematode infection, anthelmintic usage and husbandry practices on two small-scale goat farms in Malaysia.

PubMed

Wong, Flora; Sargison, Neil

2018-03-01

Haemonchosis is a common problem on goat farms in tropical countries such as Malaysia. Prevention of production losses generally depends on the use of anthelmintic drugs, but is threatened by the emergence of anthelmintic resistance. This study investigates anthelmintic efficacy on small-scale Malaysian goat farms and describes putative risk factors. Adult goats had moderate to high pre-treatment faecal trichostrongyle egg counts, despite being housed on slatted floors and fed on cut-and-carry forage, raising questions about the source of nematode infection. Our results show multiple resistance to benzimidazole and macrocyclic lactone anthelmintic drugs and allow us to discuss the genetic origins of resistance with reference to farm husbandry and management. We conclude that improvement in Malaysian goat production efficiency will require the development of sustainable helminth control strategies, underpinned by a better understanding of the origins and population genetics of anthelmintic resistance.

Diversity-oriented synthesis yields novel multistage antimalarial inhibitors.

PubMed

Kato, Nobutaka; Comer, Eamon; Sakata-Kato, Tomoyo; Sharma, Arvind; Sharma, Manmohan; Maetani, Micah; Bastien, Jessica; Brancucci, Nicolas M; Bittker, Joshua A; Corey, Victoria; Clarke, David; Derbyshire, Emily R; Dornan, Gillian L; Duffy, Sandra; Eckley, Sean; Itoe, Maurice A; Koolen, Karin M J; Lewis, Timothy A; Lui, Ping S; Lukens, Amanda K; Lund, Emily; March, Sandra; Meibalan, Elamaran; Meier, Bennett C; McPhail, Jacob A; Mitasev, Branko; Moss, Eli L; Sayes, Morgane; Van Gessel, Yvonne; Wawer, Mathias J; Yoshinaga, Takashi; Zeeman, Anne-Marie; Avery, Vicky M; Bhatia, Sangeeta N; Burke, John E; Catteruccia, Flaminia; Clardy, Jon C; Clemons, Paul A; Dechering, Koen J; Duvall, Jeremy R; Foley, Michael A; Gusovsky, Fabian; Kocken, Clemens H M; Marti, Matthias; Morningstar, Marshall L; Munoz, Benito; Neafsey, Daniel E; Sharma, Amit; Winzeler, Elizabeth A; Wirth, Dyann F; Scherer, Christina A; Schreiber, Stuart L

2016-10-20

Antimalarial drugs have thus far been chiefly derived from two sources-natural products and synthetic drug-like compounds. Here we investigate whether antimalarial agents with novel mechanisms of action could be discovered using a diverse collection of synthetic compounds that have three-dimensional features reminiscent of natural products and are underrepresented in typical screening collections. We report the identification of such compounds with both previously reported and undescribed mechanisms of action, including a series of bicyclic azetidines that inhibit a new antimalarial target, phenylalanyl-tRNA synthetase. These molecules are curative in mice at a single, low dose and show activity against all parasite life stages in multiple in vivo efficacy models. Our findings identify bicyclic azetidines with the potential to both cure and prevent transmission of the disease as well as protect at-risk populations with a single oral dose, highlighting the strength of diversity-oriented synthesis in revealing promising therapeutic targets.

QSAR modeling of GPCR ligands: methodologies and examples of applications.

PubMed

Tropsha, A; Wang, S X

2006-01-01

GPCR ligands represent not only one of the major classes of current drugs but the major continuing source of novel potent pharmaceutical agents. Because 3D structures of GPCRs as determined by experimental techniques are still unavailable, ligand-based drug discovery methods remain the major computational molecular modeling approaches to the analysis of growing data sets of tested GPCR ligands. This paper presents an overview of modern Quantitative Structure Activity Relationship (QSAR) modeling. We discuss the critical issue of model validation and the strategy for applying the successfully validated QSAR models to virtual screening of available chemical databases. We present several examples of applications of validated QSAR modeling approaches to GPCR ligands. We conclude with the comments on exciting developments in the QSAR modeling of GPCR ligands that focus on the study of emerging data sets of compounds with dual or even multiple activities against two or more of GPCRs.

Pharmacological Alternatives for the Treatment of Neurodegenerative Disorders: Wasp and Bee Venoms and Their Components as New Neuroactive Tools

PubMed Central

Silva, Juliana; Monge-Fuentes, Victoria; Gomes, Flávia; Lopes, Kamila; dos Anjos, Lilian; Campos, Gabriel; Arenas, Claudia; Biolchi, Andréia; Gonçalves, Jacqueline; Galante, Priscilla; Campos, Leandro; Mortari, Márcia

2015-01-01

Neurodegenerative diseases are relentlessly progressive, severely impacting affected patients, families and society as a whole. Increased life expectancy has made these diseases more common worldwide. Unfortunately, available drugs have insufficient therapeutic effects on many subtypes of these intractable diseases, and adverse effects hamper continued treatment. Wasp and bee venoms and their components are potential means of managing or reducing these effects and provide new alternatives for the control of neurodegenerative diseases. These venoms and their components are well-known and irrefutable sources of neuroprotectors or neuromodulators. In this respect, the present study reviews our current understanding of the mechanisms of action and future prospects regarding the use of new drugs derived from wasp and bee venom in the treatment of major neurodegenerative disorders, including Alzheimer’s Disease, Parkinson’s Disease, Epilepsy, Multiple Sclerosis and Amyotrophic Lateral Sclerosis. PMID:26295258

Source Apportionment and Risk Assessment of Emerging Contaminants: An Approach of Pharmaco-Signature in Water Systems

PubMed Central

Jiang, Jheng Jie; Lee, Chon Lin; Fang, Meng Der; Boyd, Kenneth G.; Gibb, Stuart W.

2015-01-01

This paper presents a methodology based on multivariate data analysis for characterizing potential source contributions of emerging contaminants (ECs) detected in 26 river water samples across multi-scape regions during dry and wet seasons. Based on this methodology, we unveil an approach toward potential source contributions of ECs, a concept we refer to as the “Pharmaco-signature.” Exploratory analysis of data points has been carried out by unsupervised pattern recognition (hierarchical cluster analysis, HCA) and receptor model (principal component analysis-multiple linear regression, PCA-MLR) in an attempt to demonstrate significant source contributions of ECs in different land-use zone. Robust cluster solutions grouped the database according to different EC profiles. PCA-MLR identified that 58.9% of the mean summed ECs were contributed by domestic impact, 9.7% by antibiotics application, and 31.4% by drug abuse. Diclofenac, ibuprofen, codeine, ampicillin, tetracycline, and erythromycin-H2O have significant pollution risk quotients (RQ>1), indicating potentially high risk to aquatic organisms in Taiwan. PMID:25874375

21 CFR 320.27 - Guidelines on the design of a multiple-dose in vivo bioavailability study.

Code of Federal Regulations, 2011 CFR

2011-04-01

... vivo bioavailability study. 320.27 Section 320.27 Food and Drugs FOOD AND DRUG ADMINISTRATION... Guidelines on the design of a multiple-dose in vivo bioavailability study. (a) Basic principles. (1) In... labeling of the test product. (3) A multiple-dose study may be required to determine the bioavailability of...

Neuropharmacological mechanisms of drug reward: beyond dopamine in the nucleus accumbens.

PubMed

Bardo, M T

1998-01-01

Multiple lines of research have implicated the mesolimbic dopamine system in drug reward measured by either the drug self-administration or conditioned place preference paradigm. The present review summarizes recent work that examines the neuropharmacological mechanisms by which drugs impinge on this dopaminergic neural circuitry, as well as other systems that provide input and output circuits to the mesolimbic dopamine system. Studies examining the effect of selective agonist and antagonist drugs administered systemically have indicated that multiple neurotransmitters are involved, including dopamine, serotonin, acetylcholine, glutamate, GABA, and various peptides. Direct microinjection studies have also provided crucial evidence indicating that, in addition to the mesolimbic dopamine system, other structures play a role in drug reward, including the ventral pallidum, amygdala, hippocampus, hypothalamus, and pedunculopontine tegmental nucleus. GABAergic circuitry descending from the nucleus accumbens to the pedunculopontine tegmental nucleus via the ventral pallidum appears to be especially important in directing the behavioral sequelae associated with reward produced by various drugs of abuse. However, activation of the reward circuitry is achieved differently for various drugs of abuse. With amphetamine and cocaine, initiation of reward is controlled within the nucleus accumbens and prefrontal cortex, respectively. With opiates, initiation of reward involves the ventral tegmental area, nucleus accumbens, hippocampus, and hypothalamus. It is not clear presently if these multiple anatomical structures mediate opiate reward by converging on a single output system or multiple output systems.

Combined rule extraction and feature elimination in supervised classification.

PubMed

Liu, Sheng; Patel, Ronak Y; Daga, Pankaj R; Liu, Haining; Fu, Gang; Doerksen, Robert J; Chen, Yixin; Wilkins, Dawn E

2012-09-01

There are a vast number of biology related research problems involving a combination of multiple sources of data to achieve a better understanding of the underlying problems. It is important to select and interpret the most important information from these sources. Thus it will be beneficial to have a good algorithm to simultaneously extract rules and select features for better interpretation of the predictive model. We propose an efficient algorithm, Combined Rule Extraction and Feature Elimination (CRF), based on 1-norm regularized random forests. CRF simultaneously extracts a small number of rules generated by random forests and selects important features. We applied CRF to several drug activity prediction and microarray data sets. CRF is capable of producing performance comparable with state-of-the-art prediction algorithms using a small number of decision rules. Some of the decision rules are biologically significant.

Multiscale Modeling in the Clinic: Drug Design and Development

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

Clancy, Colleen E.; An, Gary; Cannon, William R.

A wide range of length and time scales are relevant to pharmacology, especially in drug development, drug design and drug delivery. Therefore, multi-scale computational modeling and simulation methods and paradigms that advance the linkage of phenomena occurring at these multiple scales have become increasingly important. Multi-scale approaches present in silico opportunities to advance laboratory research to bedside clinical applications in pharmaceuticals research. This is achievable through the capability of modeling to reveal phenomena occurring across multiple spatial and temporal scales, which are not otherwise readily accessible to experimentation. The resultant models, when validated, are capable of making testable predictions tomore » guide drug design and delivery. In this review we describe the goals, methods, and opportunities of multi-scale modeling in drug design and development. We demonstrate the impact of multiple scales of modeling in this field. We indicate the common mathematical techniques employed for multi-scale modeling approaches used in pharmacology and present several examples illustrating the current state-of-the-art regarding drug development for: Excitable Systems (Heart); Cancer (Metastasis and Differentiation); Cancer (Angiogenesis and Drug Targeting); Metabolic Disorders; and Inflammation and Sepsis. We conclude with a focus on barriers to successful clinical translation of drug development, drug design and drug delivery multi-scale models.« less

Simultaneous quantification of reparixin and paclitaxel in plasma and urine using ultra performance liquid chromatography-tandem mass spectroscopy (UHPLC-MS/MS): Application to a preclinical pharmacokinetic study in rats.

PubMed

Malhi, Sarandeep; Stesco, Nicholas; Alrushaid, Samaa; Lakowski, Ted M; Davies, Neal M; Gu, Xiaochen

2017-03-01

A liquid chromatography-tandem mass spectroscopy (LC-MS/MS) assay was developed and validated to simultaneously quantify anticancer drugs reparixin and paclitaxel in this study. The compounds were extracted from plasma and urine samples by protein precipitation with acetone (supplemented with 0.1% formic acid). Chromatographic separation was achieved using a C18 column, and drug molecules were ionized using dual ion source electrospray and atmospheric pressure chemical ionization (DUIS: ESI-APCI). Reparixin and paclitaxel were quantified using negative and positive multiple reaction monitoring (MRM) mode, respectively. Stable isotope palcitaxel-D5 was used as the internal standard (IS). The assay was validated for specificity, recovery, carryover and sample stability under various storage conditions; it was also successfully applied to measure drug concentrations collected from a pharmacokinetic study in rats. The results confirmed that the assay was accurate and simple in quantifying both reparixin and paclitaxel in plasma and urine with minimal sample pretreatment. Copyright © 2016 Elsevier B.V. All rights reserved.

21 CFR 1250.28 - Source and handling of ice.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Source and handling of ice. 1250.28 Section 1250.28 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) REGULATIONS UNDER CERTAIN OTHER ACTS ADMINISTERED BY THE FOOD AND DRUG ADMINISTRATION INTERSTATE CONVEYANCE...

Preparation of uniform-sized multiple emulsions and micro/nano particulates for drug delivery by membrane emulsification.

PubMed

Liu, Wei; Yang, Xiang-Liang; Ho, W S Winston

2011-01-01

Much attention has in recent years been paid to fine applications of drug delivery systems, such as multiple emulsions, micro/nano solid lipid and polymer particles (spheres or capsules). Precise control of particle size and size distribution is especially important in such fine applications. Membrane emulsification can be used to prepare uniform-sized multiple emulsions and micro/nano particulates for drug delivery. It is a promising technique because of the better control of size and size distribution, the mildness of the process, the low energy consumption, easy operation and simple equipment, and amendable for large scale production. This review describes the state of the art of membrane emulsification in the preparation of monodisperse multiple emulsions and micro/nano particulates for drug delivery in recent years. The principles, influence of process parameters, advantages and disadvantages, and applications in preparing different types of drug delivery systems are reviewed. It can be concluded that the membrane emulsification technique in preparing emulsion/particulate products for drug delivery will further expand in the near future in conjunction with more basic investigations on this technique. Copyright © 2010 Wiley-Liss, Inc. and the American Pharmacists Association

A Factor Analytic Model of Drug-Related Behavior in Adolescence and Its Impact on Arrests at Multiple Stages of the Life Course

PubMed Central

2016-01-01

Objectives Recognizing the inherent variability of drug-related behaviors, this study develops an empirically-driven and holistic model of drug-related behavior during adolescence using factor analysis to simultaneously model multiple drug behaviors. Methods The factor analytic model uncovers latent dimensions of drug-related behaviors, rather than patterns of individuals. These latent dimensions are treated as empirical typologies which are then used to predict an individual’s number of arrests accrued at multiple phases of the life course. The data are robust enough to simultaneously capture drug behavior measures typically considered in isolation in the literature, and to allow for behavior to change and evolve over the period of adolescence. Results Results show that factor analysis is capable of developing highly descriptive patterns of drug offending, and that these patterns have great utility in predicting arrests. Results further demonstrate that while drug behavior patterns are predictive of arrests at the end of adolescence for both males and females, the impacts on arrests are longer lasting for females. Conclusions The various facets of drug behaviors have been a long-time concern of criminological research. However, the ability to model multiple behaviors simultaneously is often constrained by data that do not measure the constructs fully. Factor analysis is shown to be a useful technique for modeling adolescent drug involvement patterns in a way that accounts for the multitude and variability of possible behaviors, and in predicting future negative life outcomes, such as arrests. PMID:28435183

Shifting from the single- to the multitarget paradigm in drug discovery

PubMed Central

Medina-Franco, José L.; Giulianotti, Marc A.; Welmaker, Gregory S.; Houghten, Richard A.

2013-01-01

Increasing evidence that several drug compounds exert their effects through interactions with multiple targets is boosting the development of research fields that challenge the data reductionism approach. In this article, we review and discuss the concepts of drug repurposing, polypharmacology, chemogenomics, phenotypic screening and highthroughput in vivo testing of mixture-based libraries in an integrated manner. These research fields offer alternatives to the current paradigm of drug discovery, from a one target–one drug model to a multiple-target approach. Furthermore, the goals of lead identification are being expanded accordingly to identify not only ‘key’ compounds that fit with a single-target ‘lock’, but also ‘master key’ compounds that favorably interact with multiple targets (i.e. operate a set of desired locks to gain access to the expected clinical effects). PMID:23340113

Network-based Approaches in Pharmacology.

PubMed

Boezio, Baptiste; Audouze, Karine; Ducrot, Pierre; Taboureau, Olivier

2017-10-01

In drug discovery, network-based approaches are expected to spotlight our understanding of drug action across multiple layers of information. On one hand, network pharmacology considers the drug response in the context of a cellular or phenotypic network. On the other hand, a chemical-based network is a promising alternative for characterizing the chemical space. Both can provide complementary support for the development of rational drug design and better knowledge of the mechanisms underlying the multiple actions of drugs. Recent progress in both concepts is discussed here. In addition, a network-based approach using drug-target-therapy data is introduced as an example. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Racial/ethnic variations in substance-related disorders among adolescents in the United States

PubMed Central

Wu, Li-Tzy; Woody, George E.; Yang, Chongming; Pan, Jeng-Jong; Blazer, Dan G.

2012-01-01

Context While young racial/ethnic groups are the fastest growing population in the United States, data on alcohol and drug use disorders among adolescents of various racial/ethnic backgrounds are lacking. Objective To examine the magnitude of past-year Diagnostic and Statistical Manual of Mental Disorders-IV substance use disorders (alcohol, marijuana, cocaine, inhalants, hallucinogens, heroin, analgesic opioids, stimulants, sedatives, tranquilizers) among whites, Hispanics, African Americans, Native Americans, Asians/Pacific Islanders, and multiple-race adolescents. Design 2005–2008 National Surveys of Drug Use and Health. Setting Non institutionalized, household adolescents aged 12–17 years. Main Measures Substance use disorders were assessed by standardized survey questions administered by the audio computer-assisted self-interviewing method. Results Of all adolescents aged 12–17 (N=72,561), 37% used alcohol or drugs in the past year; 8% met criteria for an alcohol or drug use disorder, with Native Americans having the highest prevalence of use (48%) and disorder (15%). Analgesic opioids were the second most commonly used illegal drugs in all racial/ethnic groups, following marijuana; opioid use was comparatively prevalent among Native Americans (10%) and multiple-race adolescents (9%). Among past-year alcohol or drug users (n=27,705), Native Americans (32%), multiple-race adolescents (25%), whites (23%), and Hispanics (21%) had the highest rates of alcohol or drug use disorders. Marijuana was used by adolescents more frequently than alcohol or other drugs, and 26% of marijuana users met criteria for marijuana abuse/dependence. Controlling for adolescents’ age, socioeconomic variables, population density of residence, self-rated health, and survey year, adjusted analyses of adolescent substance users indicated elevated odds of having alcohol and drug use disorders among Native Americans, multiple-race adolescents, whites, and Hispanics compared with African Americans; the latter group did not differ from Asians/Pacific Islanders. Conclusions Substance use is widespread among Native-American, multiple-race, white, and Hispanic adolescents. These groups also are disproportionately affected by alcohol and drug use disorders. PMID:22065533

Cannabis - from cultivar to chemovar.

PubMed

Hazekamp, A; Fischedick, J T

2012-01-01

The medicinal use of Cannabis is increasing as countries worldwide are setting up official programs to provide patients with access to safe sources of medicinal-grade Cannabis. An important question that remains to be answered is which of the many varieties of Cannabis should be made available for medicinal use. Drug varieties of Cannabis are commonly distinguished through the use of popular names, with a major distinction being made between Indica and Sativa types. Although more than 700 different cultivars have already been described, it is unclear whether such classification reflects any relevant differences in chemical composition. Some attempts have been made to classify Cannabis varieties based on chemical composition, but they have mainly been useful for forensic applications, distinguishing drug varieties, with high THC content, from the non-drug hemp varieties. The biologically active terpenoids have not been included in these approaches. For a clearer understanding of the medicinal properties of the Cannabis plant, a better classification system, based on a range of potentially active constituents, is needed. The cannabinoids and terpenoids, present in high concentrations in Cannabis flowers, are the main candidates. In this study, we compared cultivars obtained from multiple sources. Based on the analysis of 28 major compounds present in these samples, followed by principal component analysis (PCA) of the quantitative data, we were able to identify the Cannabis constituents that defined the samples into distinct chemovar groups. The study indicates the usefulness of a PCA approach for chemotaxonomic classification of Cannabis varieties. Copyright © 2012 John Wiley & Sons, Ltd.

Classification of natural products as sources of drugs according to the biopharmaceutics drug disposition classification system (BDDCS).

PubMed

Li, Ji; Larregieu, Caroline A; Benet, Leslie Z

2016-12-01

Natural products (NPs) are compounds that are derived from natural sources such as plants, animals, and micro-organisms. Therapeutics has benefited from numerous drug classes derived from natural product sources. The Biopharmaceutics Drug Disposition Classification System (BDDCS) was proposed to serve as a basis for predicting the importance of transporters and enzymes in determining drug bioavailability and disposition. It categorizes drugs into one of four biopharmaceutical classes according to their water solubility and extent of metabolism. The present paper reviews 109 drugs from natural product sources: 29% belong to class 1 (high solubility, extensive metabolism), 22% to class 2 (low solubility, extensive metabolism), 40% to class 3 (high solubility, poor metabolism), and 9% to class 4 (low solubility, poor metabolism). Herein we evaluated the characteristics of NPs in terms of BDDCS class for all 109 drugs as wells as for subsets of NPs drugs derived from plant sources as antibiotics. In the 109 NPs drugs, we compiled 32 drugs from plants, 50% (16) of total in class 1, 22% (7) in class 2 and 28% (9) in class 3, none found in class 4; Meantime, the antibiotics were found 5 (16%) in class 2, 22 (71%) in class 3, and 4 (13%) in class 4; no drug was found in class 1. Based on this classification, we anticipate BDDCS to serve as a useful adjunct in evaluating the potential characteristics of new natural products. Copyright © 2016 China Pharmaceutical University. Published by Elsevier B.V. All rights reserved.

Vascular Smooth Muscle Cells From Hypertensive Patient-Derived Induced Pluripotent Stem Cells to Advance Hypertension Pharmacogenomics.

PubMed

Biel, Nikolett M; Santostefano, Katherine E; DiVita, Bayli B; El Rouby, Nihal; Carrasquilla, Santiago D; Simmons, Chelsey; Nakanishi, Mahito; Cooper-DeHoff, Rhonda M; Johnson, Julie A; Terada, Naohiro

2015-12-01

Studies in hypertension (HTN) pharmacogenomics seek to identify genetic sources of variable antihypertensive drug response. Genetic association studies have detected single-nucleotide polymorphisms (SNPs) that link to drug responses; however, to understand mechanisms underlying how genetic traits alter drug responses, a biological interface is needed. Patient-derived induced pluripotent stem cells (iPSCs) provide a potential source for studying otherwise inaccessible tissues that may be important to antihypertensive drug response. The present study established multiple iPSC lines from an HTN pharmacogenomics cohort. We demonstrated that established HTN iPSCs can robustly and reproducibly differentiate into functional vascular smooth muscle cells (VSMCs), a cell type most relevant to vasculature tone control. Moreover, a sensitive traction force microscopy assay demonstrated that iPSC-derived VSMCs show a quantitative contractile response on physiological stimulus of endothelin-1. Furthermore, the inflammatory chemokine tumor necrosis factor α induced a typical VSMC response in iPSC-derived VSMCs. These studies pave the way for a large research initiative to decode biological significance of identified SNPs in hypertension pharmacogenomics. Treatment of hypertension remains suboptimal, and a pharmacogenomics approach seeks to identify genetic biomarkers that could be used to guide treatment decisions; however, it is important to understand the biological underpinnings of genetic associations. Mouse models do not accurately recapitulate individual patient responses based on their genetics, and hypertension-relevant cells are difficult to obtain from patients. Induced pluripotent stem cell (iPSC) technology provides a great interface to bring patient cells with their genomic data into the laboratory and to study hypertensive responses. As an initial step, the present study established an iPSC bank from patients with primary hypertension and demonstrated an effective and reproducible method of generating functional vascular smooth muscle cells. ©AlphaMed Press.

Medical cannabis access, use, and substitution for prescription opioids and other substances: A survey of authorized medical cannabis patients.

PubMed

Lucas, Philippe; Walsh, Zach

2017-04-01

In 2014 Health Canada replaced the Marihuana for Medical Access Regulations (MMAR) with the Marihuana for Medical Purposes Regulations (MMPR). One of the primary changes in the new program has been to move from a single Licensed Producer (LP) of cannabis to multiple Licensed Producers. This is the first comprehensive survey of patients enrolled in the MMPR. Patients registered to purchase cannabis from Tilray, a federally authorized Licenced Producer (LP) within the MMPR, were invited to complete an online survey consisting of 107 questions on demographics, patterns of use, and cannabis substitution effect. The survey was completed by 271 respondents. Cannabis is perceived to be an effective treatment for diverse conditions, with pain and mental health the most prominent. Findings include high self-reported use of cannabis as a substitute for prescription drugs (63%), particularly pharmaceutical opioids (30%), benzodiazepines (16%), and antidepressants (12%). Patients also reported substituting cannabis for alcohol (25%), cigarettes/tobacco (12%), and illicit drugs (3%). A significant percentage of patients (42%) reported accessing cannabis from illegal/unregulated sources in addition to access via LPs, and over half (55%) were charged to receive a medical recommendation to use cannabis, with nearly 25% paying $300 or more. The finding that patients report its use as a substitute for prescription drugs supports prior research on medical cannabis users; however, this study is the first to specify the classes of prescription drugs for which cannabis it is used as a substitute, and to match this substitution to specific diagnostic categories. The findings that some authorized patients purchase cannabis from unregulated sources and that a significant percentage of patients were charged for medical cannabis recommendations highlight ongoing policy challenges for this federal program. Copyright © 2017 Elsevier B.V. All rights reserved.

Factors predicting publication of spinal cord injury trials registered on www.ClinicalTrials. gov.

PubMed

DePasse, J Mason; Park, Sara; Eltorai, Adam E M; Daniels, Alan H

2018-02-06

Treatment options for spinal cord injuries are currently limited, but multiple clinical trials are underway for a variety of interventions, drugs, and devices. The Food and Drug Administration website www.ClinicalTrials.gov catalogues these trials and includes information on the status of the trial, date of initiation and completion, source of funding, and region. This investigation assesses the factors associated with publication and the publication rate of spinal cord injury trials. Retrospective analysis of publically available data on www.ClinicalTrials.gov. The www.ClinicalTrials.gov was queried for all trials on patients with spinal cord injury, and these trials were assessed for status, type of intervention, source of funding, and region. Multiple literature searches were performed on all completed trials to determine publication status. There were 626 studies identified concerning the treatment of patients with spinal cord injury, of which 250 (39.9%) were completed. Of these, only 119 (47.6%) were published. There was no significant difference in the rate of publication between regions (p> 0.16) or by study type (p> 0.29). However, trials that were funded by the NIH were more likely to be published than trials funded by industry (p= 0.01). The current publication rate of spinal cord injury trials is only 47.6%, though this rate is similar to the publication rate for trials in other fields. NIH-funded trials are significantly more likely to become published than industry-funded trials, which could indicate that some trials remain unpublished due to undesirable results. However, it is also likely that many trials on spinal cord injury yield negative results, as treatments are often ineffective.

Feasibility and utility of applications of the common data model to multiple, disparate observational health databases.

PubMed

Voss, Erica A; Makadia, Rupa; Matcho, Amy; Ma, Qianli; Knoll, Chris; Schuemie, Martijn; DeFalco, Frank J; Londhe, Ajit; Zhu, Vivienne; Ryan, Patrick B

2015-05-01

To evaluate the utility of applying the Observational Medical Outcomes Partnership (OMOP) Common Data Model (CDM) across multiple observational databases within an organization and to apply standardized analytics tools for conducting observational research. Six deidentified patient-level datasets were transformed to the OMOP CDM. We evaluated the extent of information loss that occurred through the standardization process. We developed a standardized analytic tool to replicate the cohort construction process from a published epidemiology protocol and applied the analysis to all 6 databases to assess time-to-execution and comparability of results. Transformation to the CDM resulted in minimal information loss across all 6 databases. Patients and observations excluded were due to identified data quality issues in the source system, 96% to 99% of condition records and 90% to 99% of drug records were successfully mapped into the CDM using the standard vocabulary. The full cohort replication and descriptive baseline summary was executed for 2 cohorts in 6 databases in less than 1 hour. The standardization process improved data quality, increased efficiency, and facilitated cross-database comparisons to support a more systematic approach to observational research. Comparisons across data sources showed consistency in the impact of inclusion criteria, using the protocol and identified differences in patient characteristics and coding practices across databases. Standardizing data structure (through a CDM), content (through a standard vocabulary with source code mappings), and analytics can enable an institution to apply a network-based approach to observational research across multiple, disparate observational health databases. © The Author 2015. Published by Oxford University Press on behalf of the American Medical Informatics Association.

Prescribers prefer people: The sources of information used by doctors for prescribing suggest that the medium is more important than the message

PubMed Central

McGettigan, P; Golden, J; Fryer, J; Chan, R; Feely, J

2001-01-01

Aims The sources of prescribing information are legion but there is little knowledge about which are actually used in practice by doctors when prescribing. The aims of this study were to determine the sources of prescribing information considered important by doctors, establish which were used in practice, and investigate if hospital and primary care physicians differed in their use of the sources. Methods Two hundred general practitioners (GPs) and 230 hospital doctors were asked to rate information sources in terms of their importance for prescribing ‘old’ and ‘new’ drugs, and then to name the source from which information about the last new drug prescribed was actually derived. Results Among 108 GPs, the Drugs and Therapeutics Bulletin and medical journal articles were most frequently rated as important for information on both old and new drugs while pharmaceutical representatives and hospital/consultant recommendations were more important for information on new drugs, as opposed to old. In practice, information on the last new drug prescribed was derived from pharmaceutical representatives in 42% of cases and hospital/consultant recommendations in 36%, with other sources used infrequently. Among 118 hospital doctors, the British National Formulary (BNF) and senior colleagues were of greatest theoretical importance. In practice, information on the last new drug prescribed was derived from a broad range of sources: colleagues, 29%; pharmaceutical representatives, 18%; hospital clinical meetings, 15%; journal articles, 13%; lectures, 10%. GPs and hospital doctors differed significantly in their use of pharmaceutical representatives (42% vs 18%) and colleagues (7% vs 29%) as sources of prescribing information (P < 0.0001 for both). Conclusions The sources most frequently rated important in theory were not those most used in practice, especially among GPs. Both groups under-estimated the importance of pharmaceutical representatives. Most importantly, the sources of greatest practical importance were those involving the transfer of information through the medium of personal contact. PMID:11259994

Tools, information sources, and methods used in deciding on drug availability in HMOs.

PubMed

Barner, J C; Thomas, J

1998-01-01

The use and importance of specific decision-making tools, information sources, and drug-use management methods in determining drug availability and use in HMOs were studied. A questionnaire was sent to 303 randomly selected HMOs. Respondents were asked to rate their use of each of four formal decision-making tools and its relative importance, as well as the use and importance of eight information sources and 11 methods for managing drug availability and use, on a 5-point scale. The survey response rate was 28%. Approximately half of the respondents reported that their HMOs used decision analysis or multiattribute analysis in deciding on drug availability. If used, these tools were rated as very important. There were significant differences in levels of use by HMO type, membership size, and age. Journal articles and reference books were reported most often as information sources. Retrospective drug-use review was used very often and perceived to be very important in managing drug use. Other management methods were used only occasionally, but the importance placed on these tools when used ranged from moderately to very important. Older organizations used most of the management methods more often than did other HMOs. Decision analysis and multiattribute analysis were the most commonly used tools for deciding on which drugs to make available to HMO members, and reference books and journal articles were the most commonly used information sources. Retrospective and prospective drug-use reviews were the most commonly applied methods for managing HMO members' access to drugs.

Is anybody listening? A phenomenological study of pain in hospitalized persons with AIDS.

PubMed

Newshan, G

1998-01-01

Pain is a common problem among hospitalized persons with AIDS (PWAs), yet it has not been well studied. The purpose of this study was to understand, using the phenomenological method, the experience of pain in hospitalized PWAs. Multiple sources of data, including interviews with 11 hospitalized PWAs, literature, poetry, and film, were used to investigate the phenomenon. Five broad themes emerged: knowing pain, battling pain, having AIDS, pain's influence, and being a drug user. Multiple barriers to effective pain management were identified. Although there were commonalities in the experience of pain in chemically dependent and nonchemically dependent PWAs, unique challenges for the chemically dependent PWAs were identified. The findings indicate the importance of listening to and believing reports of pain. In addition, the findings underscore the delicate balance that exists between pain relief and relapse in PWAs with a history of chemical dependency.

Toward a complete dataset of drug-drug interaction information from publicly available sources.

PubMed

Ayvaz, Serkan; Horn, John; Hassanzadeh, Oktie; Zhu, Qian; Stan, Johann; Tatonetti, Nicholas P; Vilar, Santiago; Brochhausen, Mathias; Samwald, Matthias; Rastegar-Mojarad, Majid; Dumontier, Michel; Boyce, Richard D

2015-06-01

Although potential drug-drug interactions (PDDIs) are a significant source of preventable drug-related harm, there is currently no single complete source of PDDI information. In the current study, all publically available sources of PDDI information that could be identified using a comprehensive and broad search were combined into a single dataset. The combined dataset merged fourteen different sources including 5 clinically-oriented information sources, 4 Natural Language Processing (NLP) Corpora, and 5 Bioinformatics/Pharmacovigilance information sources. As a comprehensive PDDI source, the merged dataset might benefit the pharmacovigilance text mining community by making it possible to compare the representativeness of NLP corpora for PDDI text extraction tasks, and specifying elements that can be useful for future PDDI extraction purposes. An analysis of the overlap between and across the data sources showed that there was little overlap. Even comprehensive PDDI lists such as DrugBank, KEGG, and the NDF-RT had less than 50% overlap with each other. Moreover, all of the comprehensive lists had incomplete coverage of two data sources that focus on PDDIs of interest in most clinical settings. Based on this information, we think that systems that provide access to the comprehensive lists, such as APIs into RxNorm, should be careful to inform users that the lists may be incomplete with respect to PDDIs that drug experts suggest clinicians be aware of. In spite of the low degree of overlap, several dozen cases were identified where PDDI information provided in drug product labeling might be augmented by the merged dataset. Moreover, the combined dataset was also shown to improve the performance of an existing PDDI NLP pipeline and a recently published PDDI pharmacovigilance protocol. Future work will focus on improvement of the methods for mapping between PDDI information sources, identifying methods to improve the use of the merged dataset in PDDI NLP algorithms, integrating high-quality PDDI information from the merged dataset into Wikidata, and making the combined dataset accessible as Semantic Web Linked Data. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

Multiple Sclerosis

MedlinePlus

... progression. Some drugs are taken intravenously, some by infusion, and some oral. All drugs should be prescribed ... progression. Some drugs are taken intravenously, some by infusion, and some oral. All drugs should be prescribed ...

A Rapid Survival Assay to Measure Drug-Induced Cytotoxicity and Cell Cycle Effects

PubMed Central

Valiathan, Chandni; McFaline, Jose L.

2012-01-01

We describe a rapid method to accurately measure the cytotoxicity of mammalian cells upon exposure to various drugs. Using this assay, we obtain survival data in a fraction of the time required to perform the traditional clonogenic survival assay, considered the gold standard. The dynamic range of the assay allows sensitivity measurements on a multi-log scale allowing better resolution of comparative sensitivities. Moreover, the results obtained contain additional information on cell cycle effects of the drug treatment. Cell survival is obtained from a quantitative comparison of proliferation between drug-treated and untreated cells. During the assay, cells are treated with a drug and, following a recovery period, allowed to proliferate in the presence of BrdU. Cells that synthesize DNA in the presence of bromodeoxyuridine (BrdU) exhibit quenched Hoechst fluorescence easily detected by flow cytometry; quenching is used to determine relative proliferation in treated versus untreated cells. Finally, the multi-well setup of this assay allows the simultaneous screening of multiple cell lines, multiple doses, or multiple drugs to accurately measure cell survival and cell cycle changes after drug treatment. PMID:22133811

NATURAL PRODUCTS: A CONTINUING SOURCE OF NOVEL DRUG LEADS

PubMed Central

Cragg, Gordon M.; Newman, David J.

2013-01-01

1. Background Nature has been a source of medicinal products for millennia, with many useful drugs developed from plant sources. Following discovery of the penicillins, drug discovery from microbial sources occurred and diving techniques in the 1970s opened the seas. Combinatorial chemistry (late 1980s), shifted the focus of drug discovery efforts from Nature to the laboratory bench. 2. Scope of Review This review traces natural products drug discovery, outlining important drugs from natural sources that revolutionized treatment of serious diseases. It is clear Nature will continue to be a major source of new structural leads, and effective drug development depends on multidisciplinary collaborations. 3. Major Conclusions The explosion of genetic information led not only to novel screens, but the genetic techniques permitted the implementation of combinatorial biosynthetic technology and genome mining. The knowledge gained has allowed unknown molecules to be identified. These novel bioactive structures can be optimized by using combinatorial chemistry generating new drug candidates for many diseases. 4 General Significance: The advent of genetic techniques that permitted the isolation / expression of biosynthetic cassettes from microbes may well be the new frontier for natural products lead discovery. It is now apparent that biodiversity may be much greater in those organisms. The numbers of potential species involved in the microbial world are many orders of magnitude greater than those of plants and multi-celled animals. Coupling these numbers to the number of currently unexpressed biosynthetic clusters now identified (>10 per species) the potential of microbial diversity remains essentially untapped. PMID:23428572

Improving multiple sclerosis management and collecting safety information in the real world: the MSDS3D software approach.

PubMed

Haase, Rocco; Wunderlich, Maria; Dillenseger, Anja; Kern, Raimar; Akgün, Katja; Ziemssen, Tjalf

2018-04-01

For safety evaluation, randomized controlled trials (RCTs) are not fully able to identify rare adverse events. The richest source of safety data lies in the post-marketing phase. Real-world evidence (RWE) and observational studies are becoming increasingly popular because they reflect usefulness of drugs in real life and have the ability to discover uncommon or rare adverse drug reactions. Areas covered: Adding the documentation of psychological symptoms and other medical disciplines, the necessity for a complex documentation becomes apparent. The collection of high-quality data sets in clinical practice requires the use of special documentation software as the quality of data in RWE studies can be an issue in contrast to the data obtained from RCTs. The MSDS3D software combines documentation of patient data with patient management of patients with multiple sclerosis. Following a continuous development over several treatment-specific modules, we improved and expanded the realization of safety management in MSDS3D with regard to the characteristics of different treatments and populations. Expert opinion: eHealth-enhanced post-authorisation safety study may complete the fundamental quest of RWE for individually improved treatment decisions and balanced therapeutic risk assessment. MSDS3D is carefully designed to contribute to every single objective in this process.

Bioanalysis of antibody-drug conjugates: American Association of Pharmaceutical Scientists Antibody-Drug Conjugate Working Group position paper.

PubMed

Gorovits, Boris; Alley, Stephen C; Bilic, Sanela; Booth, Brian; Kaur, Surinder; Oldfield, Phillip; Purushothama, Shobha; Rao, Chetana; Shord, Stacy; Siguenza, Patricia

2013-05-01

Antibody-drug conjugates (ADCs) typically consist of a cytotoxic drug covalently bound to an antibody by a linker. These conjugates have the potential to substantially improve efficacy and reduce toxicity compared with cytotoxic small-molecule drugs. Since ADCs are generally complex heterogeneous mixtures of multiple species, these novel therapeutic products present unique bioanalytical challenges. The growing number of ADCs being developed across the industry suggests the need for alignment of the bioanalytical methods or approaches used to assess the multiple species and facilitate consistent interpretation of the bioanalytical data. With limited clinical data, the current strategies that can be used to provide insight into the relationship between the multiple species and the observed clinical safety and efficacy are still evolving. Considerations of the bioanalytical strategies for ADCs based on the current industry practices that take into account the complexity and heterogeneity of ADCs are discussed.

Using genome-wide CRISPR library screening with library resistant DCK to find new sources of Ara-C drug resistance in AML.

PubMed

Kurata, Morito; Rathe, Susan K; Bailey, Natashay J; Aumann, Natalie K; Jones, Justine M; Veldhuijzen, G Willemijn; Moriarity, Branden S; Largaespada, David A

2016-11-03

Acute myeloid leukemia (AML) can display de novo or acquired resistance to cytosine arabinoside (Ara-C), a primary component of induction chemotherapy. To identify genes capable of independently imposing Ara-C resistance, we applied a genome-wide CRISPR library to human U937 cells and exposed to them to Ara-C. Interestingly, all drug resistant clones contained guide RNAs for DCK. To avoid DCK gene modification, gRNA resistant DCK cDNA was created by the introduction of silent mutations. The CRISPR screening was repeated using the gRNA resistant DCK, and loss of SLC29A was identified as also being capable of conveying Ara-C drug resistance. To determine if loss of Dck results in increased sensitivity to other drugs, we conducted a screen of 446 FDA approved drugs using two Dck-defective BXH-2 derived murine AML cell lines and their Ara-C sensitive parental lines. Both cell lines showed an increase in sensitivity to prednisolone. Guide RNA resistant cDNA rescue was a legitimate strategy and multiple DCK or SLC29A deficient human cell clones were established with one clone becoming prednisolone sensitive. Dck-defective leukemic cells may become prednisolone sensitive indicating prednisolone may be an effective adjuvant therapy in some cases of DCK-negative AML.

21 CFR 640.60 - Source Plasma.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 21 Food and Drugs 7 2011-04-01 2010-04-01 true Source Plasma. 640.60 Section 640.60 Food and Drugs... STANDARDS FOR HUMAN BLOOD AND BLOOD PRODUCTS Source Plasma § 640.60 Source Plasma. The proper name of the product shall be Source Plasma. The product is defined as the fluid portion of human blood collected by...

Drug information-seeking intention and behavior after exposure to direct-to-consumer advertisement of prescription drugs.

PubMed

Liu, Yifei; Doucette, William R; Farris, Karen B; Nayakankuppam, Dhananjay

2005-06-01

Concerns about direct-to-consumer advertisement's (DTCA's) information quality have raised interest in patients' drug information-seeking after DTCA exposure. To identify predictors of patients' intentions and behaviors to seek drug information from physicians, pharmacists, and the Internet after DTCA exposure, using theories of planned behavior and self-efficacy. One thousand patients were randomly selected from 3,000 nationwide osteoarthritic patients. A self-administered survey examined predictors of intention including measurements of attitude toward behavior, subjective norm, perceived difficulty, self-efficacy, controllability, self-identity, intention, exposure to ads, and control variables. After 6 weeks, another survey measured respondents' information-seeking behavior. For patients exposed to DTCA, 6 multiple regressions were performed for information-seeking intention and behavior for 3 information sources: physicians, pharmacists, and the Internet. The response rates were 61.9% and 80.1% for the first survey and the second survey, respectively. Four hundred and fifty-four participants reported exposure to DTCA about arthritis prescription medicines in the previous month. Over 41% of the variance in intention and over 18% of the variance in behavior were explained by the regression procedures. The consistent positive predictors of intention were attitude toward behavior, self-identity, attitude toward DTCAs of arthritis medication, and osteoarthritis pain; while the consistent positive predictors of behavior were intention and osteoarthritis pain. The strongest predictors of intention were self-identity for physicians, subjective norm for pharmacists, and attitude toward behavior for the Internet. Perceived difficulty and self-efficacy did not predict intention, and self-efficacy and controllability did not predict behavior. DTCA-prompted drug information-seeking may be under patients' complete volitional control. To promote information searching, efforts could be made to affect factors predicting intention. Interventions could address patients' attitude toward behavior, the influence of their important others, and their role as information seeker, respectively, for information sources like the Internet, pharmacists, and physicians.

Efficient use of retention time for the analysis of 302 drugs in equine plasma by liquid chromatography-MS/MS with scheduled multiple reaction monitoring and instant library searching for doping control.

PubMed

Liu, Ying; Uboh, Cornelius E; Soma, Lawrence R; Li, Xiaoqing; Guan, Fuyu; You, Youwen; Chen, Jin-Wen

2011-09-01

Multiple drug target analysis (MDTA) used in doping control is more efficient than single drug target analysis (SDTA). The number of drugs with the potential for abuse is so extensive that full coverage is not possible with SDTA. To address this problem, a liquid chromatography tandem mass spectrometric method was developed for simultaneous analysis of 302 drugs using a scheduled multiple reaction monitoring (s-MRM) algorithm. With a known retention time of an analyte, the s-MRM algorithm monitors each MRM transition only around its expected retention time. Analytes were recovered from plasma by liquid-liquid extraction. Information-dependent acquisition (IDA) functionality was used to combine s-MRM with enhanced product ion (EPI) scans within the same chromatographic analysis. An EPI spectrum library was also generated for rapid identification of analytes. Analysis time for the 302 drugs was 7 min. Scheduled MRM improved the quality of the chromatograms, signal response, reproducibility, and enhanced signal-to-noise ratio (S/N), resulting in more data points. Reduction in total cycle time from 2.4 s in conventional MRM (c-MRM) to 1 s in s-MRM allowed completion of the EPI scan at the same time. The speed for screening and identification of multiple drugs in equine plasma for doping control analysis was greatly improved by this method.

Multiple Household Water Sources and Their Use in Remote Communities With Evidence From Pacific Island Countries

NASA Astrophysics Data System (ADS)

Elliott, Mark; MacDonald, Morgan C.; Chan, Terence; Kearton, Annika; Shields, Katherine F.; Bartram, Jamie K.; Hadwen, Wade L.

2017-11-01

Global water research and monitoring typically focus on the household's "main source of drinking-water." Use of multiple water sources to meet daily household needs has been noted in many developing countries but rarely quantified or reported in detail. We gathered self-reported data using a cross-sectional survey of 405 households in eight communities of the Republic of the Marshall Islands (RMI) and five Solomon Islands (SI) communities. Over 90% of households used multiple sources, with differences in sources and uses between wet and dry seasons. Most RMI households had large rainwater tanks and rationed stored rainwater for drinking throughout the dry season, whereas most SI households collected rainwater in small pots, precluding storage across seasons. Use of a source for cooking was strongly positively correlated with use for drinking, whereas use for cooking was negatively correlated or uncorrelated with nonconsumptive uses (e.g., bathing). Dry season water uses implied greater risk of water-borne disease, with fewer (frequently zero) handwashing sources reported and more unimproved sources consumed. Use of multiple sources is fundamental to household water management and feasible to monitor using electronic survey tools. We contend that recognizing multiple water sources can greatly improve understanding of household-level and community-level climate change resilience, that use of multiple sources confounds health impact studies of water interventions, and that incorporating multiple sources into water supply interventions can yield heretofore-unrealized benefits. We propose that failure to consider multiple sources undermines the design and effectiveness of global water monitoring, data interpretation, implementation, policy, and research.

Oral Disease-Modifying Therapies for Multiple Sclerosis

PubMed Central

Kim, Woojun; Zandoná, Manuella Edler; Kim, Su-Hyun

2015-01-01

Classical multiple sclerosis (MS) treatments using first-line injectable drugs, although widely applied, remain a major concern in terms of therapeutic adherence and efficacy. New oral drugs recently approved for MS treatment represent significant advances in therapy. The oral route of administration clearly promotes patient satisfaction and increases therapeutic compliance. However, these drugs may also have safety and tolerability issues, and a thorough analysis of the risks and benefits is required. Three oral drugs have been approved by regulatory agencies for MS treatment: fingolimod, teriflunomide, and dimethyl fumarate. This article reviews the mechanisms of action, safety, and efficacy of these drugs and two other drugs that have yielded positive results in phase III trials: cladribine and laquinimod. PMID:25628732

Multiple target drug cocktail design for attacking the core network markers of four cancers using ligand-based and structure-based virtual screening methods

PubMed Central

2015-01-01

Background Computer-aided drug design has a long history of being applied to discover new molecules to treat various cancers, but it has always been focused on single targets. The development of systems biology has let scientists reveal more hidden mechanisms of cancers, but attempts to apply systems biology to cancer therapies remain at preliminary stages. Our lab has successfully developed various systems biology models for several cancers. Based on these achievements, we present the first attempt to combine multiple-target therapy with systems biology. Methods In our previous study, we identified 28 significant proteins--i.e., common core network markers--of four types of cancers as house-keeping proteins of these cancers. In this study, we ranked these proteins by summing their carcinogenesis relevance values (CRVs) across the four cancers, and then performed docking and pharmacophore modeling to do virtual screening on the NCI database for anti-cancer drugs. We also performed pathway analysis on these proteins using Panther and MetaCore to reveal more mechanisms of these cancer house-keeping proteins. Results We designed several approaches to discover targets for multiple-target cocktail therapies. In the first one, we identified the top 20 drugs for each of the 28 cancer house-keeping proteins, and analyzed the docking pose to further understand the interaction mechanisms of these drugs. After screening for duplicates, we found that 13 of these drugs could target 11 proteins simultaneously. In the second approach, we chose the top 5 proteins with the highest summed CRVs and used them as the drug targets. We built a pharmacophore and applied it to do virtual screening against the Life-Chemical library for anti-cancer drugs. Based on these results, wet-lab bio-scientists could freely investigate combinations of these drugs for multiple-target therapy for cancers, in contrast to the traditional single target therapy. Conclusions Combination of systems biology with computer-aided drug design could help us develop novel drug cocktails with multiple targets. We believe this will enhance the efficiency of therapeutic practice and lead to new directions for cancer therapy. PMID:26680552

Clinical effectiveness of multiple-drug injection treatment in unruptured ectopic pregnancies: a retrospective study.

PubMed

Dai, Quan; Wang, Lu-Lu; Shao, Xiao-Hui; Wang, Si-Ming; Dong, Xiao-Qiu

2012-10-01

To study the effect of local interventional treatment of unruptured ectopic pregnancies with multiple-drug injection guided by color Doppler sonography. In this retrospective analysis, 49 patients with an unruptured ectopic pregnancy were treated with two different local injection methods administered under sonographic guidance. The patients were divided into single-drug (n = 23) and multiple-drug (n = 26) injection groups, and they received a locally administered injection of methotrexate alone or a combination including methotrexate, hemocoagulase, antibiotics, and anti-inflammatory drugs, respectively. Overall, local injection treatment was successful in 44 patients. The 5 patients with failed treatment underwent laparotomy about 1 week after single-drug injection. Serum β-human chorionic gonadotropin (β-hCG ) levels, ectopic pregnancy mass sizes, blood flow at various points after treatment, the incidence of pelvic bleeding, and the time for serum β-hCG levels to return to normal and the mass to resolve were analyzed in the remaining 44 patients. Single-drug treatment was successful in 18 patients; 10 of 23 had low to moderate pelvic bleeding after treatment, and 5 were referred for surgery. All 26 patients were successfully treated by multiple-drug injection. Only 2 patients had a small amount of pelvic bleeding. Differences between groups were statistically significant (P < .05) for surgery rates, the incidence of pelvic bleeding, transient increases in serum β-hCG levels, mean days to normal β-hCG levels, mean days of mass resolution, and mean mass diameters 1 to 6 weeks after treatment. Local multiple-drug injection under color Doppler guidance is a new, safe, and effective method for treating unruptured ectopic pregnancies. It accelerates the serum β-hCG decline and facilitates mass resolution. This regimen is associated with a very low rate of pelvic bleeding, improves the success rate of conservative treatment, and, therefore, has value as an important clinical application.

21 CFR 1250.25 - Source identification and inspection of food and drink.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Source identification and inspection of food and drink. 1250.25 Section 1250.25 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) REGULATIONS UNDER CERTAIN OTHER ACTS ADMINISTERED BY THE FOOD AND DRUG ADMINISTRATION INTERSTATE CONVEYANCE SANITATION Foo...

TYPES AND QUANTITIES OF LEFTOVER DRUGS ...

EPA Pesticide Factsheets

BACKGROUND: Pharmaceuticals designed for humans and animals often remain unused. Leftover and accumulated drugs represent suboptimal delivery of health care and environmentally unsound disposal, which can pose exposure risks for humans and wildlife.OBJECTIVES: A major unknown with respect to drugs as pollutants is what fractions of drug residues occurring in the ambient environment result from discarding leftover drugs. To gauge the significance of leftover drugs as potential pollutants, data are needed on the types, quantities, and frequencies with which drugs accumulate. Absence of this data has prevented assessments of the significance of drug accumulation and disposal as a contributing source of drug residues in the environment.METHODS: One particular source of drug accumulation is those drugs that become

Regression Models for the Analysis of Longitudinal Gaussian Data from Multiple Sources

PubMed Central

O’Brien, Liam M.; Fitzmaurice, Garrett M.

2006-01-01

We present a regression model for the joint analysis of longitudinal multiple source Gaussian data. Longitudinal multiple source data arise when repeated measurements are taken from two or more sources, and each source provides a measure of the same underlying variable and on the same scale. This type of data generally produces a relatively large number of observations per subject; thus estimation of an unstructured covariance matrix often may not be possible. We consider two methods by which parsimonious models for the covariance can be obtained for longitudinal multiple source data. The methods are illustrated with an example of multiple informant data arising from a longitudinal interventional trial in psychiatry. PMID:15726666

Gene duplication and divergence affecting drug content in Cannabis sativa.

PubMed

Weiblen, George D; Wenger, Jonathan P; Craft, Kathleen J; ElSohly, Mahmoud A; Mehmedic, Zlatko; Treiber, Erin L; Marks, M David

2015-12-01

Cannabis sativa is an economically important source of durable fibers, nutritious seeds, and psychoactive drugs but few economic plants are so poorly understood genetically. Marijuana and hemp were crossed to evaluate competing models of cannabinoid inheritance and to explain the predominance of tetrahydrocannabinolic acid (THCA) in marijuana compared with cannabidiolic acid (CBDA) in hemp. Individuals in the resulting F2 population were assessed for differential expression of cannabinoid synthase genes and were used in linkage mapping. Genetic markers associated with divergent cannabinoid phenotypes were identified. Although phenotypic segregation and a major quantitative trait locus (QTL) for the THCA/CBDA ratio were consistent with a simple model of codominant alleles at a single locus, the diversity of THCA and CBDA synthase sequences observed in the mapping population, the position of enzyme coding loci on the map, and patterns of expression suggest multiple linked loci. Phylogenetic analysis further suggests a history of duplication and divergence affecting drug content. Marijuana is distinguished from hemp by a nonfunctional CBDA synthase that appears to have been positively selected to enhance psychoactivity. An unlinked QTL for cannabinoid quantity may also have played a role in the recent escalation of drug potency. © 2015 The Authors. New Phytologist © 2015 New Phytologist Trust.

Can Nanomedicines Kill Cancer Stem Cells?

PubMed Central

Zhao, Yi; Alakhova, Daria Y.; Kabanov, Alexander V.

2014-01-01

Most tumors are heterogeneous and many cancers contain small population of highly tumorigenic and intrinsically drug resistant cancer stem cells (CSCs). Like normal stem cell, CSCs have ability to self-renew and differentiate to other tumor cell types. They are believed to be a source for drug resistance, tumor recurrence and metastasis. CSCs often overexpress drug efflux transporters, spend most of their time in non-dividing G0 cell cycle state, and therefore, can escape the conventional chemotherapies. Thus, targeting CSCs is essential for developing novel therapies to prevent cancer relapse and emerging of drug resistance. Nanocarrier-based therapeutic agents (nanomedicines) have been used to achieve longer circulation times, better stability and bioavailability over current therapeutics. Recently, some groups have successfully applied nanomedicines to target CSCs to eliminate the tumor and prevent its recurrence. These approaches include 1) delivery of therapeutic agents (small molecules, siRNA, antibodies) that affect embryonic signaling pathways implicated in self-renewal and differentiation in CSCs, 2) inhibiting drug efflux transporters in an attempt to sensitize CSCs to therapy, 3) targeting metabolism in CSCs through nanoformulated chemicals and field-responsive magnetic nanoparticles and carbon nanotubes, and 4) disruption of multiple pathways in drug resistant cells using combination of chemotherapeutic drugs with amphiphilic Pluronic block copolymers. Despite clear progress of these studies the challenges of targeting CSCs by nanomedicines still exist and leave plenty of room for improvement and development. This review summarizes biological processes that are related to CSCs, overviews the current state of anti-CSCs therapies, and discusses state-of-the-art nanomedicine approaches developed to kill CSCs. PMID:24120657

Borneol, a novel agent that improves central nervous system drug delivery by enhancing blood-brain barrier permeability.

PubMed

Zhang, Qun-Lin; Fu, Bingmei M; Zhang, Zhang-Jin

2017-11-01

The clinical application of central nervous system (CNS) drugs is limited by their poor bioavailability due to the blood-brain barrier (BBB). Borneol is a naturally occurring compound in a class of 'orifice-opening' agents often used for resuscitative purposes in traditional Chinese medicine. A growing body of evidence confirms that the 'orifice-opening' effect of borneol is principally derived from opening the BBB. Borneol is therefore believed to be an effective adjuvant that can improve drug delivery to the brain. The purpose of this paper is to provide a comprehensive review of information accumulated over the past two decades on borneol's chemical features, sources, toxic and kinetic profiles, enhancing effects on BBB permeability and their putative mechanisms, improvements in CNS drug delivery, and pharmaceutical forms. The BBB-opening effect of borneol is a reversible physiological process characterized by rapid and transient penetration of the BBB and highly specific brain regional distribution. Borneol also protects the structural integrity of the BBB against pathological damage. The enhancement of the BBB permeability is associated with the modulation of multiple ATP-binding cassette transporters, including P-glycoprotein; tight junction proteins; and predominant enhancement of vasodilatory neurotransmitters. Systemic co-administration with borneol improves drug delivery to the brain in a region-, dose- and time-dependent manner. Several pharmaceutical forms of borneol have been developed to improve the kinetic and toxic profiles of co-administered drugs and enhance their delivery to the brain. Borneol is a promising novel agent that deserves further development as a BBB permeation enhancer for CNS drug delivery.

Using cheminformatics to predict cross reactivity of “designer drugs” to their currently available immunoassays

PubMed Central

2014-01-01

Background A challenge for drug of abuse testing is presented by ‘designer drugs’, compounds typically discovered by modifications of existing clinical drug classes such as amphetamines and cannabinoids. Drug of abuse screening immunoassays directed at amphetamine or methamphetamine only detect a small subset of designer amphetamine-like drugs, and those immunoassays designed for tetrahydrocannabinol metabolites generally do not cross-react with synthetic cannabinoids lacking the classic cannabinoid chemical backbone. This suggests complexity in understanding how to detect and identify whether a patient has taken a molecule of one class or another, impacting clinical care. Methods Cross-reactivity data from immunoassays specifically targeting designer amphetamine-like and synthetic cannabinoid drugs was collected from multiple published sources, and virtual chemical libraries for molecular similarity analysis were built. The virtual library for synthetic cannabinoid analysis contained a total of 169 structures, while the virtual library for amphetamine-type stimulants contained 288 compounds. Two-dimensional (2D) similarity for each test compound was compared to the target molecule of the immunoassay undergoing analysis. Results 2D similarity differentiated between cross-reactive and non-cross-reactive compounds for immunoassays targeting mephedrone/methcathinone, 3,4-methylenedioxypyrovalerone, benzylpiperazine, mephentermine, and synthetic cannabinoids. Conclusions In this study, we applied 2D molecular similarity analysis to the designer amphetamine-type stimulants and synthetic cannabinoids. Similarity calculations can be used to more efficiently decide which drugs and metabolites should be tested in cross-reactivity studies, as well as to design experiments and potentially predict antigens that would lead to immunoassays with cross reactivity for a broader array of designer drugs. PMID:24851137

Changing effects of direct-to-consumer broadcast drug advertising information sources on prescription drug requests.

PubMed

Lee, Annisa Lai

2009-06-01

This study tracks the changes of the effects of 4 information sources for direct-to-consumer drug advertising on patients' requests for prescription drugs from physicians since the inception of the "Guidance for Industry about Consumer-directed Broadcast Advertisements." The Guidance advises pharmaceuticals to use four information sources for consumers to seek further information to supplement broadcast drug advertisements: small-print information, the Internet, a toll-free number, and health-care providers (nurses, doctors, and pharmacists). Logistic models were created by using survey data collected by the Food and Drug Administration in 1999 and 2002. Results show that throughout the years, health-care providers remain the most used and strongest means associated with patients' direct requests for nonspecific and specific prescription drugs from doctors. The small-print information source gains power and changes from an indirect means associated with patients' discussing drugs with health-care providers to a direct means associated with patients' asking about nonspecific and specific drugs from their doctors. The Internet is not directly related to drug requests, but the effect of its association with patients seeking information from health-care providers grew 11-fold over the course of the study. The toll-free number lost its power altogether for both direct request for a prescription drug and further discussion with health-care providers. Patient demographics will be considered for specific policy implications.

Effect of intravenous drug administration mode on drug distribution in a tumor slab: a finite Fourier transform analysis.

PubMed

Subramaniam, B; Claudius, J S

1990-03-08

Cancer therapy using chemotherapeutic drugs frequently involves injection of the drug into the body through some intravenous mode of administration, viz, continuous (drip) infusion or single/multiple bolus injection(s). An understanding of the effect of the various modes of administration upon tumor penetration of drug is essential to rational design of drug therapy. This paper investigates drug penetration into a model tumor of slab geometry (between two capillaries) in which the overall transport rate of drug is limited by intra-tumor transport characterized by an effective diffusion coefficient. Employing the method of Finite Fourier Transforms (FFT), analytical solutions have been obtained for transient drug distribution in both the plasma and the tumor following three modes of administration, viz, continuous infusion, single bolus injection and equally-spaced equal-dose multiple bolus injections, of a given amount of drug. The qualitative trends exhibited by the plasma drug distribution profiles are consistent with reported experimental studies. Two concepts, viz, the dimensionless decay constant and the plasma/tumor drug concentration trajectories, are found to be particularly useful in the rational design of drug therapy. The dimensionless decay constant provides a measure of the rate of drug decay in the plasma relative to the rate of drug diffusion into the tumor and is thus characteristic of the tumor/drug system. The magnitude of this parameter dictates the choice of drug administration mode for minimizing drug decay in the plasma while simultaneously maximizing drug transport into the tumor. The concentration trajectories provide a measure of the plasma drug concentration relative to the tumor drug concentration at various times following injection. When the tumor drug concentration exceeds the plasma drug concentration, the drug will begin to diffuse out of the tumor. Knowledge of the time at which this diffusion reversal occurs is especially useful for optimum scheduling of subsequent bolus injections in a multiple bolus dosing regimen. There are no reported applications of the FFT method to solve repeated input functions in either the chemical engineering or pharmaceutical science literature. Thus, the application of FFT method to solve multiple bolus injections is a unique one. Use of this FFT based analysis as a predictor tool can limit the number of costly experiments which are being done now to achieve this purpose. Even though the model in its present form is simplified, the analysis thereof has nevertheless led to a better understanding of the various factors that must be taken into account for rational design of drug therapy.

Alterations in taste perception due to recreational drug use are due to smoking a substance rather than ingesting it.

PubMed

Dovey, Terence M; Boyland, Emma J; Trayner, Penelope; Miller, Jo; Rarmoul-Bouhadjar, Amin; Cole, Jon; Halford, Jason C G

2016-12-01

Two studies explored the differences in tastant (salt, sour, bitter, sweet and spicy) concentration preference between recreational drug users and abstainers. In study 1, 250 opportunistically recruited abstainers, cannabis only users and multiple-drug users completed psychometric questionnaires and a concentration preference tastant test. In study 2, 76 participants purposefully recruited abstainers, daily tobacco users, recreational cannabis users and daily cannabis users completed the same protocol as study 1. Study 1 demonstrated that both multiple drug users and cannabis users had a higher preference for salt and sour tastants than abstainers. Study 2 showed that daily cannabis and tobacco users had a higher preference for sweet and spicy tastants than recreational cannabis users and abstainers. As predicted, recreational drug users scored higher on both sensation-seeking and impulsivity compared to abstainers. Participants who habitually smoke tobacco or cannabis daily have different concentration preference for specific tastants. The aim of the current study was to provide an explanation for the inconsistency in published results on taste preferences in recreational drug users. The data offered in this paper indicate that variation in recruitment strategy, definition of 'drug users', and mode of drug delivery, as well as multiple drug use, may explain the preference for stronger tastants in habitual drug users. Future research exploring the psychobiological underpinnings of the impact of drug use on food preferences should carefully define recreational drug user groups. Copyright © 2016 Elsevier Ltd. All rights reserved.

[The relevance of multiple sclerosis drugs in private health insurance (PHI)].

PubMed

Wild, F

2015-06-01

The development of expenses and prescriptions in the pharmacotherapy for multiple sclerosis (MS) is examined on the basis of prescription data of 14 PHI firms. The drugs for the treatment of MS are among the most top-selling drugs in the PHI. From 2007 to 2012, the expenses increase 2.33-fold. The main cause is the increas of the prescription figures. In 2012, about 8,400 privately insured persons receive an MS drug. The prevalence of MS is 2.3 times higher in women than in men Impro ved diagnostic possibilities and expensive new drugs will lead to a dynamic cost de velopment in the next years.

Open Drug Discovery Toolkit (ODDT): a new open-source player in the drug discovery field.

PubMed

Wójcikowski, Maciej; Zielenkiewicz, Piotr; Siedlecki, Pawel

2015-01-01

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

Lipid-associated Oral Delivery: Mechanisms and Analysis of Oral Absorption Enhancement

PubMed Central

Rezhdo, Oljora; Speciner, Lauren; Carrier, Rebecca L.

2016-01-01

The majority of newly discovered oral drugs are poorly water soluble, and co-administration with lipids has proven effective in significantly enhancing bioavailability of some compounds with low aqueous solubility. Yet, lipid-based delivery technologies have not been widely employed in commercial oral products. Lipids can impact drug transport and fate in the gastrointestinal (GI) tract through multiple mechanisms including enhancement of solubility and dissolution kinetics, enhancement of permeation through the intestinal mucosa, and triggering drug precipitation upon lipid emulsion depletion (e.g., by digestion). The effect of lipids on drug absorption is currently not quantitatively predictable, in part due to the multiple complex dynamic processes that can be impacted by lipids. Quantitative mechanistic analysis of the processes significant to lipid system function and overall impact on drug absorption can aid understanding of drug-lipid interactions in the GI tract and exploitation of such interactions to achieve optimal lipid-based drug delivery. In this review, we discuss the impact of co-delivered lipids and lipid digestion on drug dissolution, partitioning, and absorption in the context of the experimental tools and associated kinetic expressions used to study and model these processes. The potential benefit of a systems-based consideration of the concurrent multiple dynamic processes occurring upon co-dosing lipids and drugs to predict the impact of lipids on drug absorption and enable rational design of lipid-based delivery systems is presented. PMID:27520734

Childhood Trauma and Illicit Drug Use in Adolescence: A Population-Based National Comorbidity Survey Replication–Adolescent Supplement Study

PubMed Central

Carliner, Hannah; Keyes, Katherine M.; McLaughlin, Katie A.; Meyers, Jacquelyn L.; Dunn, Erin C.; Martins, Silvia S.

2016-01-01

Objective Although potentially traumatic events (PTEs) are established risk factors for substance use disorders among adults, little is known about associations with drug use during adolescence, an important developmental stage for drug use prevention. We examined whether childhood PTEs were associated with illicit drug use among a representative sample of US adolescents. Method Data were drawn from the National Comorbidity Survey Replication–Adolescent Supplement (NCS-A), which included adolescents aged 13-18 years (N=9,956). Weighted logistic regression models estimated risk ratios for lifetime use of marijuana, cocaine, nonmedical prescription drugs, other drugs, and multiple drugs. Results Exposure to any PTE prior to age 11 was reported by 36% of the sample and was associated with higher risk for use of marijuana (risk ratio [RR] = 1.50), cocaine (RR = 2.78), prescription drugs (RR=1.80), other drugs (RR=1.90), and multiple drugs (RR=1.74). A positive monotonic relationship was observed between number of PTEs and marijuana, other drug, and multiple drug use. Interpersonal violence was associated with all drug use outcomes. Accidents and unspecified events were associated with higher risk for marijuana, cocaine, and prescription drug use. Conclusion Potentially traumatic events in childhood are associated with risk for illicit drug use among US adolescents. These findings add to the literature by illustrating a potentially modifiable health behavior that may be a target for intervention; and that adolescents with a trauma history are a high-risk group for illicit drug use and may benefit from trauma-focused prevention efforts that specifically address traumatic memories and coping strategies for dealing with stressful life events. PMID:27453084

Childhood Trauma and Illicit Drug Use in Adolescence: A Population-Based National Comorbidity Survey Replication-Adolescent Supplement Study.

PubMed

Carliner, Hannah; Keyes, Katherine M; McLaughlin, Katie A; Meyers, Jacquelyn L; Dunn, Erin C; Martins, Silvia S

2016-08-01

Although potentially traumatic events (PTEs) are established risk factors for substance use disorders among adults, little is known about associations with drug use during adolescence, an important developmental stage for drug use prevention. We examined whether childhood PTEs were associated with illicit drug use among a representative sample of US adolescents. Data were drawn from the National Comorbidity Survey Replication-Adolescent Supplement (NCS-A), which included adolescents aged 13 to 18 years (N = 9,956). Weighted logistic regression models estimated risk ratios for lifetime use of marijuana, cocaine, nonmedical prescription drugs, other drugs, and multiple drugs. Exposure to any PTE before age 11 years was reported by 36% of the sample and was associated with higher risk for use of marijuana (risk ratio [RR] = 1.50), cocaine (RR = 2.78), prescription drugs (RR = 1.80), other drugs (RR = 1.90), and multiple drugs (RR = 1.74). A positive monotonic relationship was observed between number of PTEs and marijuana, other drug, and multiple drug use. Interpersonal violence was associated with all drug use outcomes. Accidents and unspecified events were associated with higher risk for marijuana, cocaine, and prescription drug use. Potentially traumatic events in childhood are associated with risk for illicit drug use among US adolescents. These findings add to the literature by illustrating a potentially modifiable health behavior that may be a target for intervention. The results also highlight that adolescents with a trauma history are a high-risk group for illicit drug use and may benefit from trauma-focused prevention efforts that specifically address traumatic memories and coping strategies for dealing with stressful life events. Copyright © 2016 American Academy of Child and Adolescent Psychiatry. Published by Elsevier Inc. All rights reserved.

The Hospital-Based Drug Information Center.

ERIC Educational Resources Information Center

Hopkins, Leigh

1982-01-01

Discusses the rise of drug information centers in hospitals and medical centers, highlighting staffing, functions, typical categories of questions received by centers, and sources used. An appendix of drug information sources included in texts, updated services, journals, and computer databases is provided. Thirteen references are listed. (EJS)

21 CFR 892.5730 - Radionuclide brachytherapy source.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Radionuclide brachytherapy source. 892.5730 Section 892.5730 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES RADIOLOGY DEVICES Therapeutic Devices § 892.5730 Radionuclide brachytherapy...

L-asparaginase as a critical component to combat Acute Lymphoblastic Leukaemia (ALL): A novel approach to target ALL.

PubMed

Ali, Usman; Naveed, Muhammad; Ullah, Abid; Ali, Khadija; Shah, Sayed Afzal; Fahad, Shah; Mumtaz, Abdul Samad

2016-01-15

L-asparaginase, an anti-leukaemic drug that has been approved for clinical use for many years in the treatment of childhood Acute Lymphoblastic Leukaemia (ALL), is obtained from bacterial origin (Escherichia coli and Erwinia carotovora). The efficacy of L-asparaginase has been discussed for the past 40 years, and an ideal substitute for the enzyme has not yet been developed. The early clearance from plasma (short half-life) and requirement for multiple administrations and hence frequent physician visits make the overall treatment cost quite high. In addition, a high rate of allergic reactions in patients receiving treatment with the enzyme isolated from bacterial sources make its clinical application challenging. For these reasons, various attempts are being made to overcome these barriers. Therefore, the present article reviews studies focused on seeking substitutes for L-asparaginase through alternative sources including bacteria, fungi, actinomycetes, algae and plants to overcome these limitations. In addition, the role of chemical modifications and protein engineering approaches to enhance the drug's efficacy are also discussed. Moreover, an overview has also been provided in the current review regarding the contradiction among various researchers regarding the significance of the enzyme's glutaminase activity. Copyright © 2015 Elsevier B.V. All rights reserved.

A Low Cost/Low Power Open Source Sensor System for Automated Tuberculosis Drug Susceptibility Testing

PubMed Central

Kim, Kyukwang; Kim, Hyeong Keun; Lim, Hwijoon; Myung, Hyun

2016-01-01

In this research an open source, low power sensor node was developed to check the growth of mycobacteria in a culture bottle with a nitrate reductase assay method for a drug susceptibility test. The sensor system reports the temperature and color sensor output frequency change of the culture bottle when the device is triggered. After the culture process is finished, a nitrite ion detecting solution based on a commercial nitrite ion detection kit is injected into the culture bottle by a syringe pump to check bacterial growth by the formation of a pigment by the reaction between the solution and the color sensor. Sensor status and NRA results are broadcasted via a Bluetooth low energy beacon. An Android application was developed to collect the broadcasted data, classify the status of cultured samples from multiple devices, and visualize the data for the end users, circumventing the need to examine each culture bottle manually during a long culture period. The authors expect that usage of the developed sensor will decrease the cost and required labor for handling large amounts of patient samples in local health centers in developing countries. All 3D-printerable hardware parts, a circuit diagram, and software are available online. PMID:27338406

Recommendations for Optimizing Tuberculosis Treatment: Therapeutic Drug Monitoring, Pharmacogenetics, and Nutritional Status Considerations

PubMed Central

Choi, Rihwa; Jeong, Byeong-Ho

2017-01-01

Although tuberculosis is largely a curable disease, it remains a major cause of morbidity and mortality worldwide. Although the standard 6-month treatment regimen is highly effective for drug-susceptible tuberculosis, the use of multiple drugs over long periods of time can cause frequent adverse drug reactions. In addition, some patients with drug-susceptible tuberculosis do not respond adequately to treatment and develop treatment failure and drug resistance. Response to tuberculosis treatment could be affected by multiple factors associated with the host-pathogen interaction including genetic factors and the nutritional status of the host. These factors should be considered for effective tuberculosis control. Therefore, therapeutic drug monitoring (TDM), which is individualized drug dosing guided by serum drug concentrations during treatment, and pharmacogenetics-based personalized dosing guidelines of anti-tuberculosis drugs could reduce the incidence of adverse drug reactions and increase the likelihood of successful treatment outcomes. Moreover, assessment and management of comorbid conditions including nutritional status could improve anti-tuberculosis treatment response. PMID:28028995

Recommendations for Optimizing Tuberculosis Treatment: Therapeutic Drug Monitoring, Pharmacogenetics, and Nutritional Status Considerations.

PubMed

Choi, Rihwa; Jeong, Byeong Ho; Koh, Won Jung; Lee, Soo Youn

2017-03-01

Although tuberculosis is largely a curable disease, it remains a major cause of morbidity and mortality worldwide. Although the standard 6-month treatment regimen is highly effective for drug-susceptible tuberculosis, the use of multiple drugs over long periods of time can cause frequent adverse drug reactions. In addition, some patients with drug-susceptible tuberculosis do not respond adequately to treatment and develop treatment failure and drug resistance. Response to tuberculosis treatment could be affected by multiple factors associated with the host-pathogen interaction including genetic factors and the nutritional status of the host. These factors should be considered for effective tuberculosis control. Therefore, therapeutic drug monitoring (TDM), which is individualized drug dosing guided by serum drug concentrations during treatment, and pharmacogenetics-based personalized dosing guidelines of anti-tuberculosis drugs could reduce the incidence of adverse drug reactions and increase the likelihood of successful treatment outcomes. Moreover, assessment and management of comorbid conditions including nutritional status could improve anti-tuberculosis treatment response.

Advancing drug delivery systems for the treatment of multiple sclerosis.

PubMed

Tabansky, Inna; Messina, Mark D; Bangeranye, Catherine; Goldstein, Jeffrey; Blitz-Shabbir, Karen M; Machado, Suly; Jeganathan, Venkatesh; Wright, Paul; Najjar, Souhel; Cao, Yonghao; Sands, Warren; Keskin, Derin B; Stern, Joel N H

2015-12-01

Multiple sclerosis (MS) is a chronic inflammatory autoimmune disease of the central nervous system. It is characterized by demyelination of neurons and loss of neuronal axons and oligodendrocytes. In MS, auto-reactive T cells and B cells cross the blood-brain barrier (BBB), causing perivenous demyelinating lesions that form multiple discrete inflammatory demyelinated plaques located primarily in the white matter. In chronic MS, cortical demyelination and progressive axonal transections develop. Treatment for MS can be stratified into disease-modifying therapies (DMTs) and symptomatic therapy. DMTs aim to decrease circulating immune cells or to prevent these cells from crossing the BBB and reduce the inflammatory response. There are currently 10 DMTs approved for the relapsing forms of MS; these vary with regard to their efficacy, route and frequency of administration, adverse effects, and toxicity profile. Better drug delivery systems are being developed in order to decrease adverse effects, increase drug efficacy, and increase patient compliance through the direct targeting of pathologic cells. Here, we address the uses and benefits of advanced drug delivery systems, including nanoparticles, microparticles, fusion antibodies, and liposomal formulations. By altering the properties of therapeutic particles and enhancing targeting, breakthrough drug delivery technologies potentially applicable to multiple disease treatments may rapidly emerge.

Pricing of multiple dosage prescription medications: an analysis of the Ontario Drug Benefit Formulary.

PubMed

Lexchin, Joel

2009-07-01

This paper investigates the pricing strategy (perfect flat pricing, perfect monotonic pricing, intermediate) used for multiple dosage medications listed in the Ontario Drug Benefit Formulary. All multiple dosage solid medications containing a single active ingredient newly listed in the Ontario Drug Benefit Formulary between 1996 and 2005 were identified. The relationship between price and dosage was calculated using a previously developed method. Seventy-three multiple dosage medications were introduced. Where medications were equivalent to existing ones in most cases companies followed the pricing strategy used by therapeutically equivalent drugs already in the formulary. Where there were no equivalent products companies did not adopt any particular pricing strategy. There was no difference in the way that companies priced scored tablets versus unscored tablets and capsules or in the way that they priced drugs that had objective measurements of efficacy/effectiveness, for example blood pressure, versus those that did not have these measurements. When Monotonic pricing is used it leads to higher expenditures whereas flat pricing results in lower expenditures and offers more predictability in expenditures. Provincial governments should consider requiring flat pricing in return for formulary listing.

21 CFR 866.5660 - Multiple autoantibodies immunological test system.

Code of Federal Regulations, 2011 CFR

2011-04-01

.... 866.5660 Section 866.5660 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN... the autoantibodies (antibodies produced against the body's own tissues) in serum and other body fluids. Measurement of multiple autoantibodies aids in the diagnosis of autoimmune disorders (disease produced when...

21 CFR 866.5660 - Multiple autoantibodies immunological test system.

Code of Federal Regulations, 2014 CFR

2014-04-01

.... 866.5660 Section 866.5660 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN... the autoantibodies (antibodies produced against the body's own tissues) in serum and other body fluids. Measurement of multiple autoantibodies aids in the diagnosis of autoimmune disorders (disease produced when...

21 CFR 866.5660 - Multiple autoantibodies immunological test system.

Code of Federal Regulations, 2013 CFR

2013-04-01

.... 866.5660 Section 866.5660 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN... the autoantibodies (antibodies produced against the body's own tissues) in serum and other body fluids. Measurement of multiple autoantibodies aids in the diagnosis of autoimmune disorders (disease produced when...

21 CFR 866.5660 - Multiple autoantibodies immunological test system.

Code of Federal Regulations, 2012 CFR

2012-04-01

.... 866.5660 Section 866.5660 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN... the autoantibodies (antibodies produced against the body's own tissues) in serum and other body fluids. Measurement of multiple autoantibodies aids in the diagnosis of autoimmune disorders (disease produced when...

Multiple Drug-Use Patterns Among a Group of High School Students: Regular Users vs. Nonusers of Specific Drug Types

ERIC Educational Resources Information Center

Seffrin, John R.; Seehafer, Roger W.

1976-01-01

Although no cause-effect relationship can be shown, regular drug use seems to predispose one to further drug experimentation and use, while non-use of a particular drug seems to predispose one to non-use of other drugs. (Author/MB)

Analysis of reference sources used in drug-related Wikipedia articles.

PubMed

Koppen, Laura; Phillips, Jennifer; Papageorgiou, Renee

2015-07-01

References from drug-related Wikipedia articles and a drug information database were compared. Drugs in Food and Drug Administration (FDA) MedWatch alerts from January-July 2013 were searched in Wikipedia and Lexicomp to compare reference types and to assess the time for drug safety information to be incorporated into Wikipedia articles. Wikipedia most commonly cited peer-reviewed journal articles (49.2%) and news articles (12.0%). MedWatch citations were incorporated into Wikipedia on average in 5.9 days. Wikipedia cited various sources but may not be a reliable, up-to-date resource for drug safety information.

Types and quantities of leftover drugs entering the environment via disposal to sewage--revealed by coroner records.

PubMed

Ruhoy, Ilene Sue; Daughton, Christian G

2007-12-15

Pharmaceuticals designed for humans and animals often remain unused for a variety of reasons, ranging from expiration to a patient's non-compliance. These leftover, accumulated drugs represent sub-optimal delivery of health care and the potential for environmentally unsound disposal, which can pose exposure risks for humans and wildlife. A major unknown with respect to drugs as pollutants is what fractions of drug residues occurring in the ambient environment result from discarding leftover drugs. To gauge the significance of leftover drugs as potential pollutants, data are needed on the types, quantities, and frequencies with which drugs accumulate. Absence of this data has prevented assessments of the significance of drug accumulation and disposal as a contributing source of drug residues in the environment. One particular source of drug accumulation is those drugs that become "orphaned" by the death of a consumer. A new approach to acquiring the data needed to assess the magnitude and extent of drug disposal as a source of environmental pollution is presented by using the inventories of drugs maintained by coroner offices. The data from one metropolitan coroner's office demonstrates proof of concept. Coroner data on leftover drugs are useful for measuring the types and amounts of drugs accumulated by consumers. This inventory also provides an accurate measure of the individual active ingredients actually disposed into sewage by coroners. The types of questions these data can address are presented, and the possible uses of these data for deriving estimates of source contributions from the population at large are discussed. The approach is proposed for nationwide implementation (and automation) to better understand the significance of consumer disposal of medications.

Prevalence of Potential and Clinically Relevant Statin-Drug Interactions in Frail and Robust Older Inpatients.

PubMed

Thai, Michele; Hilmer, Sarah; Pearson, Sallie-Anne; Reeve, Emily; Gnjidic, Danijela

2015-10-01

A significant proportion of older people are prescribed statins and are also exposed to polypharmacy, placing them at increased risk of statin-drug interactions. To describe the prevalence rates of potential and clinically relevant statin-drug interactions in older inpatients according to frailty status. A cross-sectional study of patients aged ≥65 years who were prescribed a statin and were admitted to a teaching hospital between 30 July and 10 October 2014 in Sydney, Australia, was conducted. Data on socio-demographics, comorbidities and medications were collected using a standardized questionnaire. Potential statin-drug interactions were defined if listed in the Australian Medicines Handbook and three international drug information sources: the British National Formulary, Drug Interaction Facts and Drug-Reax(®). Clinically relevant statin-drug interactions were defined as interactions with the highest severity rating in at least two of the three international drug information sources. Frailty was assessed using the Reported Edmonton Frail Scale. A total of 180 participants were recruited (median age 78 years, interquartile range 14), 35.0% frail and 65.0% robust. Potential statin-drug interactions were identified in 10% of participants, 12.7% of frail participants and 8.5% of robust participants. Clinically relevant statin-drug interactions were identified in 7.8% of participants, 9.5% of frail participants and 6.8% of robust participants. Depending on the drug information source used, the prevalence rates of potential and clinically relevant statin-drug interactions ranged between 14.4 and 35.6% and between 14.4 and 20.6%, respectively. In our study of frail and robust older inpatients taking statins, the overall prevalence of potential statin-drug interactions was low and varied significantly according to the drug information source used.

Risk of fetal death associated with maternal drug dependence and placental abruption: a population-based study.

PubMed

McDonald, Sarah D; Vermeulen, Marian J; Ray, Joel G

2007-07-01

Substance use in pregnancy is associated with placental abruption, but the risk of fetal death independent of abruption remains undetermined. Our objective was to examine the effect of maternal drug dependence on placental abruption and on fetal death in association with abruption and independent of it. To examine placental abruption and fetal death, we performed a retrospective population-based study of 1 854 463 consecutive deliveries of liveborn and stillborn infants occurring between January 1, 1995 and March 31, 2001, using the Canadian Institute for Health Information Discharge Abstract Database. Maternal drug dependence was associated with a tripling of the risk of placental abruption in singleton pregnancies (adjusted odds ratio [OR] 3.1; 95% confidence intervals [CI] 2.6-3.7), but not in multiple gestations (adjusted OR 0.88; 95% CI 0.12-6.4). Maternal drug dependence was associated with an increased risk of fetal death independent of abruption (adjusted OR 1.6: 95% CI 1.1-2.2) in singleton pregnancies, but not in multiples. Risk of fetal death was increased with placental abruption in both singleton and multiple gestations, even after controlling for drug dependence (adjusted OR 11.4 in singleton pregnancy; 95% CI 10.6-12.2, and 3.4 in multiple pregnancy; 95% CI 2.4-4.9). Maternal drug use is associated with an increased risk of intrauterine fetal death independent of placental abruption. In singleton pregnancies, maternal drug dependence is associated with an increased risk of placental abruption.

Circumvention of Mcl-1-dependent drug resistance by simultaneous Chk1 and MEK1/2 inhibition in human multiple myeloma cells.

PubMed

Pei, Xin-Yan; Dai, Yun; Felthousen, Jessica; Chen, Shuang; Takabatake, Yukie; Zhou, Liang; Youssefian, Leena E; Sanderson, Michael W; Bodie, Wesley W; Kramer, Lora B; Orlowski, Robert Z; Grant, Steven

2014-01-01

The anti-apoptotic protein Mcl-1 plays a major role in multiple myeloma (MM) cell survival as well as bortezomib- and microenvironmental forms of drug resistance in this disease. Consequently, there is a critical need for strategies capable of targeting Mcl-1-dependent drug resistance in MM. The present results indicate that a regimen combining Chk1 with MEK1/2 inhibitors effectively kills cells displaying multiple forms of drug resistance stemming from Mcl-1 up-regulation in association with direct transcriptional Mcl-1 down-regulation and indirect disabling of Mcl-1 anti-apoptotic function through Bim up-regulation and increased Bim/Mcl-1 binding. These actions release Bak from Mcl-1, accompanied by Bak/Bax activation. Analogous events were observed in both drug-naïve and acquired bortezomib-resistant MM cells displaying increased Mcl-1 but diminished Bim expression, or cells ectopically expressing Mcl-1. Moreover, concomitant Chk1 and MEK1/2 inhibition blocked Mcl-1 up-regulation induced by IL-6/IGF-1 or co-culture with stromal cells, effectively overcoming microenvironment-related drug resistance. Finally, this regimen down-regulated Mcl-1 and robustly killed primary CD138+ MM cells, but not normal hematopoietic cells. Together, these findings provide novel evidence that this targeted combination strategy could be effective in the setting of multiple forms of Mcl-1-related drug resistance in MM.

Circumvention of Mcl-1-Dependent Drug Resistance by Simultaneous Chk1 and MEK1/2 Inhibition in Human Multiple Myeloma Cells

PubMed Central

Pei, Xin-Yan; Dai, Yun; Felthousen, Jessica; Chen, Shuang; Takabatake, Yukie; Zhou, Liang; Youssefian, Leena E.; Sanderson, Michael W.; Bodie, Wesley W.; Kramer, Lora B.; Orlowski, Robert Z.; Grant, Steven

2014-01-01

The anti-apoptotic protein Mcl-1 plays a major role in multiple myeloma (MM) cell survival as well as bortezomib- and microenvironmental forms of drug resistance in this disease. Consequently, there is a critical need for strategies capable of targeting Mcl-1-dependent drug resistance in MM. The present results indicate that a regimen combining Chk1 with MEK1/2 inhibitors effectively kills cells displaying multiple forms of drug resistance stemming from Mcl-1 up-regulation in association with direct transcriptional Mcl-1 down-regulation and indirect disabling of Mcl-1 anti-apoptotic function through Bim up-regulation and increased Bim/Mcl-1 binding. These actions release Bak from Mcl-1, accompanied by Bak/Bax activation. Analogous events were observed in both drug-naïve and acquired bortezomib-resistant MM cells displaying increased Mcl-1 but diminished Bim expression, or cells ectopically expressing Mcl-1. Moreover, concomitant Chk1 and MEK1/2 inhibition blocked Mcl-1 up-regulation induced by IL-6/IGF-1 or co-culture with stromal cells, effectively overcoming microenvironment-related drug resistance. Finally, this regimen down-regulated Mcl-1 and robustly killed primary CD138+ MM cells, but not normal hematopoietic cells. Together, these findings provide novel evidence that this targeted combination strategy could be effective in the setting of multiple forms of Mcl-1-related drug resistance in MM. PMID:24594907

Child abuse, drug addiction and mental health problems of incarcerated women in Israel.

PubMed

Chen, Gila; Gueta, Keren

2015-01-01

The mental health problems and pathways to drug addiction and crime among female inmates have long been of interest to researchers and practitioners. The purpose of the current study was to examine the possible association between multiple types of childhood abuse, mental health problems, and drug addiction and the incarceration of 50 Israeli women in prison. The findings indicated that female inmates come from risky families with a high prevalence of family mental health problems, parental drug addiction and crime, and sibling drug addiction and crime. Furthermore, they revealed that incarcerated women from risky families were victims of multiple types of childhood abuse and neglect by their parents, as well as their siblings. Overall, the results suggest that the adverse consequences of a family's mental health problems are much more dramatic than we assumed to date, and that women are more likely than men to be the victims of multiple types of childhood abuse and neglect, as well as suffering more severe psychiatric problems, depression, and drug addiction. The implications of these findings are discussed. Copyright © 2015 Elsevier Ltd. All rights reserved.

QuantWorm: a comprehensive software package for Caenorhabditis elegans phenotypic assays.

PubMed

Jung, Sang-Kyu; Aleman-Meza, Boanerges; Riepe, Celeste; Zhong, Weiwei

2014-01-01

Phenotypic assays are crucial in genetics; however, traditional methods that rely on human observation are unsuitable for quantitative, large-scale experiments. Furthermore, there is an increasing need for comprehensive analyses of multiple phenotypes to provide multidimensional information. Here we developed an automated, high-throughput computer imaging system for quantifying multiple Caenorhabditis elegans phenotypes. Our imaging system is composed of a microscope equipped with a digital camera and a motorized stage connected to a computer running the QuantWorm software package. Currently, the software package contains one data acquisition module and four image analysis programs: WormLifespan, WormLocomotion, WormLength, and WormEgg. The data acquisition module collects images and videos. The WormLifespan software counts the number of moving worms by using two time-lapse images; the WormLocomotion software computes the velocity of moving worms; the WormLength software measures worm body size; and the WormEgg software counts the number of eggs. To evaluate the performance of our software, we compared the results of our software with manual measurements. We then demonstrated the application of the QuantWorm software in a drug assay and a genetic assay. Overall, the QuantWorm software provided accurate measurements at a high speed. Software source code, executable programs, and sample images are available at www.quantworm.org. Our software package has several advantages over current imaging systems for C. elegans. It is an all-in-one package for quantifying multiple phenotypes. The QuantWorm software is written in Java and its source code is freely available, so it does not require use of commercial software or libraries. It can be run on multiple platforms and easily customized to cope with new methods and requirements.

Drug Safety: Managing Multiple Drugs

MedlinePlus

... you take the right pill at the right time. Resources To learn more about your drugs, visit: • www.ConsumerReportsHealth.org/BestBuyDrugs • www.medlineplus.gov This series is produced by Consumers Union and Consumer Reports ...

46 CFR 111.10-5 - Multiple energy sources.

Code of Federal Regulations, 2010 CFR

2010-10-01

... 46 Shipping 4 2010-10-01 2010-10-01 false Multiple energy sources. 111.10-5 Section 111.10-5...-GENERAL REQUIREMENTS Power Supply § 111.10-5 Multiple energy sources. Failure of any single generating set energy source such as a boiler, diesel, gas turbine, or steam turbine must not cause all generating sets...

46 CFR 111.10-5 - Multiple energy sources.

Code of Federal Regulations, 2011 CFR

2011-10-01

... 46 Shipping 4 2011-10-01 2011-10-01 false Multiple energy sources. 111.10-5 Section 111.10-5...-GENERAL REQUIREMENTS Power Supply § 111.10-5 Multiple energy sources. Failure of any single generating set energy source such as a boiler, diesel, gas turbine, or steam turbine must not cause all generating sets...

46 CFR 111.10-5 - Multiple energy sources.

Code of Federal Regulations, 2013 CFR

2013-10-01

... 46 Shipping 4 2013-10-01 2013-10-01 false Multiple energy sources. 111.10-5 Section 111.10-5...-GENERAL REQUIREMENTS Power Supply § 111.10-5 Multiple energy sources. Failure of any single generating set energy source such as a boiler, diesel, gas turbine, or steam turbine must not cause all generating sets...

46 CFR 111.10-5 - Multiple energy sources.

Code of Federal Regulations, 2014 CFR

2014-10-01

... 46 Shipping 4 2014-10-01 2014-10-01 false Multiple energy sources. 111.10-5 Section 111.10-5...-GENERAL REQUIREMENTS Power Supply § 111.10-5 Multiple energy sources. Failure of any single generating set energy source such as a boiler, diesel, gas turbine, or steam turbine must not cause all generating sets...

46 CFR 111.10-5 - Multiple energy sources.

Code of Federal Regulations, 2012 CFR

2012-10-01

... 46 Shipping 4 2012-10-01 2012-10-01 false Multiple energy sources. 111.10-5 Section 111.10-5...-GENERAL REQUIREMENTS Power Supply § 111.10-5 Multiple energy sources. Failure of any single generating set energy source such as a boiler, diesel, gas turbine, or steam turbine must not cause all generating sets...

A rapid situation assessment of drug use in Papua New Guinea.

PubMed

McDonald, David

2005-01-01

Papua New Guinea (PNG) is an Asia Pacific country that we hear little about in the drug and alcohol area. Recently at the APEC meeting in Chile, the Australian Prime Minister, Mr John Howard, announced that PNG would be one of the countries of focus with regards to public health programs and HIV AIDS assistance by Australia in the future. This is a timely report of a rapid situation assessment (RSA) of drug use and drug-related harm in Papua New Guinea (PNG) conducted in 1998-1999, with comments on developments since that time. The author of this paper, David McDonald, was appointed as the international consultant to work with the PNG National Narcotics Bureau to undertake an assessment of drug use in PNG, and is well-equipped to report on the drug and alcohol situation in that country. The rapid assessment study was conducted to provide up-to-date, factual information about drugs in PNG that could contribute to the development of a national drug strategy for PNG. The focus was on illegal drugs in accordance with the mandates of the auspicing bodies--namely cannabis and home-brewed alcohol. In keeping with the methodology for rapid assessment, the author utilised multiple information sources including published literature, administrative by-product data, case studies, a key informants' study and structured interviews with drug users. It was found that alcohol--both licit and home brew, as well as high potency cannabis, were the major substance problems in PNG. This paper, based on a more detailed report available through the author, provides a snap-shot of substance use problems in PNG. However, the author reports that problems in public sector management within and external to the sponsoring agency, the National Narcotics Bureau, have meant that the proposed national drug control strategy has not yet been developed.

Context and characteristics of illicit drug use in coastal and interior Tanzania.

PubMed

Tiberio, Jenny; Laurent, Yovin Ivo; Ndayongeje, Joel; Msami, Amani; Welty, Susie; Ngonyani, Alois; Mwankemwa, Syangu; Makumbuli, Moza; McFarland, Willi; Morris, Meghan D

2018-01-01

An increase in heroin seizures in East Africa may signal wider local consumption of illicit drugs. Most information about drug use in Tanzania is from the economic capital, Dar es Salaam, and well-travelled Zanzibar. More data are needed on the extent, trends, and characteristics of illicit drug use in the vast coast and interior of the country. The study was a rapid assessment, triangulating data from in-depth interviews of primary key informants (people who use drugs [PWUD]), secondary informants (police, community members, service providers), and ethnographic mapping of hotspots in 12 regions of Tanzania. We conducted 436 in-depth interviews from September 2013 to August 2014. Regions were categorized as (1) nascent: drug use is beginning to take root; (2) established: drug use has existed for some time; or (3) pervasive: drug use is spreading into new sub-groups/areas. Multiple sources corroborated that illicit drug use has been increasing in all regions. Most PWUD worked in the cash economy as bus touts, labourers, fishermen, miners, or sex workers, or stole to survive or support their habit. PWUD congregated around bus stops along transit corridors, in abandoned buildings, and in low-income residential areas. Informants described less visible PWUD among military, police, and working-class people. Cannabis was the most common, smoked alone or with tobacco and heroin ("cocktail"). Heroin was available in all regions. Cocaine was less common, likely due to high price and variable availability. Substances such as petrol, shoe polish, and glue were used as inhalants. Illicit drug use is widespread with variable features beyond cosmopolitan areas of Tanzania. Improving transportation infrastructure and economic opportunities combined with poverty and inequality appear key factors for increasing use. Findings call attention to increasing and widening drug use in Tanzania and the need to plan prevention, treatment, and harm-reduction measures nationally. Copyright © 2017 Elsevier B.V. All rights reserved.

Infections in patients with multiple sclerosis: Implications for disease-modifying therapy.

PubMed

Celius, E G

2017-11-01

Patients with multiple sclerosis have an increased risk of infections compared to the general population. The increased risk has been described for decades and is not alone attributed to the use of disease-modifying drugs, but secondary to the disability. The introduction of more potent immunomodulatory drugs may cause an additional challenge, and depending on the mechanism of action, a treatment-induced increased risk of bacterial, viral, fungal or parasitic infections is observed. The choice of treatment in the individual patient with infections and multiple sclerosis must be guided by the drugs' specific mechanism of action, the drug-specific risk of infection and comorbidities. Increased monitoring and follow-up through treatment registries is warranted to increase our understanding and thereby improve management. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Legal and Illegal Patterns of Drug Distribution in the United States

ERIC Educational Resources Information Center

Caliguri, Joseph P.

1976-01-01

Along with large supply sources of legal and illegal drug substances, diversion and distribution systems have developed to feed and maintain the demand. This presentation provides information on the diverting of drugs from legal and illegal sources as well as the characteristics of the distribution patterns. (Author)

Annual Report on the State of the Drugs Problem in the European Union, 2000.

ERIC Educational Resources Information Center

European Monitoring Centre for Drugs and Drug Addiction, Lisbon (Portugal).

This report presents an overview of the drug phenomenon in Europe at the start of the new millennium. The first chapter begins with a discussion of overall drug trends. Specifically, it examines trends in drug use and the consequences including multiple drug use; problem drug use and demand for treatment; drug-related deaths; drug-related…

Preparing Nursing Home Data from Multiple Sites for Clinical Research – A Case Study Using Observational Health Data Sciences and Informatics

PubMed Central

Boyce, Richard D.; Handler, Steven M.; Karp, Jordan F.; Perera, Subashan; Reynolds, Charles F.

2016-01-01

Introduction: A potential barrier to nursing home research is the limited availability of research quality data in electronic form. We describe a case study of converting electronic health data from five skilled nursing facilities to a research quality longitudinal dataset by means of open-source tools produced by the Observational Health Data Sciences and Informatics (OHDSI) collaborative. Methods: The Long-Term Care Minimum Data Set (MDS), drug dispensing, and fall incident data from five SNFs were extracted, translated, and loaded into version 4 of the OHDSI common data model. Quality assurance involved identifying errors using the Achilles data characterization tool and comparing both quality measures and drug exposures in the new database for concordance with externally available sources. Findings: Records for a total 4,519 patients (95.1%) made it into the final database. Achilles identified 10 different types of errors that were addressed in the final dataset. Drug exposures based on dispensing were generally accurate when compared with medication administration data from the pharmacy services provider. Quality measures were generally concordant between the new database and Nursing Home Compare for measures with a prevalence ≥ 10%. Fall data recorded in MDS was found to be more complete than data from fall incident reports. Conclusions: The new dataset is ready to support observational research on topics of clinical importance in the nursing home including patient-level prediction of falls. The extraction, translation, and loading process enabled the use of OHDSI data characterization tools that improved the quality of the final dataset. PMID:27891528

Development and evaluation of a novel modified-release pellet-based tablet system for the delivery of loratadine and pseudoephedrine hydrochloride as model drugs.

PubMed

Zeeshan, Farrukh; Bukhari, Nadeem Irfan

2010-06-01

Modified-release multiple-unit tablets of loratadine and pseudoephedrine hydrochloride with different release profiles were prepared from the immediate-release pellets comprising the above two drugs and prolonged-release pellets containing only pseudoephedrine hydrochloride. The immediate-release pellets containing pseudoephedrine hydrochloride alone or in combination with loratadine were prepared using extrusion-spheronization method. The pellets of pseudoephedrine hydrochloride were coated to prolong the drug release up to 12 h. Both immediate- and prolonged-release pellets were filled into hard gelatin capsule and also compressed into tablets using inert tabletting granules of microcrystalline cellulose Ceolus KG-801. The in vitro drug dissolution study conducted using high-performance liquid chromatography method showed that both multiple-unit capsules and multiple-unit tablets released loratadine completely within a time period of 2 h, whereas the immediate-release portion of pseudoephedrine hydrochloride was liberated completely within the first 10 min of dissolution study. On the other hand, the release of pseudoephedrine hydrochloride from the prolonged release coated pellets was prolonged up to 12 hr and followed zero-order release kinetic. The drug dissolution profiles of multiple-unit tablets and multiple-unit capsules were found to be closely similar, indicating that the integrity of pellets remained unaffected during the compression process. Moreover, the friability, hardness, and disintegration time of multiple-unit tablets were found to be within BP specifications. In conclusion, modified-release pellet-based tablet system for the delivery of loratadine and pseudoephedrine hydrochloride was successfully developed and evaluated.

Free radicals: properties, sources, targets, and their implication in various diseases.

PubMed

Phaniendra, Alugoju; Jestadi, Dinesh Babu; Periyasamy, Latha

2015-01-01

Free radicals and other oxidants have gained importance in the field of biology due to their central role in various physiological conditions as well as their implication in a diverse range of diseases. The free radicals, both the reactive oxygen species (ROS) and reactive nitrogen species (RNS), are derived from both endogenous sources (mitochondria, peroxisomes, endoplasmic reticulum, phagocytic cells etc.) and exogenous sources (pollution, alcohol, tobacco smoke, heavy metals, transition metals, industrial solvents, pesticides, certain drugs like halothane, paracetamol, and radiation). Free radicals can adversely affect various important classes of biological molecules such as nucleic acids, lipids, and proteins, thereby altering the normal redox status leading to increased oxidative stress. The free radicals induced oxidative stress has been reported to be involved in several diseased conditions such as diabetes mellitus, neurodegenerative disorders (Parkinson's disease-PD, Alzheimer's disease-AD and Multiple sclerosis-MS), cardiovascular diseases (atherosclerosis and hypertension), respiratory diseases (asthma), cataract development, rheumatoid arthritis and in various cancers (colorectal, prostate, breast, lung, bladder cancers). This review deals with chemistry, formation and sources, and molecular targets of free radicals and it provides a brief overview on the pathogenesis of various diseased conditions caused by ROS/RNS.

Effectiveness of multiple sclerosis treatment with current immunomodulatory drugs.

PubMed

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.

Discovery and resupply of pharmacologically active plant-derived natural products: A review.

PubMed

Atanasov, Atanas G; Waltenberger, Birgit; Pferschy-Wenzig, Eva-Maria; Linder, Thomas; Wawrosch, Christoph; Uhrin, Pavel; Temml, Veronika; Wang, Limei; Schwaiger, Stefan; Heiss, Elke H; Rollinger, Judith M; Schuster, Daniela; Breuss, Johannes M; Bochkov, Valery; Mihovilovic, Marko D; Kopp, Brigitte; Bauer, Rudolf; Dirsch, Verena M; Stuppner, Hermann

2015-12-01

Medicinal plants have historically proven their value as a source of molecules with therapeutic potential, and nowadays still represent an important pool for the identification of novel drug leads. In the past decades, pharmaceutical industry focused mainly on libraries of synthetic compounds as drug discovery source. They are comparably easy to produce and resupply, and demonstrate good compatibility with established high throughput screening (HTS) platforms. However, at the same time there has been a declining trend in the number of new drugs reaching the market, raising renewed scientific interest in drug discovery from natural sources, despite of its known challenges. In this survey, a brief outline of historical development is provided together with a comprehensive overview of used approaches and recent developments relevant to plant-derived natural product drug discovery. Associated challenges and major strengths of natural product-based drug discovery are critically discussed. A snapshot of the advanced plant-derived natural products that are currently in actively recruiting clinical trials is also presented. Importantly, the transition of a natural compound from a "screening hit" through a "drug lead" to a "marketed drug" is associated with increasingly challenging demands for compound amount, which often cannot be met by re-isolation from the respective plant sources. In this regard, existing alternatives for resupply are also discussed, including different biotechnology approaches and total organic synthesis. While the intrinsic complexity of natural product-based drug discovery necessitates highly integrated interdisciplinary approaches, the reviewed scientific developments, recent technological advances, and research trends clearly indicate that natural products will be among the most important sources of new drugs also in the future. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

Manipulation of the mouse genome: a multiple impact resource for drug discovery and development.

PubMed

Prosser, Haydn; Rastan, Sohaila

2003-05-01

Few would deny that the pharmaceutical industry's investment in genomics throughout the 1990s has yet to deliver in terms of drugs on the market. The reasons are complex and beyond the scope of this review. The unique ability to manipulate the mouse genome, however, has already had a positive impact on all stages of the drug discovery process and, increasingly, on the drug development process too. We give an overview of some recent applications of so-called 'transgenic' mouse technology in pharmaceutical research and development. We show how genetic manipulation in the mouse can be employed at multiple points in the drug discovery and development process, providing new solutions to old problems.

The emergence of designed multiple ligands for neurodegenerative disorders.

PubMed

Geldenhuys, Werner J; Youdim, Moussa B H; Carroll, Richard T; Van der Schyf, Cornelis J

2011-09-01

The incidence of neurodegenerative diseases has seen a constant increase in the global population, and is likely to be the result of extended life expectancy brought about by better health care. Despite this increase in the incidence of neurodegenerative diseases, there has been a dearth in the introduction of new disease-modifying therapies that are approved to prevent or delay the onset of these diseases, or reverse the degenerative processes in brain. Mounting evidence in the peer-reviewed literature shows that the etiopathology of these diseases is extremely complex and heterogeneous, resulting in significant comorbidity and therefore unlikely to be mitigated by any drug acting on a single pathway or target. A recent trend in drug design and discovery is the rational design or serendipitous discovery of novel drug entities with the ability to address multiple drug targets that form part of the complex pathophysiology of a particular disease state. In this review we discuss the rationale for developing such multifunctional drugs (also called designed multiple ligands or DMLs), and why these drug candidates seem to offer better outcomes in many cases compared to single-targeted drugs in pre-clinical studies for neurodegenerative diseases such as Alzheimer's and Parkinson's disease. Examples are drawn from the literature of drug candidates that have already reached the market, some unsuccessful attempts, and others that are still in the drug development pipeline. Copyright © 2011. Published by Elsevier Ltd.

The source and diversion of pharmaceutical drugs for non-medical use: A systematic review and meta-analysis.

PubMed

Hulme, Shann; Bright, David; Nielsen, Suzanne

2018-05-01

The non-medical use (NMU) of pharmaceutical drugs is an increasing public health concern. This systematic review consolidates current knowledge about how pharmaceutical drugs are obtained for NMU and the processes and people involved in diversion. Peer-reviewed and grey literature databases were searched for empirical studies published between 1996 and 2017 that examined the source or diversion of pharmaceutical opioids, sedatives or stimulants for NMU in countries with reported misuse problems. Pooled prevalence meta-analyses using random effects models were used to estimate the prevalence of medical and non-medical sourcing reported by end-users, and gifting, selling and trading by various populations. This review synthesizes the findings of 54 cross-sectional studies via meta-analyses, with a remaining 95 studies examined through narrative review. Pharmaceutical drugs are primarily sourced for NMU from friends and family (57%, 95% CI 53%-62%, I 2  = 98.5, n = 30) and despite perceptions of healthcare professionals to the contrary, illegitimate practices such as doctor shopping are uncommon (7%, 95% CI 6%-10%, I 2  = 97.4, n = 29). Those at risk of diversion include patients displaying aberrant medication behaviors, people with substance use issues and students in fraternity/sorority environments. Sourcing via dealers is also common (32%, 95% CI 23%-41%, I 2  = 99.8, n = 25) and particularly so among people who use illicit drugs (47%, 95% CI 35%-60%, I 2  = 99.1, n = 15). There is little to no organized criminal involvement in the pharmaceutical black market. Pharmaceutical drugs for NMU are primarily sourced by end-users through social networks. Future research should examine how dealers source pharmaceutical drugs. Copyright © 2018 Elsevier B.V. All rights reserved.

"Who has ever loved a drug addict? It's a lie. They think a 'teja' is as bad person": multiple stigmas faced by women who inject drugs in coastal Kenya.

PubMed

Mburu, Gitau; Ayon, Sylvia; Tsai, Alexander C; Ndimbii, James; Wang, Bangyuan; Strathdee, Steffanie; Seeley, Janet

2018-05-25

A tenth of all people who inject drugs in Kenya are women, yet their social contexts and experiences remain poorly understood. This paper reports how multiple forms of stigma are experienced by women who inject drugs in coastal Kenya and the impact that they have on their ability to access essential health services. In 2015, in-depth interviews and focus group discussions were held with 45 women who inject drugs in two coastal towns. These data were supplemented with in-depth interviews with five individual stakeholders involved in service provision to this population. Data were analyzed thematically using NVivo. Women who inject drugs experience multiple stigmas, often simultaneously. These included the external stigma and self-stigma of injection drug use, external gender-related stigma of being a female injecting drug user, and the external stigma of being HIV positive (i.e., among those living with HIV). Stigma led to rejection, social exclusion, low self-esteem, and delay or denial of services at health facilities. HIV and harm reduction programs should incorporate interventions that address different forms of stigma among women who inject drugs in coastal Kenya. Addressing stigma will require a combination of individual, social, and structural interventions, such as collective empowerment of injecting drug users, training of healthcare providers on issues and needs of women who inject drugs, peer accompaniment to health facilities, addressing wider social determinants of stigma and discrimination, and expansion of harm reduction interventions to change perceptions of communities towards women who inject drugs.

21 CFR 101.54 - Nutrient content claims for “good source,” “high,” “more,” and “high potency.”

Code of Federal Regulations, 2013 CFR

2013-04-01

... 21 Food and Drugs 2 2013-04-01 2013-04-01 false Nutrient content claims for âgood source,â âhigh,â âmore,â and âhigh potency.â 101.54 Section 101.54 Food and Drugs FOOD AND DRUG ADMINISTRATION... Requirements for Nutrient Content Claims § 101.54 Nutrient content claims for “good source,” “high,” “more...

21 CFR 101.54 - Nutrient content claims for “good source,” “high,” “more,” and “high potency.”

Code of Federal Regulations, 2012 CFR

2012-04-01

... 21 Food and Drugs 2 2012-04-01 2012-04-01 false Nutrient content claims for âgood source,â âhigh,â âmore,â and âhigh potency.â 101.54 Section 101.54 Food and Drugs FOOD AND DRUG ADMINISTRATION... Requirements for Nutrient Content Claims § 101.54 Nutrient content claims for “good source,” “high,” “more...

21 CFR 101.54 - Nutrient content claims for “good source,” “high,” “more,” and “high potency.”

Code of Federal Regulations, 2014 CFR

2014-04-01

... 21 Food and Drugs 2 2014-04-01 2014-04-01 false Nutrient content claims for âgood source,â âhigh,â âmore,â and âhigh potency.â 101.54 Section 101.54 Food and Drugs FOOD AND DRUG ADMINISTRATION... Requirements for Nutrient Content Claims § 101.54 Nutrient content claims for “good source,” “high,” “more...

The promises of stem cells: stem cell therapy for movement disorders.

PubMed

Mochizuki, Hideki; Choong, Chi-Jing; Yasuda, Toru

2014-01-01

Despite the multitude of intensive research, the exact pathophysiological mechanisms underlying movement disorders including Parkinson's disease, multiple system atrophy and Huntington's disease remain more or less elusive. Treatments to halt these disease progressions are currently unavailable. With the recent induced pluripotent stem cells breakthrough and accomplishment, stem cell research, as the vast majority of scientists agree, holds great promise for relieving and treating debilitating movement disorders. As stem cells are the precursors of all cells in the human body, an understanding of the molecular mechanisms that govern how they develop and work would provide us many fundamental insights into human biology of health and disease. Moreover, stem-cell-derived neurons may be a renewable source of replacement cells for damaged neurons in movement disorders. While stem cells show potential for regenerative medicine, their use as tools for research and drug testing is thought to have more immediate impact. The use of stem-cell-based drug screening technology could be a big boost in drug discovery for these movement disorders. Particular attention should also be given to the involvement of neural stem cells in adult neurogenesis so as to encourage its development as a therapeutic option. Copyright © 2013 Elsevier Ltd. All rights reserved.

COMMUNICATING RISK IN THE CONTEXT OF METHADONE FORMULATION CHANGES: A QUALITATIVE STUDY OF OVERDOSE WARNING POSTERS IN VANCOUVER, CANADA

PubMed Central

Markwick, Nicole; McNeil, Ryan; Anderson, Solanna; Small, Will; Kerr, Thomas

2015-01-01

BACKGROUND British Columbia, Canada’s provincial methadone program recently replaced their existing methadone formulation with a formulation ten times more concentrated. The transition raised concerns about heightened risk of accidental overdose, leading two organizations to disseminate methadone overdose warning posters during the transitional period. This study explores people who use drugs’ (PWUD) perceptions of these warning posters. METHODS Qualitative interviews were conducted with thirty-four PWUD enrolled in methadone maintenance treatment in Vancouver. Participants were recruited from ongoing cohort studies of drug-using individuals. Interview transcripts were analyzed thematically, focusing on participants’ perceptions of the warning posters and potential impacts on drug-related risks. RESULTS Overdose warning posters constituted a key source of information about the methadone formulation change, but did not provide adequate information for all participants. Participants articulated a preference for descriptive language, focusing on changes in concentration rather than “strength”, and universal hazard symbols to effectively communicate overdose risks. CONCLUSION Participants indicated that warnings employing descriptive language more effectively communicated risk of methadone overdose. Future overdose warnings for drug-using populations must provide adequate information for the intended audience, and be communicated to PWUD through multiple channels. PMID:26644025

Prediction of Drug-Drug Interactions with Crizotinib as the CYP3A Substrate Using a Physiologically Based Pharmacokinetic Model.

PubMed

Yamazaki, Shinji; Johnson, Theodore R; Smith, Bill J

2015-10-01

An orally available multiple tyrosine kinase inhibitor, crizotinib (Xalkori), is a CYP3A substrate, moderate time-dependent inhibitor, and weak inducer. The main objectives of the present study were to: 1) develop and refine a physiologically based pharmacokinetic (PBPK) model of crizotinib on the basis of clinical single- and multiple-dose results, 2) verify the crizotinib PBPK model from crizotinib single-dose drug-drug interaction (DDI) results with multiple-dose coadministration of ketoconazole or rifampin, and 3) apply the crizotinib PBPK model to predict crizotinib multiple-dose DDI outcomes. We also focused on gaining insights into the underlying mechanisms mediating crizotinib DDIs using a dynamic PBPK model, the Simcyp population-based simulator. First, PBPK model-predicted crizotinib exposures adequately matched clinically observed results in the single- and multiple-dose studies. Second, the model-predicted crizotinib exposures sufficiently matched clinically observed results in the crizotinib single-dose DDI studies with ketoconazole or rifampin, resulting in the reasonably predicted fold-increases in crizotinib exposures. Finally, the predicted fold-increases in crizotinib exposures in the multiple-dose DDI studies were roughly comparable to those in the single-dose DDI studies, suggesting that the effects of crizotinib CYP3A time-dependent inhibition (net inhibition) on the multiple-dose DDI outcomes would be negligible. Therefore, crizotinib dose-adjustment in the multiple-dose DDI studies could be made on the basis of currently available single-dose results. Overall, we believe that the crizotinib PBPK model developed, refined, and verified in the present study would adequately predict crizotinib oral exposures in other clinical studies, such as DDIs with weak/moderate CYP3A inhibitors/inducers and drug-disease interactions in patients with hepatic or renal impairment. Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics.

Factors other than the Duke criteria associated with infective endocarditis among injection drug users.

PubMed

Palepu, Anita; Cheung, Stephen S; Montessori, Valentina; Woods, Ryan; Thompson, Christopher R

2002-08-01

Modified Duke criteria were applied to consecutive injection drug users (IDUs) who were admitted to an inner-city hospital with a clinical suspicion of infective endocarditis, and the presence of any other clinical variables that were predictive of the presence of infective endocarditis was determined. Clinical data on consecutive IDUs who were hospitalized over 15 months in Vancouver were collected. Data included the admission history, and findings on physical examination and on initial laboratory investigations. Each subject's course in hospital was followed until discharge or death during the index hospitalization. Follow-up data collected included culture results, the interpretation of the echocardiogram and the discharge diagnosis. The modified Duke criteria were used for the diagnosis of infective endocarditis (definite, possible or rejected). Multiple logistic regression was used to determine what clinical variables (exclusive of the Duke criteria) available within 48 hours of presentation were independent predictors of infective endocarditis. One hundred IDUs were enrolled. Fifty-one were female, and 58 were HIV-positive. Twenty-three met the modified Duke criteria for definite infective endocarditis, and 25 had possible infective endocarditis. IDUs with definite infective endocarditis were more commonly noted to have evidence of vascular phenomena (arterial embolism, septic pulmonary infarction, mycotic aneurysm, intracranial hemorrhage or Janeway lesions) (6 [26%]) than those who had possible endocarditis (1 [4%]). Those with definite infective endocarditis more often had multiple opacities on chest radiography (56% v. < 12%), and fewer had an obvious source of infection (52% v. 72% and 81% of possible and rejected infective endocarditis, respectively). Among febrile IDUs, definite endocarditis was highly associated with having no obvious source of infection (odds ratio 3.1 [95% confidence interval 1.1-8.7]) compared with febrile IDUs with an obvious source of infection. In similarly compared groups, the presence of hematuria, proteinuria or pyuria was also predictive of definite endocarditis (odds ratio 2.9 [95% CI 1.1-8.6]). Among IDUs, the modified Duke criteria are useful for classifying cases with definite infective endocarditis and rejecting cases without infective endocarditis. The classification of possible infective endocarditis is suitable for this population.

Multiple heart-cutting and comprehensive two-dimensional liquid chromatography hyphenated to mass spectrometry for the characterization of the antibody-drug conjugate ado-trastuzumab emtansine.

PubMed

Sandra, Koen; Vanhoenacker, Gerd; Vandenheede, Isabel; Steenbeke, Mieke; Joseph, Maureen; Sandra, Pat

2016-10-01

Antibody-drug conjugates might be the magic bullets referred to by Paul Ehrlich over 100 years ago. Together with a huge therapeutic potential, these molecules come with a structural complexity that drives state-of-the-art chromatography and mass spectrometry to its limits. The use of multiple heart-cutting (mLC-LC) and comprehensive (LC×LC) multidimensional LC in combination with high resolution mass spectrometry for the characterization of the lysine conjugated antibody-drug conjugate ado-trastuzumab emtansine, commercialized as Kadcyla, is presented. By combining protein and peptide measurements, attributes such as drug loading, drug distribution and drug conjugation sites can be assessed in an elegant manner. Copyright © 2016 Elsevier B.V. All rights reserved.

Lipid-associated oral delivery: Mechanisms and analysis of oral absorption enhancement.

PubMed

Rezhdo, Oljora; Speciner, Lauren; Carrier, Rebecca

2016-10-28

The majority of newly discovered oral drugs are poorly water soluble, and co-administration with lipids has proven effective in significantly enhancing bioavailability of some compounds with low aqueous solubility. Yet, lipid-based delivery technologies have not been widely employed in commercial oral products. Lipids can impact drug transport and fate in the gastrointestinal (GI) tract through multiple mechanisms including enhancement of solubility and dissolution kinetics, enhancement of permeation through the intestinal mucosa, and triggering drug precipitation upon lipid emulsion depletion (e.g., by digestion). The effect of lipids on drug absorption is currently not quantitatively predictable, in part due to the multiple complex dynamic processes that can be impacted by lipids. Quantitative mechanistic analysis of the processes significant to lipid system function and overall impact on drug absorption can aid in the understanding of drug-lipid interactions in the GI tract and exploitation of such interactions to achieve optimal lipid-based drug delivery. In this review, we discuss the impact of co-delivered lipids and lipid digestion on drug dissolution, partitioning, and absorption in the context of the experimental tools and associated kinetic expressions used to study and model these processes. The potential benefit of a systems-based consideration of the concurrent multiple dynamic processes occurring upon co-dosing lipids and drugs to predict the impact of lipids on drug absorption and enable rational design of lipid-based delivery systems is presented. Copyright © 2016 Elsevier B.V. All rights reserved.

Brunn: an open source laboratory information system for microplates with a graphical plate layout design process.

PubMed

Alvarsson, Jonathan; Andersson, Claes; Spjuth, Ola; Larsson, Rolf; Wikberg, Jarl E S

2011-05-20

Compound profiling and drug screening generates large amounts of data and is generally based on microplate assays. Current information systems used for handling this are mainly commercial, closed source, expensive, and heavyweight and there is a need for a flexible lightweight open system for handling plate design, and validation and preparation of data. A Bioclipse plugin consisting of a client part and a relational database was constructed. A multiple-step plate layout point-and-click interface was implemented inside Bioclipse. The system contains a data validation step, where outliers can be removed, and finally a plate report with all relevant calculated data, including dose-response curves. Brunn is capable of handling the data from microplate assays. It can create dose-response curves and calculate IC50 values. Using a system of this sort facilitates work in the laboratory. Being able to reuse already constructed plates and plate layouts by starting out from an earlier step in the plate layout design process saves time and cuts down on error sources.

[Current therapy of multiple sclerosis].

PubMed

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.

Salmonella, Shigella and growth potential of other food-borne pathogens in Ethiopian street vended foods.

PubMed

Muleta, D; Ashenafi, M

2001-11-01

To evaluate the bacteriological safety of food items sold by street vendors with regard to Salmonella and Shigella and to assess the growth potential of some foodborne pathogens in some street foods. Collection of street-vended foods and laboratory based microbiological analysis. Microbiology Laboratory, Department of Biology, Addis Ababa University, Addis Ababa, Ethiopia. Most of the street food samples had aerobic mesophilic counts >10(7) cfu/g. Nine "kitfo" and one "egg sandwich" samples yielded Salmonella. Shigella was isolated from three "macaroni" samples. The Salmonella isolates were sensitive to all ten drugs tested but the Shigella isolates had multiple resistance against five drugs. In a challenge study, Salmonella typhimurium, Shigella flexneri and Staphylococcus aureus grew in street-vended food samples to hazardous levels within eight to twelve hours. Street foods are heavily contaminated with micro-organisms and are potential sources of food borne infections. Health hazards from street foods may be significantly minimised by consumption within four hours of preparation.

4-aminoquinoline analogues and its platinum (II) complexes as antimalarial agents.

PubMed

de Souza, Nicolli Bellotti; Carmo, Arturene M L; Lagatta, Davi C; Alves, Márcio José Martins; Fontes, Ana Paula Soares; Coimbra, Elaine Soares; da Silva, Adilson David; Abramo, Clarice

2011-07-01

The high incidence of malaria and drug-resistant strains of Plasmodium have turned this disease into a problem of major health importance. One of the approaches used to control it is to search for new antimalarial agents, such as quinoline derivates. This class of compounds composes a broad group of antimalarial agents, which are largely employed, and inhibits the formation of β-haematin (malaria pigment), which is lethal to the parasite. More specifically, 4-aminoquinoline derivates represent potential sources of antimalarials, as the example of chloroquine, the most used antimalarial worldwide. In order to assess antimalarial activity, 12 4-aminoquinoline derived drugs were obtained and some of these derivatives were used to obtain platinum complexes platinum (II). These compounds were tested in vivo in a murine model and revealed remarkable inhibition of parasite multiplication values, whose majority ranged from 50 to 80%. In addition they were not cytotoxic. Thus, they may be object of further research for new antimalarial agents. Copyright © 2011 Elsevier Masson SAS. All rights reserved.

Antibacterial activity of natural spices on multiple drug resistant Escherichia coli isolated from drinking water, Bangladesh

PubMed Central

2011-01-01

Background Spices traditionally have been used as coloring agents, flavoring agents, preservatives, food additives and medicine in Bangladesh. The present work aimed to find out the antimicrobial activity of natural spices on multi-drug resistant Escherichia coli isolates. Methods Anti-bacterial potentials of six crude plant extracts (Allium sativum, Zingiber officinale, Allium cepa, Coriandrum sativum, Piper nigrum and Citrus aurantifolia) were tested against five Escherichia coli isolated from potable water sources at kushtia, Bangladesh. Results All the bacterial isolates were susceptible to undiluted lime-juice. None of them were found to be susceptible against the aqueous extracts of garlic, onion, coriander, pepper and ginger alone. However, all the isolates were susceptible when subjected to 1:1:1 aqueous extract of lime, garlic and ginger. The highest inhibition zone was observed with lime (11 mm). Conclusion Natural spices might have anti-bacterial activity against enteric pathogens and could be used for prevention of diarrheal diseases. Further evaluation is necessary. PMID:21406097

Antibacterial activity of natural spices on multiple drug resistant Escherichia coli isolated from drinking water, Bangladesh.

PubMed

Rahman, Shahedur; Parvez, Anowar Khasru; Islam, Rezuanul; Khan, Mahboob Hossain

2011-03-15

Spices traditionally have been used as coloring agents, flavoring agents, preservatives, food additives and medicine in Bangladesh. The present work aimed to find out the antimicrobial activity of natural spices on multi-drug resistant Escherichia coli isolates. Anti-bacterial potentials of six crude plant extracts (Allium sativum, Zingiber officinale, Allium cepa, Coriandrum sativum, Piper nigrum and Citrus aurantifolia) were tested against five Escherichia coli isolated from potable water sources at kushtia, Bangladesh. All the bacterial isolates were susceptible to undiluted lime-juice. None of them were found to be susceptible against the aqueous extracts of garlic, onion, coriander, pepper and ginger alone. However, all the isolates were susceptible when subjected to 1:1:1 aqueous extract of lime, garlic and ginger. The highest inhibition zone was observed with lime (11 mm). Natural spices might have anti-bacterial activity against enteric pathogens and could be used for prevention of diarrheal diseases. Further evaluation is necessary.

The politics and strategy of industry self-regulation: the pharmaceutical industry's principles for ethical direct-to-consumer advertising as a deceptive blocking strategy.

PubMed

Arnold, Denis G; Oakley, James L

2013-06-01

As the pharmaceutical industry lobbies European regulators to permit direct-to-consumer advertising (DTCA) of prescription drugs in the European Union, we found that five leading companies violated industry-developed and -promulgated standards for ethical advertising in the United States. Utilizing multiple data sources and methods, we demonstrate a consistent failure by companies that market erectile dysfunction drugs to comply with the industry's guiding principles for ethical DTCA over a four-year period despite pledges of compliance by company leaders. Noncompliance resulted in children being exposed to sexually themed promotional messages more than 100 billion times. We argue that the guidelines are a coordinated effort by the industry to prevent unwanted federal regulation, and we introduce the concept of a blocking strategy to explain company behavior and to advance theoretical understanding of firms' public affairs strategies. We recommend policy responses to prevent deceptive practices, protect children from adult content, and promote genuine health care education.

Optimized approaches for quantification of drug transporters in tissues and cells by MRM proteomics.

PubMed

Prasad, Bhagwat; Unadkat, Jashvant D

2014-07-01

Drug transporter expression in tissues (in vivo) usually differs from that in cell lines used to measure transporter activity (in vitro). Therefore, quantification of transporter expression in tissues and cell lines is important to develop scaling factor for in vitro to in vivo extrapolation (IVIVE) of transporter-mediated drug disposition. Since traditional immunoquantification methods are semiquantitative, targeted proteomics is now emerging as a superior method to quantify proteins, including membrane transporters. This superiority is derived from the selectivity, precision, accuracy, and speed of analysis by liquid chromatography tandem mass spectrometry (LC-MS/MS) in multiple reaction monitoring (MRM) mode. Moreover, LC-MS/MS proteomics has broader applicability because it does not require selective antibodies for individual proteins. There are a number of recent research and review papers that discuss the use of LC-MS/MS for transporter quantification. Here, we have compiled from the literature various elements of MRM proteomics to provide a comprehensive systematic strategy to quantify drug transporters. This review emphasizes practical aspects and challenges in surrogate peptide selection, peptide qualification, peptide synthesis and characterization, membrane protein isolation, protein digestion, sample preparation, LC-MS/MS parameter optimization, method validation, and sample analysis. In particular, bioinformatic tools used in method development and sample analysis are discussed in detail. Various pre-analytical and analytical sources of variability that should be considered during transporter quantification are highlighted. All these steps are illustrated using P-glycoprotein (P-gp) as a case example. Greater use of quantitative transporter proteomics will lead to a better understanding of the role of drug transporters in drug disposition.

Development of multiclass methods for drug residues in eggs: hydrophilic solid-phase extraction cleanup and liquid chromatography/tandem mass spectrometry analysis of tetracycline, fluoroquinolone, sulfonamide, and beta-lactam residues.

PubMed

Heller, David N; Nochetto, Cristina B; Rummel, Nathan G; Thomas, Michael H

2006-07-26

A method was developed for detection of a variety of polar drug residues in eggs via liquid chromatography/tandem mass spectrometry (LC/MS/MS) with electrospray ionization (ESI). A total of twenty-nine target analytes from four drug classes-sulfonamides, tetracyclines, fluoroquinolones, and beta-lactams-were extracted from eggs using a hydrophilic-lipophilic balance polymer solid-phase extraction (SPE) cartridge. The extraction technique was developed for use at a target concentration of 100 ng/mL (ppb), and it was applied to eggs containing incurred residues from dosed laying hens. The ESI source was tuned using a single, generic set of tuning parameters, and analytes were separated with a phenyl-bonded silica cartridge column using an LC gradient. In a related study, residues of beta-lactam drugs were not found by LC/MS/MS in eggs from hens dosed orally with beta-lactam drugs. LC/MS/MS performance was evaluated on two generations of ion trap mass spectrometers, and key operational parameters were identified for each instrument. The ion trap acquisition methods could be set up for screening (a single product ion) or confirmation (multiple product ions). The lower limit of detection for screening purposes was 10-50 ppb (sulfonamides), 10-20 ppb (fluoroquinolones), and 10-50 ppb (tetracyclines), depending on the drug, instrument, and acquisition method. Development of this method demonstrates the feasibility of generic SPE, LC, and MS conditions for multiclass LC/MS residue screening.

Prevalence and correlates of substance use among trans*female youth ages 16–24 years in the San Francisco Bay Area

PubMed Central

Rowe, Chris; Santos, Glenn-Milo; McFarland, Willi; Wilson, Erin C.

2014-01-01

Background Substance use is highly prevalent among transgender (trans*) females and has been associated with negative health outcomes, including HIV infection. Little is known about psychosocial risk factors that may influence the onset of substance use among trans*female youth, which can contribute to health disparities during adulthood. Methods We conducted a secondary data analysis of a study on HIV risk and resilience among trans*female youth (N=292). Prevalence of substance use was assessed and multivariable logistic regression models were used to examine the relationship between posttraumatic stress disorder (PTSD), psychological distress, gender-related discrimination, parental drug or alcohol problems (PDAP) and multiple substance use outcomes. Results Most (69%) of the trans*female youth reported recent drug use. In multivariable analyses, those with PTSD had increased odds of drug use [AOR=1.94 (95%CI=1.09–3.44)]. Those who experienced gender-related discrimination had increased odds of drug use [AOR=2.28 (95%CI=1.17–4.44)], drug use concurrent with sex [AOR=2.35 (95%CI=1.11–4.98)] and use of multiple drugs [AOR=3.24 (95%CI=1.52–6.88)]. Those with psychological distress had increased odds of using multiple heavy drugs [AOR=2.27 (95%CI=1.01–5.12)]. Those with PDAP had increased odds of drugs use [AOR=2.62 (95%CI=1.43–4.82)], drug use concurrent with sex [AOR=2.01 (95%CI, 1.15–3.51)] and use of multiple drugs [AOR=2.10 (95%CI=1.22–3.62)]. Conclusions Substance use is highly prevalent among trans*female youth and was significantly associated with psychosocial risk factors. In order to effectively address substance use among trans*female youth, efforts must address coping related to gender-based discrimination and trauma. Furthermore, structural level interventions aiming to reduce stigma and gender-identity discrimination might also be effective. PMID:25548025

Prevalence and correlates of substance use among trans female youth ages 16-24 years in the San Francisco Bay Area.

PubMed

Rowe, Chris; Santos, Glenn-Milo; McFarland, Willi; Wilson, Erin C

2015-02-01

Substance use is highly prevalent among transgender (trans*) females and has been associated with negative health outcomes, including HIV infection. Little is known about psychosocial risk factors that may influence the onset of substance use among trans*female youth, which can contribute to health disparities during adulthood. We conducted a secondary data analysis of a study on HIV risk and resilience among trans*female youth (N=292). Prevalence of substance use was assessed and multivariable logistic regression models were used to examine the relationship between posttraumatic stress disorder (PTSD), psychological distress, gender-related discrimination, parental drug or alcohol problems (PDAP) and multiple substance use outcomes. Most (69%) of the trans*female youth reported recent drug use. In multivariable analyses, those with PTSD had increased odds of drug use [AOR=1.94 (95% CI=1.09-3.44)]. Those who experienced gender-related discrimination had increased odds of drug use [AOR=2.28 (95% CI=1.17-4.44)], drug use concurrent with sex [AOR=2.35 (95% CI=1.11-4.98)] and use of multiple drugs [AOR=3.24 (95% CI=1.52-6.88)]. Those with psychological distress had increased odds of using multiple heavy drugs [AOR=2.27 (95% CI=1.01-5.12)]. Those with PDAP had increased odds of drugs use [AOR=2.62 (95% CI=1.43-4.82)], drug use concurrent with sex [AOR=2.01 (95% CI, 1.15-3.51)] and use of multiple drugs [AOR=2.10 (95% CI=1.22-3.62)]. Substance use is highly prevalent among trans*female youth and was significantly associated with psychosocial risk factors. In order to effectively address substance use among trans*female youth, efforts must address coping related to gender-based discrimination and trauma. Furthermore, structural level interventions aiming to reduce stigma and gender-identity discrimination might also be effective. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Predicting Drug Concentration‐Time Profiles in Multiple CNS Compartments Using a Comprehensive Physiologically‐Based Pharmacokinetic Model

PubMed Central

Yamamoto, Yumi; Välitalo, Pyry A.; Huntjens, Dymphy R.; Proost, Johannes H.; Vermeulen, An; Krauwinkel, Walter; Beukers, Margot W.; van den Berg, Dirk‐Jan; Hartman, Robin; Wong, Yin Cheong; Danhof, Meindert; van Hasselt, John G. C.

2017-01-01

Drug development targeting the central nervous system (CNS) is challenging due to poor predictability of drug concentrations in various CNS compartments. We developed a generic physiologically based pharmacokinetic (PBPK) model for prediction of drug concentrations in physiologically relevant CNS compartments. System‐specific and drug‐specific model parameters were derived from literature and in silico predictions. The model was validated using detailed concentration‐time profiles from 10 drugs in rat plasma, brain extracellular fluid, 2 cerebrospinal fluid sites, and total brain tissue. These drugs, all small molecules, were selected to cover a wide range of physicochemical properties. The concentration‐time profiles for these drugs were adequately predicted across the CNS compartments (symmetric mean absolute percentage error for the model prediction was <91%). In conclusion, the developed PBPK model can be used to predict temporal concentration profiles of drugs in multiple relevant CNS compartments, which we consider valuable information for efficient CNS drug development. PMID:28891201

MEDICATION DISPOSAL AS A SOURCE FOR DRUGS AS ...

EPA Pesticide Factsheets

The major routes by which pharmaceuticals enter the environment are excretion, bathing, anddisposal of leftover, unwanted medications. Pharmaceuticals designed for humans and animalsoften remain unused. Leftover, accumulated drugs represent potentially environmentallyunsound disposal and suboptimal delivery of health care. They also can pose acute exposurerisks for humans and wildlife. Active pharmaceutical ingredients (APIs) directly enter theenvironment primarily via sewage. Among the three routes of entry, the relative contributions ofeach are poorly understood. In contrast to excretion, which as a source comprises continual lowlevelcontributions from multitudes of people, drug disposal comprises acute but transient andepisodic contributions from fewer people. The only route that is subject most easily to pollutionprevention or source control measures is disposal.A major unknown with respect to drugs as pollutants is what fractions of drug residues occurringin the ambient environment result from discarding leftover drugs. No studies exist that provideobjective data from well-defined populations to support any type of conclusion. Given theimportance of environmental stewardship to sustainability, a means for assessing the relativecontributions of APIs resulting from disposal would be useful in justifying the resources thatmight be devoted to controlling this source - - for example, by way of consumer

Concordance of motor vehicle crash, emergency department, and inpatient hospitalization data sets in the identification of drugs in injured drivers.

PubMed

Bunn, T; Singleton, M; Nicholson, V; Slavova, S

2013-01-01

Prescription drug overdoses, abuse, and sales have increased dramatically in the United States in the last decade. The purpose of the present study was to link crash data with emergency department (ED) and inpatient hospitalization data to assess the concordance between the data sets in the identification of the presence of drugs among injured motor vehicle drivers (passenger cars, passenger trucks, light trucks, and semi-trucks) in Kentucky. Kentucky CRASH data were probabilistically linked to ED data sets for years 2008-2010 and to inpatient hospitalization data sets for years 2000-2010. Statistical analyses were performed. Of the 72,529 linked crash/ED visits, there were 473 drivers with an associated nondependent abuse of drugs diagnosis in the ED, and 930 drivers had drug involvement recorded in the CRASH data (only 163 cases overlapped with drug involvement both recorded in CRASH data and coded as nondependent abuse of drugs in the ED); 64 drivers had multiple drug types present in their system. Of the 20,860 total linked crash/inpatient hospitalization cases, there were 973 drivers diagnosed with nondependent abuse of drugs in the inpatient hospitalization record and 499 drivers had drug involvement recorded in the CRASH data (only 207 overlapped); 250 drivers were diagnosed with multiple drugs in their system. Surveillance data from multiple public health data sets is necessary to identify the presence of drugs in injured drivers involved in motor vehicle crashes. The use of a single surveillance data set alone may significantly underreport the number of drugged drivers who were injured in a motor vehicle collision.

Utah Drug Use Questionnaire.

ERIC Educational Resources Information Center

Governor's Citizen Advisory Committee on Drugs, Salt Lake City, UT.

This questionnaire assesses drug use practices in junior and senior high school students. The 21 multiple choice items pertain to drug use practices, use history, available of drugs, main reason for drug use, and demographic data. The questionnaire is untimed, group administered, and may be given by the classroom teacher in about 10 minutes. Item…

Utah Drop-Out Drug Use Questionnaire.

ERIC Educational Resources Information Center

Governor's Citizen Advisory Committee on Drugs, Salt Lake City, UT.

This questionnaire assesses drug use practices in high school drop-outs. The 79 items (multiple choice or apply/not apply) are concerned with demographic data and use, use history, reasons for use/nonuse, attitudes toward drugs, availability of drugs, and drug information with respect to narcotics, amphetamines, LSD, Marijuana, and barbiturates.…

New York Community Environment Study Questionnaire.

ERIC Educational Resources Information Center

Glaser, Daniel; Snow, Mary

This questionnaire assesses neighborhood drug problem concern, drug use practices, knowledge of drugs and agencies dealing with drugs, and views on drug education in persons aged 13 or older. The questionnaire has 31 items (multiple-choice or free response), most with several parts. The items deal with demographic and personal data, problems in…

Experiences in anti-tuberculosis treatment in patients with multiple previous treatments and its impact on drug resistant tuberculosis epidemics

PubMed Central

Xu, Biao; Zhao, Qi; Hu, Yi; Shi, Ying; Wang, Weibing; Diwan, Vinod K.

2014-01-01

Background Tuberculosis (TB) patients with a history of multiple anti-TB treatments are the ‘neglected’ group to the free anti-TB treatment policy in China. Objective To understand the experiences of TB patients with multiple previous treatments with regard to bacteriological diagnosis and treatment regimens, especially for second-line anti-TB drugs, and how this might influence the risks of multidrug and extensively drug-resistant TB (M/XDR-TB). Design A cross-sectional study was conducted in 10 county/district TB clinics in five provinces of China. The study participants were TB patients that had at least two previous treatment episodes that lasted longer than 1 month each. Face-to-face interviews and drug susceptibility testing (DST) were conducted with the consenting participants. Results A total of 328 TB patients were recruited. The proportion of multidrug-resistant tuberculosis (MDR-TB) was 58.2% in the 287 DST-confirmed patients. Forty-two percent of the patients did not complete their first treatment course. About 23.8% of the participants had a history of taking second-line drugs, and more than 77.8% of them were treated in county TB dispensaries where only sputum microscopy was applied. Multivariate analysis found that the use of second-line drugs was significantly associated with frequency of previous treatments (p<0.01), but not with drug resistance profiles of patients. Conclusions Patients with multiple previous treatments are at extremely high risk of MDR-TB in China. The unregulated use of second-line drugs bring about the threat of XDR-TB epidemic. DST-guided treatment and strict regulations of anti-TB treatment should be assured for the high-risk TB patients for the prevention and control of M/XDR-TB. PMID:25138531

Personality, Motivation, and Adolescent Drug Use Patterns

ERIC Educational Resources Information Center

Krug, Samuel E.; Henry, Thomas J.

1974-01-01

Interrelationships between patterns of drug abuse and personality and motivation were determined for male and female subjects. Significant sex differences were found with respect to drug behavior. Females used amphetamines more frequently than males and also showed greater multiple drug use. (Author)

Statistical approaches for the determination of cut points in anti-drug antibody bioassays.

PubMed

Schaarschmidt, Frank; Hofmann, Matthias; Jaki, Thomas; Grün, Bettina; Hothorn, Ludwig A

2015-03-01

Cut points in immunogenicity assays are used to classify future specimens into anti-drug antibody (ADA) positive or negative. To determine a cut point during pre-study validation, drug-naive specimens are often analyzed on multiple microtiter plates taking sources of future variability into account, such as runs, days, analysts, gender, drug-spiked and the biological variability of un-spiked specimens themselves. Five phenomena may complicate the statistical cut point estimation: i) drug-naive specimens may contain already ADA-positives or lead to signals that erroneously appear to be ADA-positive, ii) mean differences between plates may remain after normalization of observations by negative control means, iii) experimental designs may contain several factors in a crossed or hierarchical structure, iv) low sample sizes in such complex designs lead to low power for pre-tests on distribution, outliers and variance structure, and v) the choice between normal and log-normal distribution has a serious impact on the cut point. We discuss statistical approaches to account for these complex data: i) mixture models, which can be used to analyze sets of specimens containing an unknown, possibly larger proportion of ADA-positive specimens, ii) random effects models, followed by the estimation of prediction intervals, which provide cut points while accounting for several factors, and iii) diagnostic plots, which allow the post hoc assessment of model assumptions. All methods discussed are available in the corresponding R add-on package mixADA. Copyright © 2015 Elsevier B.V. All rights reserved.

Social support and amphetamine-type stimulant use among female sex workers in China.

PubMed

Zhao, Qun; Mao, Yuchen; Li, Xiaoming; Zhou, Yuejiao; Shen, Zhiyong

2017-10-01

Existing research has suggested a positive role of social support in reducing drug use among female sex workers (FSWs). However, there is limited research on the role of social support in amphetamine-type stimulant (ATS) use among FSWs in China. This study explored the present situation of ATS use among FSWs in Guangxi, China and examined the associations of different types of social support from different sources with ATS use. A sample of 1022 FSWs was recruited from 56 commercial sex venues in Guangxi Autonomous Region in China. Bivariate comparison was used to compare demographic characteristics and source of emotional or tangible social support across frequency of ATS use among FSWs. The relationship between social support and ATS use was examined using multiple ordinal logistic regression models controlling for the potential confounding effects of demographic variables. The multiple ordinal logistic regression indicated that FSWs who were from younger age groups (aOR = 10.88 for age group <20; aOR = 2.80 for age group 20-23), and from all higher-income venues (aOR = 1.96 for venue level 1; aOR = 2.28 for venue level 2; aOR = 1.81 for venue level 3) tended to use ATS more frequently. They also tended to use ATS more frequently when they depended on their boyfriends (aOR = 1.08) for emotional support or on their co-workers for tangible support (aOR = 1.17). Different types of social support from different sources can be either positively or negatively associated with ATS use among FSWs, therefore, the future intervention efforts should differentiate and target different types and different sources of social support in response to the living and work conditions of FSWs.

Epigenetic polypharmacology: from combination therapy to multitargeted drugs.

PubMed

de Lera, Angel R; Ganesan, A

The modern drug discovery process has largely focused its attention in the so-called magic bullets, single chemical entities that exhibit high selectivity and potency for a particular target. This approach was based on the assumption that the deregulation of a protein was causally linked to a disease state, and the pharmacological intervention through inhibition of the deregulated target was able to restore normal cell function. However, the use of cocktails or multicomponent drugs to address several targets simultaneously is also popular to treat multifactorial diseases such as cancer and neurological disorders. We review the state of the art with such combinations that have an epigenetic target as one of their mechanisms of action. Epigenetic drug discovery is a rapidly advancing field, and drugs targeting epigenetic enzymes are in the clinic for the treatment of hematological cancers. Approved and experimental epigenetic drugs are undergoing clinical trials in combination with other therapeutic agents via fused or linked pharmacophores in order to benefit from synergistic effects of polypharmacology. In addition, ligands are being discovered which, as single chemical entities, are able to modulate multiple epigenetic targets simultaneously (multitarget epigenetic drugs). These multiple ligands should in principle have a lower risk of drug-drug interactions and drug resistance compared to cocktails or multicomponent drugs. This new generation may rival the so-called magic bullets in the treatment of diseases that arise as a consequence of the deregulation of multiple signaling pathways provided the challenge of optimization of the activities shown by the pharmacophores with the different targets is addressed.

Multispectral therapeutic endoscopy imaging and intervention

NASA Astrophysics Data System (ADS)

Bala, John L.; Schwaitzberg, Steven D.

2007-02-01

With the debut of antibiotic drug therapy, and as a result of its ease of use and general success in treating infection, drugs have become the treatment of choice for most bacterial infections. However, the advent of multiple, very aggressive drug-resistant bacteria, an increasing population which cannot tolerate drugs, and the high cost of drug therapy suggest that a new modality for treating infections is needed. The complex interplay of clonal spread, persistence, transfer of resistance elements and cell-to-cell interaction all contribute to the difficulty in developing drugs to treat new antibiotic-resistant bacterial strains. A dynamic non-drug system, using extant pulsed ultraviolet lightwave technology to kill infection, is being developed to destroy pathogens. This paper theorizes that the shock effect of pulsed xenon's high energy ultraviolet pulses at wavelengths between 250-270nm separates the bacteria's DNA bands, and, subsequently, destroys them. Preliminary laboratory tests have demonstrated the ability of the technology to destroy Staphylococcus aureus, Pseudomonas aeruginosa Escherichia coli, Helicobacter pylori, Acinetobacter baumannii, Klebsiella punemonia, Bacillus subtillis, and Aspergillus fumigates at penetration depths of greater than 3mm in fluids with 100% effectiveness in less than five seconds of exposure to pulsed xenon lightwaves. Micro Invasive Technology, Inc is developing .pulsed xenon therapeutic catheters and endoscopic instruments for internal antimicrobial eradication and topographical devices for prophylactic wound, burn and surgical entrance/exit site sterilization. Pulsed Xenon light sources have a broad optical spectrum (190-1200nm), and can generate light pulses with sufficient energy for combined imaging and therapeutic intervention by multiplexing a fiber optic pathway into the body. In addition, Pulsed Xenon has proven ability to activate photo reactive dyes; share endoscopic lightguides with lasers while, simultaneously, capturing high quality visual and activated video images.

Hair-based rapid analyses for multiple drugs in forensics and doping: application of dynamic multiple reaction monitoring with LC-MS/MS.

PubMed

Shah, Iltaf; Petroczi, Andrea; Uvacsek, Martina; Ránky, Márta; Naughton, Declan P

2014-01-01

Considerable efforts are being extended to develop more effective methods to detect drugs in forensic science for applications such as preventing doping in sport. The aim of this study was to develop a sensitive and accurate method for analytes of forensic and toxicological nature in human hair at sub-pg levels. The hair test covers a range of different classes of drugs and metabolites of forensic and toxicological nature including selected anabolic steroids, cocaine, amphetamines, cannabinoids, opiates, bronchodilators, phencyclidine and ketamine. For extraction purposes, the hair samples were decontaminated using dichloromethane, ground and treated with 1 M sodium hydroxide and neutralised with hydrochloric acid and phosphate buffer and the homogenate was later extracted with hexane using liquid-liquid extraction (LLE). Following extraction from hair samples, drug-screening employed liquid chromatography coupled to tandem mass spectrometric (LC-MS/MS) analysis using dynamic multiple reaction monitoring (DYN-MRM) method using proprietary software. The screening method (for > 200 drugs/metabolites) was calibrated with a tailored drug mixture and was validated for 20 selected drugs for this study. Using standard additions to hair sample extracts, validation was in line with FDA guidance. A Zorbax Eclipse plus C18 (2.1 mm internal diameter × 100 mm length × 1.8 μm particle size) column was used for analysis. Total instrument run time was 8 minutes with no noted matrix interferences. The LOD of compounds ranged between 0.05-0.5 pg/mg of hair. 233 human hair samples were screened using this new method and samples were confirmed positive for 20 different drugs, mainly steroids and drugs of abuse. This is the first report of the application of this proprietary system to investigate the presence of drugs in human hair samples. The method is selective, sensitive and robust for the screening and confirmation of multiple drugs in a single analysis and has potential as a very useful tool for the analysis of large array of controlled substances and drugs of abuse.

Surrogate endpoints in clinical trials of chronic kidney disease progression: moving from single to multiple risk marker response scores.

PubMed

Schievink, Bauke; Mol, Peter G M; Lambers Heerspink, Hiddo J

2015-11-01

There is increased interest in developing surrogate endpoints for clinical trials of chronic kidney disease progression, as the established clinically meaningful endpoint end-stage renal disease requires large and lengthy trials to assess drug efficacy. We describe recent developments in the search for novel surrogate endpoints. Declines in estimated glomerular filtration rate (eGFR) of 30% or 40% and albuminuria have been proposed as surrogates for end-stage renal disease. However, changes in eGFR or albuminuria may not be valid under all circumstances as drugs always have effects on multiple renal risk markers. Changes in each of these other 'off-target' risk markers can alter renal risk (either beneficially or adversely), and can thereby confound the relationship between surrogates that are based on single risk markers and renal outcome. Risk algorithms that integrate the short-term drug effects on multiple risk markers to predict drug effects on hard renal outcomes may therefore be more accurate. The validity of these risk algorithms is currently investigated. Given that drugs affect multiple renal risk markers, risk scores that integrate these effects are a promising alternative to using eGFR decline or albuminuria. Proper validation is required before these risk scores can be implemented.

Fitting tissue chips and microphysiological systems into the grand scheme of medicine, biology, pharmacology, and toxicology.

PubMed

Watson, David E; Hunziker, Rosemarie; Wikswo, John P

2017-10-01

Microphysiological systems (MPS), which include engineered organoids (EOs), single organ/tissue chips (TCs), and multiple organs interconnected to create miniature in vitro models of human physiological systems, are rapidly becoming effective tools for drug development and the mechanistic understanding of tissue physiology and pathophysiology. The second MPS thematic issue of Experimental Biology and Medicine comprises 15 articles by scientists and engineers from the National Institutes of Health, the IQ Consortium, the Food and Drug Administration, and Environmental Protection Agency, an MPS company, and academia. Topics include the progress, challenges, and future of organs-on-chips, dissemination of TCs into Pharma, children's health protection, liver zonation, liver chips and their coupling to interconnected systems, gastrointestinal MPS, maturation of immature cardiomyocytes in a heart-on-a-chip, coculture of multiple cell types in a human skin construct, use of synthetic hydrogels to create EOs that form neural tissue models, the blood-brain barrier-on-a-chip, MPS models of coupled female reproductive organs, coupling MPS devices to create a body-on-a-chip, and the use of a microformulator to recapitulate endocrine circadian rhythms. While MPS hardware has been relatively stable since the last MPS thematic issue, there have been significant advances in cell sourcing, with increased reliance on human-induced pluripotent stem cells, and in characterization of the genetic and functional cell state in MPS bioreactors. There is growing appreciation of the need to minimize perfusate-to-cell-volume ratios and respect physiological scaling of coupled TCs. Questions asked by drug developers are followed by an analysis of the potential value, costs, and needs of Pharma. Of highest value and lowest switching costs may be the development of MPS disease models to aid in the discovery of disease mechanisms; novel compounds including probes, leads, and clinical candidates; and mechanism of action of drug candidates. Impact statement Microphysiological systems (MPS), which include engineered organoids and both individual and coupled organs-on-chips and tissue chips, are a rapidly growing topic of research that addresses the known limitations of conventional cellular monoculture on flat plastic - a well-perfected set of techniques that produces reliable, statistically significant results that may not adequately represent human biology and disease. As reviewed in this article and the others in this thematic issue, MPS research has made notable progress in the past three years in both cell sourcing and characterization. As the field matures, currently identified challenges are being addressed, and new ones are being recognized. Building upon investments by the Defense Advanced Research Projects Agency, National Institutes of Health, Food and Drug Administration, Defense Threat Reduction Agency, and Environmental Protection Agency of more than $200 million since 2012 and sizable corporate spending, academic and commercial players in the MPS community are demonstrating their ability to meet the translational challenges required to apply MPS technologies to accelerate drug development and advance toxicology.

Detection of plasmids and class 1 integrons in Salmonella enterica serovar agona isolated from NARMS slaughter samples collected in the years 1997-2003.

PubMed

Douris, Aphrodite; Fedorka-Cray, Paula J; Jackson, Charlene R

2007-01-01

A total of 60 Salmonella enterica serovar Agona isolates (25 pan-susceptible isolates and 35 isolates resistant to five or more antimicrobials) submitted to the National Antimicrobial Resistance Monitoring System-Enteric Bacteria (NARMS) from 1997 through 2003 were examined for plasmids and class 1 integrons. Samples originated from cattle, turkey, chicken, and swine presented at federally inspected slaughter and processing plants. Large plasmids (33-291 kb) were present in 83% of the isolates resistant to five or more antimicrobials; however, 16% of the pan-susceptible isolates also had large plasmids. The presence of large plasmids did not correspond to the isolate source or the year the isolate was recovered but did appear to correspond to XbaI pulsed-field gel electrophoresis (PFGE) patterns. Two sizes of large plasmids appeared most often: 145.4 kb and 97 kb. Class 1 integrons were not detected on plasmids but were detected on the chromosome of 8% (2/25) of the pan-susceptible isolates and 49% (17/35) of the isolates with multiple drug resistance. Expression of multiple drug resistance among S. Agona isolates occurred regardless of the presence of class 1 integrons, suggesting that plasmids play an equally important role in the development of resistant S. Agona. More research is needed to understand better the mechanisms by which S. Agona acquires, harbors, and transfers resistance determinants.

Discovery and resupply of pharmacologically active plant-derived natural products: A review

PubMed Central

Linder, Thomas; Wawrosch, Christoph; Uhrin, Pavel; Temml, Veronika; Wang, Limei; Schwaiger, Stefan; Heiss, Elke H.; Rollinger, Judith M.; Schuster, Daniela; Breuss, Johannes M.; Bochkov, Valery; Mihovilovic, Marko D.; Kopp, Brigitte; Bauer, Rudolf; Dirsch, Verena M.; Stuppner, Hermann

2016-01-01

Medicinal plants have historically proven their value as a source of molecules with therapeutic potential, and nowadays still represent an important pool for the identification of novel drug leads. In the past decades, pharmaceutical industry focused mainly on libraries of synthetic compounds as drug discovery source. They are comparably easy to produce and resupply, and demonstrate good compatibility with established high throughput screening (HTS) platforms. However, at the same time there has been a declining trend in the number of new drugs reaching the market, raising renewed scientific interest in drug discovery from natural sources, despite of its known challenges. In this survey, a brief outline of historical development is provided together with a comprehensive overview of used approaches and recent developments relevant to plant-derived natural product drug discovery. Associated challenges and major strengths of natural product-based drug discovery are critically discussed. A snapshot of the advanced plant-derived natural products that are currently in actively recruiting clinical trials is also presented. Importantly, the transition of a natural compound from a “screening hit” through a “drug lead” to a “marketed drug” is associated with increasingly challenging demands for compound amount, which often cannot be met by re-isolation from the respective plant sources. In this regard, existing alternatives for resupply are also discussed, including different biotechnology approaches and total organic synthesis. While the intrinsic complexity of natural product-based drug discovery necessitates highly integrated interdisciplinary approaches, the reviewed scientific developments, recent technological advances, and research trends clearly indicate that natural products will be among the most important sources of new drugs also in the future. PMID:26281720

A Kernel for Open Source Drug Discovery in Tropical Diseases

PubMed Central

Ortí, Leticia; Carbajo, Rodrigo J.; Pieper, Ursula; Eswar, Narayanan; Maurer, Stephen M.; Rai, Arti K.; Taylor, Ginger; Todd, Matthew H.; Pineda-Lucena, Antonio; Sali, Andrej; Marti-Renom, Marc A.

2009-01-01

Background Conventional patent-based drug development incentives work badly for the developing world, where commercial markets are usually small to non-existent. For this reason, the past decade has seen extensive experimentation with alternative R&D institutions ranging from private–public partnerships to development prizes. Despite extensive discussion, however, one of the most promising avenues—open source drug discovery—has remained elusive. We argue that the stumbling block has been the absence of a critical mass of preexisting work that volunteers can improve through a series of granular contributions. Historically, open source software collaborations have almost never succeeded without such “kernels”. Methodology/Principal Findings Here, we use a computational pipeline for: (i) comparative structure modeling of target proteins, (ii) predicting the localization of ligand binding sites on their surfaces, and (iii) assessing the similarity of the predicted ligands to known drugs. Our kernel currently contains 143 and 297 protein targets from ten pathogen genomes that are predicted to bind a known drug or a molecule similar to a known drug, respectively. The kernel provides a source of potential drug targets and drug candidates around which an online open source community can nucleate. Using NMR spectroscopy, we have experimentally tested our predictions for two of these targets, confirming one and invalidating the other. Conclusions/Significance The TDI kernel, which is being offered under the Creative Commons attribution share-alike license for free and unrestricted use, can be accessed on the World Wide Web at http://www.tropicaldisease.org. We hope that the kernel will facilitate collaborative efforts towards the discovery of new drugs against parasites that cause tropical diseases. PMID:19381286

Duplicative medications in patients who visit multiple medical institutions among the insured of a corporate health insurance society in Japan.

PubMed

Kinoshita, Hiroki; Kobayashi, Yasuki; Fukuda, Takashi

2008-01-01

The objective of this paper is to describe the frequency of duplicative medication use and to estimate the drug cost associated with duplicative medications in patients who visit multiple medical institutions in Japan. The subjects of this study were insurants of a corporate health insurance society. We examined claims of insurants who received prescriptions from multiple medical institutions in April 2002. We examined characteristics of insurants who received duplicative medications and calculated the cost of duplicated drugs. 8.8% received drugs with the same mechanism of action for overlapping administration periods. In terms of comparison among three age groups, 0-19 years old, 20-69 years old, and 70 years old or older, the percentage was higher in 0-19-year-old patients than in the other age groups. The cost of duplicated drugs was found to be 0.7% or 0.5% of the total drug cost, when calculated with higher-priced drugs and lower-priced drugs, respectively. This study suggests that pediatric and teenage patients as well as elderly patients require prudent management of medication to avoid duplicative medications and that at least an estimated 5.2-7.2 billion yen may be saved if duplicative medications can be completely eliminated nationwide.

Incidence of Exposure of Patients in the United States to Multiple Drugs for Which Pharmacogenomic Guidelines Are Available.

PubMed

Samwald, Matthias; Xu, Hong; Blagec, Kathrin; Empey, Philip E; Malone, Daniel C; Ahmed, Seid Mussa; Ryan, Patrick; Hofer, Sebastian; Boyce, Richard D

2016-01-01

Pre-emptive pharmacogenomic (PGx) testing of a panel of genes may be easier to implement and more cost-effective than reactive pharmacogenomic testing if a sufficient number of medications are covered by a single test and future medication exposure can be anticipated. We analysed the incidence of exposure of individual patients in the United States to multiple drugs for which pharmacogenomic guidelines are available (PGx drugs) within a selected four-year period (2009-2012) in order to identify and quantify the incidence of pharmacotherapy in a nation-wide patient population that could be impacted by pre-emptive PGx testing based on currently available clinical guidelines. In total, 73 024 095 patient records from private insurance, Medicare Supplemental and Medicaid were included. Patients enrolled in Medicare Supplemental age > = 65 or Medicaid age 40-64 had the highest incidence of PGx drug use, with approximately half of the patients receiving at least one PGx drug during the 4 year period and one fourth to one third of patients receiving two or more PGx drugs. These data suggest that exposure to multiple PGx drugs is common and that it may be beneficial to implement wide-scale pre-emptive genomic testing. Future work should therefore concentrate on investigating the cost-effectiveness of multiplexed pre-emptive testing strategies.

Molecular Insights into the Effects of Media-Drug and Carrier-Drug Interactions on pH-Responsive Drug Carriers.

PubMed

Katiyar, Ratna S; Jha, Prateek K

2018-05-10

We have performed two sets of all atom molecular dynamics (MD) simulations of poly(acrylic acid) (PAA) oligomers, considered as a model pH-responsive drug carrier. In the first set, multiple oligomers of PAA are simulated in model gastric and intestinal fluids, where the degree of deprotonation of PAA oligomers is varied with the medium pH. Since the gastric fluid has a pH substantially lower than that of intestinal fluid, PAA is relatively lesser ionized in gastric fluid and forms aggregates. In the second set, we simulated multiple oligomers of PAA with multiple molecules of a cationic anticancer drug, doxorubicin (DOX), for a range of pH values representative of various physiological conditions. The diffusion coefficient of DOX decreases with an increase in pH due to an increase in the ionic complexation of PAA with DOX, despite a decrease in PAA aggregation. Our findings are in agreement with recent experimental reports on pH-triggered targeting of tumor cells by the PAA-DOX system. Results of these two sets of studies establish that both carrier aggregation and carrier-drug interactions are competing influences that together determine the drug release from pH-responsive polymers.

Controlling subcellular delivery to optimize therapeutic effect

PubMed Central

Mossalam, Mohanad; Dixon, Andrew S; Lim, Carol S

2010-01-01

This article focuses on drug targeting to specific cellular organelles for therapeutic purposes. Drugs can be delivered to all major organelles of the cell (cytosol, endosome/lysosome, nucleus, nucleolus, mitochondria, endoplasmic reticulum, Golgi apparatus, peroxisomes and proteasomes) where they exert specific effects in those particular subcellular compartments. Delivery can be achieved by chemical (e.g., polymeric) or biological (e.g., signal sequences) means. Unidirectional targeting to individual organelles has proven to be immensely successful for drug therapy. Newer technologies that accommodate multiple signals (e.g., protein switch and virus-like delivery systems) mimic nature and allow for a more sophisticated approach to drug delivery. Harnessing different methods of targeting multiple organelles in a cell will lead to better drug delivery and improvements in disease therapy. PMID:21113240

Polypharmacology of Approved Anticancer Drugs.

PubMed

Amelio, Ivano; Lisitsa, Andrey; Knight, Richard A; Melino, Gerry; Antonov, Alexey V

2017-01-01

The major drug discovery efforts in oncology have been concentrated on the development of selective molecules that are supposed to act specifically on one anticancer mechanism by modulating a single or several closely related drug targets. However, a bird's eye view on data from multiple available bioassays implies that most approved anticancer agents do, in fact, target many more proteins with different functions. Here we will review and systematize currently available information on the targets of several anticancer drugs along with revision of their potential mechanisms of action. Polypharmacology of the current antineoplastic agents suggests that drug clinical efficacy in oncology can be achieved only via modulation of multiple cellular mechanisms. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

[Psychoactive substances use and health-related quality of life among school age adolescents].

PubMed

Vilugrón Aravena, Fabiola; Hidalgo-Rasmussen, Carlos Alejandro; Molina G, Temístocles; Gras Pérez, María Eugenia; Font-Mayolas, Silvia

2017-12-01

Background The use of psychoactive substances among adolescents is a major social and public health concern. Aim To analyze association of substance abuse and multiple drug use with health-related quality of life (HRQOL) in adolescents attending a high school in Valparaiso, Chile. Material and Methods Analytical cross-sectional study conducted in a sample of adolescents attending high school. HRQOL was assessed using KIDSCREEN-52 questionnaire and substance use was measured using the Global school-based student health survey. Participants had to complete online, self-administered, anonymous questionnaires. Multiple logistic regression analyses were conducted to calculate Odd ratios. Results A total of 550 adolescents aged 16 ± 1 years old completed the questionnaires. Thirty nine percent consumed alcohol during the last month, 31% smoked, 33% used marijuana and 33% admitted the use of multiple drugs. High-risk alcohol consumption was associated with a lower perception of psychological well-being, self-perception and school environment. This last dimension was affected in those who admitted marijuana use during the last month. Multiple drug use (three substances) was associated with a lower perception of physical and psychological well-being, self-perception, relationship with parents, family life and school environment. Conclusions High-risk alcohol consumption and multiple drug use (three substances) have a negative impact on the HRQOL of school age adolescents.

Depression and social support among women living with the substance abuse, violence, and HIV/AIDS syndemic: a qualitative exploration.

PubMed

Illangasekare, Samantha L; Burke, Jessica G; Chander, Geetanjali; Gielen, Andrea C

2014-01-01

Intimate partner violence (IPV), HIV/AIDS, and substance use are described as the SAVA "syndemic" among low-income urban women because of their intersecting and synergistic presence in these women's lives. Depressive symptoms are significantly associated with these SAVA factors and although social support is potentially protective for depression, little is understood about its impact on depression associated with the SAVA syndemic. This paper investigates how women living with SAVA experience and describe depressive symptoms, and examines how the types of social support they access impact their experiences of SAVA and depressive symptoms. Qualitative, in-depth interviews were conducted with 24 HIV-positive, low-income, urban women who experienced IPV and used cocaine or heroin in their lifetime. Interviews were analyzed based on study aims, principles of thematic content analysis, and grounded theory. Women identified multiple SAVA factors as catalysts for depression and noted their synergistic effect on depressive symptoms, which were both a trigger for and a result of drug use. Women accessed varying sources of social support to address their SAVA factors and associated symptoms of depression, relying on informal sources for instrumental support related to IPV and formal sources for support related to HIV, drug use, and depression. These findings have important implications for health providers who serve SAVA-affected women, and suggest that comprehensively addressing all SAVA factors (and IPV in particular) and improving their access to quality social support at critical times is essential to improve their mental health. Copyright © 2014 Jacobs Institute of Women's Health. Published by Elsevier Inc. All rights reserved.

Healthcare resource utilization following switch or discontinuation in multiple sclerosis patients on disease modifying drugs.

PubMed

Reynolds, Matthew W; Stephen, Reejis; Seaman, Chris; Rajagopalan, Kitty

2010-03-01

The objective of this study was to explore the cost and utilization in the period following discontinuations or switches of disease modifying drugs (DMDs) for patients with multiple sclerosis (MS). Secondary objectives included an assessment of the time to switch or discontinuation from index DMD treatment. Cases were defined as a billed MS diagnosis in continuously enrolled patients initiated with interferon-beta1a IM, interferon-beta1b SC, glatiramer acetate, and interferon-beta1a SC found in the PharMetrics Patient-Centric Database. Information on patient demographics, diagnoses, procedures, pharmacy-dispensed drugs, and costs was extracted; reasons for discontinuation and expenses outside of the healthcare system were not available. Treatment discontinuations and switches between study drugs were defined using pharmacy prescription patterns and analyzed by descriptive and regression methods. The non-pharmacy medical costs in the 18 months following switching or discontinuation were compared to the costs in a randomly selected similar period for those patients who did not switch or discontinue these agents. A total of 5,772 MS patients were continuously enrolled and were treated with one or more of the four drugs of interest, and about half of these patients switched drugs or discontinued treatment for at least 90 days. Patients initiated with interferon-beta1b SC were more likely to discontinue treatment compared to interferon-beta1a IM users. Non-pharmaceutical medical costs were highest for those switching treatments followed by those discontinuing DMDs in the 18 months following a switch or discontinuation, compared to persistent users of these drugs. Interferon beta1b SC initiators had higher costs following changes or discontinuations, while glatiramer acetate and interferon-beta1a SC users had lower subsequent costs compared to interferon-beta1a IM users. Unfortunately, the reasons for stopping the initial treatment cannot be determined from analysis of an administrative claims database. Also, the MS cases followed in this analysis are billing diagnostic events unconfirmed through a review of medical records or other data sources. The results are unstratified in terms of severity and thus while treatment patterns may vary for patients with different types of MS (e.g., progressive vs. relapsing-remitting), this cannot be examined in this analysis. Changing or discontinuing DMDs is common among MS patients and is associated with higher non-pharmaceutical medical costs that vary based on the initiating drug and other demographics characteristics.

Multi-drug loaded micelles delivering chemotherapy and targeted therapies directed against HSP90 and the PI3K/AKT/mTOR pathway in prostate cancer.

PubMed

Le, Bao; Powers, Ginny L; Tam, Yu Tong; Schumacher, Nicholas; Malinowski, Rita L; Steinke, Laura; Kwon, Glen; Marker, Paul C

2017-01-01

Advanced prostate cancers that are resistant to all current therapies create a need for new therapeutic strategies. One recent innovative approach to cancer therapy is the simultaneous use of multiple FDA-approved drugs to target multiple pathways. A challenge for this approach is caused by the different solubility requirements of each individual drug, resulting in the need for a drug vehicle that is non-toxic and capable of carrying multiple water-insoluble antitumor drugs. Micelles have recently been shown to be new candidate drug solubilizers for anti cancer therapy. This study set out to examine the potential use of multi-drug loaded micelles for prostate cancer treatment in preclinical models including cell line and mouse models for prostate cancers with Pten deletions. Specifically antimitotic agent docetaxel, mTOR inhibitor rapamycin, and HSP90 inhibitor 17-N-allylamino-17-demethoxygeldanamycin were incorporated into the micelle system (DR17) and tested for antitumor efficacy. In vitro growth inhibition of prostate cancer cells was greater when all three drugs were used in combination compared to each individual drug, and packaging the drugs into micelles enhanced the cytotoxic effects. At the molecular level DR17 targeted simultaneously several molecular signaling axes important in prostate cancer including androgen receptor, mTOR, and PI3K/AKT. In a mouse genetic model of prostate cancer, DR17 treatment decreased prostate weight, which was achieved by both increasing caspase-dependent cell death and decreasing cell proliferation. Similar effects were also observed when DR17 was administered to nude mice bearing prostate cancer cells xenografts. These results suggest that combining these three cancer drugs in multi-drug loaded micelles may be a promising strategy for prostate cancer therapy.

Knowledge, Attitudes, and Substance Use Practices Among Street Children in Western Kenya

PubMed Central

Embleton, Lonnie; Ayuku, David; Atwoli, Lukoye; Vreeman, Rachel; Braitstein, Paula

2013-01-01

The study describes the knowledge of and attitudes toward substance use among street-involved youth in Kenya, and how they relate to their substance use practices. In 2011, 146 children and youth ages 10–19 years, classified as either children on the street or children of the street were recruited to participate in a cross-sectional survey in Eldoret, Kenya. Bivariate analysis using χ2 or Fisher’s Exact Test was used to test the associations between variables, and multiple logistic regression analysis was used to identify independent covariates associated with lifetime and current drug use. The study’s limitations and source of funding are noted. PMID:22780841

Substance use and experienced stigmatization among ethnic minority men who have sex with men in the United States.

PubMed

Paul, Jay P; Boylan, Ross; Gregorich, Steve; Ayala, George; Choi, Kyung-Hee

2014-01-01

Research has documented deleterious effects of racism among ethnic minorities and of homophobia among men who have sex with men (MSM). Less is known about the impact of multiple forms of stigmatization on ethnic minority MSM. This study examined substance use by African American, Asian/Pacific Islander and Latino MSM, and the associations of experienced racism and homophobia from various sources with polydrug use and stimulant drug use. Experienced racism within the general community was associated with higher levels of use; other forms of discrimination were either not associated with polydrug or stimulant use or had more complex relationships with use. Implications for further research and interventions are discussed.

Conestat alfa for the treatment of angioedema attacks

PubMed Central

Davis, Benjamin; Bernstein, Jonathan A

2011-01-01

Recently, multiple C1 inhibitor (C1-INH) replacement products have been approved for the treatment of hereditary angioedema (HAE). This review summarizes HAE and its current treatment modalities and focuses on findings from bench to bedside trials of a new C1-INH replacement, conestat alfa. Conestat alfa is unique among the other C1-INH replacement products because it is produced from transgenic rabbits rather than derived from human plasma donors, which can potentially allow an unlimited source of drug without any concern of infectious transmission. The clinical trial data generated to date indicate that conestat alfa is safe and effective for the treatment of acute HAE attacks. PMID:21753889

Messages about methadone and buprenorphine in reality television: a content analysis of celebrity rehab with Dr. Drew.

PubMed

Roose, Robert; Fuentes, Liza; Cheema, Mandeep

2012-08-01

Medication-assisted treatment for opioid dependence is safe and effective, yet negative perceptions about methadone and buprenorphine may discourage patients from entering treatment. One source of information that may influence viewers' perceptions is television. We performed a content analysis of a popular reality television program on addiction treatment. Although many patients had histories of opioid use, there were no positive messages about methadone or buprenorphine. The two main messages were that they (1) are primarily drugs of abuse, and (2) not acceptable treatment options. These messages reinforce negative stereotypes and may perpetuate stigma. There were multiple missed opportunities to provide evidence-based information.

Heterogeneous data fusion for brain tumor classification.

PubMed

Metsis, Vangelis; Huang, Heng; Andronesi, Ovidiu C; Makedon, Fillia; Tzika, Aria

2012-10-01

Current research in biomedical informatics involves analysis of multiple heterogeneous data sets. This includes patient demographics, clinical and pathology data, treatment history, patient outcomes as well as gene expression, DNA sequences and other information sources such as gene ontology. Analysis of these data sets could lead to better disease diagnosis, prognosis, treatment and drug discovery. In this report, we present a novel machine learning framework for brain tumor classification based on heterogeneous data fusion of metabolic and molecular datasets, including state-of-the-art high-resolution magic angle spinning (HRMAS) proton (1H) magnetic resonance spectroscopy and gene transcriptome profiling, obtained from intact brain tumor biopsies. Our experimental results show that our novel framework outperforms any analysis using individual dataset.

Fatal poisonings involving propoxyphene before and after voluntary withdrawal from the United States' market: An analysis from the state of Florida.

PubMed

Delcher, Chris; Chen, Guanming; Wang, Yanning; Slavova, Svetla; Goldberger, Bruce A

2017-11-01

The synthetic opioid propoxyphene was a schedule IV controlled substance with multiple reported health risks before the US Food and Drug Administration issued a request for voluntary market withdrawal in November 2010. The purpose of this study is to investigate the characteristics and occurrences of propoxyphene-related deaths in Florida before and after voluntary market removal. Decedent-level toxicology data from Florida's Medical Examiners Commission was used to compare the temporal, polysubstance use, sociodemographic, and geographic profiles associated with propoxyphene-involved deaths for a pre-withdrawal (November 2008-November 2010) and post-withdrawal (December 2010-December 2012) period. Sensitivity analyses using multiple data sources, including Florida's Prescription Drug Monitoring Program and other states' data, were conducted to examine potential reporting bias. Results showed that the number of propoxyphene-involved deaths declined by 84% from 580 deaths to 92 deaths after market withdrawal. The co-occurrence of other prevalent drugs, such as oxycodone (17.2% to 26.1%, p=0.0422) increased significantly in the post-withdrawal study period. A larger proportion of the propoxyphene-related deaths were reported from South Florida after the withdrawal (28.4% to 56.5%, p<0.0001). No significant changes in age and race/ethnicity were observed. Sensitivity analyses revealed that several deaths occurred in other states after market withdrawal, as recently as 2016. Our findings are consistent with previous studies that propoxyphene was still available after removal from the US market. Continued surveillance is recommended after highly abused opioids are withdrawn from the market due to on-going safety risks. Copyright © 2017 Elsevier B.V. All rights reserved.

Effects of Drugs and Drug Combinations in Pigeons Trained to Discriminate among Pentobarbital, Dizocilpine, a Combination of These Drugs, and Saline

ERIC Educational Resources Information Center

McMillan, D. E.; Wessinger, William D.; Li, Mi

2009-01-01

Drugs with multiple actions can have complex discriminative-stimulus properties. An approach to studying such drugs is to train subjects to discriminate among drug combinations and individual drugs in the combination so that all of the complex discriminative stimuli are present during training. In the current experiments, a four-choice procedure…

Chemical proteomics for target discovery of head-to-tail cyclized mini-proteins

NASA Astrophysics Data System (ADS)

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

2017-10-01

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

On the possibility of the multiple inductively coupled plasma and helicon plasma sources for large-area processes

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

Lee, Jin-Won; Lee, Yun-Seong, E-mail: leeeeys@kaist.ac.kr; Chang, Hong-Young

2014-08-15

In this study, we attempted to determine the possibility of multiple inductively coupled plasma (ICP) and helicon plasma sources for large-area processes. Experiments were performed with the one and two coils to measure plasma and electrical parameters, and a circuit simulation was performed to measure the current at each coil in the 2-coil experiment. Based on the result, we could determine the possibility of multiple ICP sources due to a direct change of impedance due to current and saturation of impedance due to the skin-depth effect. However, a helicon plasma source is difficult to adapt to the multiple sources duemore » to the consistent change of real impedance due to mode transition and the low uniformity of the B-field confinement. As a result, it is expected that ICP can be adapted to multiple sources for large-area processes.« less

University of Michigan Drug Education Questionnaire.

ERIC Educational Resources Information Center

Francis, John Bruce; Patch, David J.

This questionnaire assesses attitudes toward potential drug education programs and drug use practices in college students. The 87 items (multiple choice or free response) pertain to the history and extent of usage of 27 different drugs, including two non-existent drugs which may be utilized as a validity check; attitude toward the content, format,…

77 FR 2724 - CVS Caremark Corporation; Analysis of Proposed Consent Order To Aid Public Comment

Federal Register 2010, 2011, 2012, 2013, 2014

2012-01-19

... Medicare drug plans and Medicare Part D drugs. CVSC currently owns multiple subsidiaries, including RxAmerica, that offer Medicare Part D prescription drug plans. Medicare Part D is a prescription drug... Part D benefits, beneficiaries must enroll in a Medicare drug plan administered by an insurer or other...

Assessing the Financial Benefits of Faster Development Times: The Case of Single-source Versus Multi-vendor Outsourced Biopharmaceutical Manufacturing.

PubMed

DiMasi, Joseph A; Smith, Zachary; Getz, Kenneth A

2018-05-10

The extent to which new drug developers can benefit financially from shorter development times has implications for development efficiency and innovation incentives. We provided a real-world example of such gains by using recent estimates of drug development costs and returns. Time and fee data were obtained on 5 single-source manufacturing projects. Time and fees were modeled for these projects as if the drug substance and drug product processes had been contracted separately from 2 vendors. The multi-vendor model was taken as the base case, and financial impacts from single-source contracting were determined relative to the base case. The mean and median after-tax financial benefits of shorter development times from single-source contracting were $44.7 million and $34.9 million, respectively (2016 dollars). The after-tax increases in sponsor fees from single-source contracting were small in comparison (mean and median of $0.65 million and $0.25 million). For the data we examined, single-source contracting yielded substantial financial benefits over multi-source contracting, even after accounting for somewhat higher sponsor fees. Copyright © 2018 Elsevier HS Journals, Inc. All rights reserved.

21 CFR 516.129 - Content and format of a request for determination of eligibility for indexing.

Code of Federal Regulations, 2012 CFR

2012-04-01

... of eligibility for indexing. 516.129 Section 516.129 Food and Drugs FOOD AND DRUG ADMINISTRATION... Species § 516.129 Content and format of a request for determination of eligibility for indexing. (a) Each... request for determination of eligibility for indexing may involve multiple intended uses and/or multiple...

21 CFR 516.129 - Content and format of a request for determination of eligibility for indexing.

Code of Federal Regulations, 2014 CFR

2014-04-01

... of eligibility for indexing. 516.129 Section 516.129 Food and Drugs FOOD AND DRUG ADMINISTRATION... Species § 516.129 Content and format of a request for determination of eligibility for indexing. (a) Each... request for determination of eligibility for indexing may involve multiple intended uses and/or multiple...

21 CFR 516.129 - Content and format of a request for determination of eligibility for indexing.

Code of Federal Regulations, 2013 CFR

2013-04-01

... of eligibility for indexing. 516.129 Section 516.129 Food and Drugs FOOD AND DRUG ADMINISTRATION... Species § 516.129 Content and format of a request for determination of eligibility for indexing. (a) Each... request for determination of eligibility for indexing may involve multiple intended uses and/or multiple...

A practical approach to reduce interference due to in-source collision-induced dissociation of acylglucuronides in LC-MS/MS.

PubMed

Mess, Jean-Nicholas; Bérubé, Eugénie-Raphaelle; Furtado, Milton; Garofolo, Fabio

2011-08-01

In LC-MS/MS, glucuronide conjugated metabolites may convert back to the parent drug due to in-source collision-induced dissociation (CID). During the bioanalysis of naproxen, it was noticed that naproxen acylglucuronide exhibited intense in-source CID to the naproxen [M+H](+) ion under positive ESI. However, no in-source CID of the acylglucuronide to the naproxen [M+NH(4)](+) adduct was observed. Furthermore, absolutely no in-source CID was detected under negative ESI. This phenomenon was not only observed for naproxen acylglucuronide but for eight other acylglucuronides compounds. We have shown that monitoring the parent drug [M-H](-) or [M+NH(4)](+) whenever possible could be an easy approach used by bioanalytical scientists to minimize the impact of in-source CID of acylglucuronides to the parent drug.

Drug Resistance in Newly Presenting and Previously Treated Tuberculosis Patients in Guangxi Province, People's Republic of China.

PubMed

Luo, Dan; Zhao, Jinming; Lin, Mei; Liu, Feiying; Huang, Shuhai; Zhang, Yingkun; Huang, Minying; Li, Juan; Zhou, Yang; Lan, Rushu; Zhao, Yanlin

2017-05-01

Drug-resistant Mycobacterium tuberculosis strains are a major threat to the control of tuberculosis (TB), but the prevalence of drug-resistant TB is still unknown in the southern ethnic region of China. A cluster-randomized sampling method was used to include the study population. Isolates were tested for resistance to 6 antituberculosis drugs, and genotyped to identify Beijing strains. Overall, 11.3% (139/1229) of new cases and 33.0% (126/382) of retreated cases had drug-resistant tuberculosis. Multiple previous TB treatment episodes and multiple treatment interruptions were risk factors for both drug-resistant and multidrug-resistant TB among retreated cases. A total of 53.2% of the patients were infected with a Beijing strain of M tuberculosis. Infection with a Beijing strain was significantly associated with drug resistance among new cases (odds ratio, 1.44; 95% CI, 1.01-2.07). Novel strategies to rapid diagnosis and effective treatment are urgently needed to prevent the development of drug resistance.

Evaluation of Electroencephalography Source Localization Algorithms with Multiple Cortical Sources.

PubMed

Bradley, Allison; Yao, Jun; Dewald, Jules; Richter, Claus-Peter

2016-01-01

Source localization algorithms often show multiple active cortical areas as the source of electroencephalography (EEG). Yet, there is little data quantifying the accuracy of these results. In this paper, the performance of current source density source localization algorithms for the detection of multiple cortical sources of EEG data has been characterized. EEG data were generated by simulating multiple cortical sources (2-4) with the same strength or two sources with relative strength ratios of 1:1 to 4:1, and adding noise. These data were used to reconstruct the cortical sources using current source density (CSD) algorithms: sLORETA, MNLS, and LORETA using a p-norm with p equal to 1, 1.5 and 2. Precision (percentage of the reconstructed activity corresponding to simulated activity) and Recall (percentage of the simulated sources reconstructed) of each of the CSD algorithms were calculated. While sLORETA has the best performance when only one source is present, when two or more sources are present LORETA with p equal to 1.5 performs better. When the relative strength of one of the sources is decreased, all algorithms have more difficulty reconstructing that source. However, LORETA 1.5 continues to outperform other algorithms. If only the strongest source is of interest sLORETA is recommended, while LORETA with p equal to 1.5 is recommended if two or more of the cortical sources are of interest. These results provide guidance for choosing a CSD algorithm to locate multiple cortical sources of EEG and for interpreting the results of these algorithms.

Evaluation of Electroencephalography Source Localization Algorithms with Multiple Cortical Sources

PubMed Central

Bradley, Allison; Yao, Jun; Dewald, Jules; Richter, Claus-Peter

2016-01-01

Background Source localization algorithms often show multiple active cortical areas as the source of electroencephalography (EEG). Yet, there is little data quantifying the accuracy of these results. In this paper, the performance of current source density source localization algorithms for the detection of multiple cortical sources of EEG data has been characterized. Methods EEG data were generated by simulating multiple cortical sources (2–4) with the same strength or two sources with relative strength ratios of 1:1 to 4:1, and adding noise. These data were used to reconstruct the cortical sources using current source density (CSD) algorithms: sLORETA, MNLS, and LORETA using a p-norm with p equal to 1, 1.5 and 2. Precision (percentage of the reconstructed activity corresponding to simulated activity) and Recall (percentage of the simulated sources reconstructed) of each of the CSD algorithms were calculated. Results While sLORETA has the best performance when only one source is present, when two or more sources are present LORETA with p equal to 1.5 performs better. When the relative strength of one of the sources is decreased, all algorithms have more difficulty reconstructing that source. However, LORETA 1.5 continues to outperform other algorithms. If only the strongest source is of interest sLORETA is recommended, while LORETA with p equal to 1.5 is recommended if two or more of the cortical sources are of interest. These results provide guidance for choosing a CSD algorithm to locate multiple cortical sources of EEG and for interpreting the results of these algorithms. PMID:26809000

Multiple Sources of Prescription Payment and Risky Opioid Therapy Among Veterans.

PubMed

Becker, William C; Fenton, Brenda T; Brandt, Cynthia A; Doyle, Erin L; Francis, Joseph; Goulet, Joseph L; Moore, Brent A; Torrise, Virginia; Kerns, Robert D; Kreiner, Peter W

2017-07-01

Opioid overdose and other related harms are a major source of morbidity and mortality among US Veterans, in part due to high-risk opioid prescribing. We sought to determine whether having multiple sources of payment for opioids-as a marker for out-of-system access-is associated with risky opioid therapy among veterans. Cross-sectional study examining the association between multiple sources of payment and risky opioid therapy among all individuals with Veterans Health Administration (VHA) payment for opioid analgesic prescriptions in Kentucky during fiscal year 2014-2015. Source of payment categories: (1) VHA only source of payment (sole source); (2) sources of payment were VHA and at least 1 cash payment [VHA+cash payment(s)] whether or not there was a third source of payment; and (3) at least one other noncash source: Medicare, Medicaid, or private insurance [VHA+noncash source(s)]. Our outcomes were 2 risky opioid therapies: combination opioid/benzodiazepine therapy and high-dose opioid therapy, defined as morphine equivalent daily dose ≥90 mg. Of the 14,795 individuals in the analytic sample, there were 81.9% in the sole source category, 6.6% in the VHA+cash payment(s) category, and 11.5% in the VHA+noncash source(s) category. In logistic regression, controlling for age and sex, persons with multiple payment sources had significantly higher odds of each risky opioid therapy, with those in the VHA+cash having significantly higher odds than those in the VHA+noncash source(s) group. Prescribers should examine the prescription monitoring program as multiple payment sources increase the odds of risky opioid therapy.

Surveillance of drug abuse in Hong Kong by hair analysis using LC-MS/MS.

PubMed

Leung, K Wing; Wong, Zack C F; Ho, Janet Y M; Yip, Ada W S; Cheung, Jerry K H; Ho, Karen K L; Duan, Ran; Tsim, Karl W K

2018-06-01

The aim of this study is to reveal the habits of drug abusers in hair samples from drug rehabilitation units in Hong Kong. With the application of liquid chromatography-tandem mass spectrometry (LC-MS/MS) technology, a total of 1771 hair samples were analyzed during the period of hair testing service (January 2012 to March 2016) provided to 14 drug rehabilitation units including non-governmental organizations (NGOs), rehabilitation centers, and medical clinics. Hair samples were analyzed for abused drugs and their metabolites simultaneously, including ketamine, norketamine, cocaine, benzoylecgonine, cocaethylene, norcocaine, codeine, MDMA, MDA, MDEA, amphetamine, methamphetamine, morphine, 6-acetylmorphine, phencyclidine, and methadone. The results showed that ketamine (77.2%), cocaine (21.3%), and methamphetamine (16.5%) were the frequently detected drugs among those drug abusers, which is consistent with the reported data. In addition, the usage of multiple drugs was also observed in the hair samples. About 29% of drug-positive samples were detected with multiple drug use. Our studies prove that our locally developed hair drug-testing method and service can be a valid tool to monitor the use of abused drugs, and which could facilitate rehabilitation program management. Copyright © 2017 John Wiley & Sons, Ltd.

Organic nanoparticle systems for spatiotemporal control of multimodal chemotherapy

PubMed Central

Meng, Fanfei; Han, Ning; Yeo, Yoon

2017-01-01

Introduction Chemotherapeutic drugs are used in combination to target multiple mechanisms involved in cancer cell survival and proliferation. Carriers are developed to deliver drug combinations to common target tissues in optimal ratios and desirable sequences. Nanoparticles (NP) have been a popular choice for this purpose due to their ability to increase the circulation half-life and tumor accumulation of a drug. Areas covered We review organic NP carriers based on polymers, proteins, peptides, and lipids for simultaneous delivery of multiple anticancer drugs, drug/sensitizer combinations, drug/photodynamic- or photothermal therapy combinations, and drug/gene therapeutics with examples in the past three years. Sequential delivery of drug combinations, based on either sequential administration or built-in release control, is introduced with an emphasis on the mechanistic understanding of such control. Expert opinion Recent studies demonstrate how a drug carrier can contribute to co-localizing drug combinations in optimal ratios and dosing sequences to maximize the synergistic effects. We identify several areas for improvement in future research, including the choice of drug combinations, circulation stability of carriers, spatiotemporal control of drug release, and the evaluation and clinical translation of combination delivery. PMID:27476442

Thromboelastographic evidence of inhibition of fibrinolysis after ε-aminocaproic acid administration in a dog with suspected acute traumatic coagulopathy.

PubMed

Yoo, Seung H; Venn, Emilee; Sullivan, Lauren A; Olver, Christine S

2016-09-01

To describe the thromboelastographic changes in fibrinolysis with ε-aminocaproic acid treatment in a dog with suspected acute traumatic coagulopathy. A 9-year-old female spayed Airedale Terrier was presented with multiple injuries consistent with motor vehicle trauma. After surgical repair of a diaphragmatic hernia and minor laceration of the right cranial lung lobe, the dog continued to produce copious volumes of hemorrhagic fluid from the thoracic cavity despite multiple plasma transfusions, autotransfusions, and failure to locate a definitive source of bleeding during 2 separate surgeries. ε-Aminocaproic acid treatment was initiated and was associated with rapid clinical improvement and diminished fibrinolysis based on a modified plasma-based thromboelastogram. This report describes thromboelastographic evidence of inhibition of fibrinolysis after ε-aminocaproic acid administration in a dog with suspected acute traumatic coagulopathy. Thromboelastrography may be useful in monitoring therapy with antifibrinolytic drugs. © Veterinary Emergency and Critical Care Society 2016.

Advancement of multifunctional hybrid nanogel systems: Construction and application in drug co-delivery and imaging technique.

PubMed

Ma, Yakun; Ge, Yanxiu; Li, Lingbing

2017-02-01

Nanogel-based multifunctional drug delivery systems, especially hybrid nanogels and multicompartment nanogels have drawn more and more extensive attention from the researchers in pharmacy because it can result in achieving a superior functionality through the synergistic property enhancement of each component. The unique hybrid and compartmentalized structures provide the great potential for co-delivery of multiple agents even the multiple agents with different physicochemical properties. Otherwise the hybrid nanogel encapsulating optical and magnetic resonance imaging contrast can be utilized in imaging technique for disease diagnosis. More importantly through nanogel-based multifunctional drug delivery systems the stimuli-responsive features might be easily employed for the design of targeted release of drug. This review summarizes the construction of diverse hybrid nanogels and multicompartment nanogels. The application in co-delivery of multiple agents and imaging agents for diagnosis as well as the application in the design of stimuli-responsive multifunctional nanogels as drug delivery are also reviewed and discussed. The future prospects in application of multifunctional nanogels will be also discussed in this review. Copyright © 2016 Elsevier B.V. All rights reserved.

Characterization of p38 MAPK isoforms for drug resistance study using systems biology approach.

PubMed

Peng, Huiming; Peng, Tao; Wen, Jianguo; Engler, David A; Matsunami, Risë K; Su, Jing; Zhang, Le; Chang, Chung-Che Jeff; Zhou, Xiaobo

2014-07-01

p38 mitogen-activated protein kinase activation plays an important role in resistance to chemotherapeutic cytotoxic drugs in treating multiple myeloma (MM). However, how the p38 mitogen-activated protein kinase signaling pathway is involved in drug resistance, in particular the roles that the various p38 isoforms play, remains largely unknown. To explore the underlying mechanisms, we developed a novel systems biology approach by integrating liquid chromatography-mass spectrometry and reverse phase protein array data from human MM cell lines with computational pathway models in which the unknown parameters were inferred using a proposed novel algorithm called modularized factor graph. New mechanisms predicted by our models suggest that combined activation of various p38 isoforms may result in drug resistance in MM via regulating the related pathways including extracellular signal-regulated kinase (ERK) pathway and NFкB pathway. ERK pathway regulating cell growth is synergistically regulated by p38δ isoform, whereas nuclear factor kappa B (NFкB) pathway regulating cell apoptosis is synergistically regulated by p38α isoform. This finding that p38δ isoform promotes the phosphorylation of ERK1/2 in MM cells treated with bortezomib was validated by western blotting. Based on the predicted mechanisms, we further screened drug combinations in silico and found that a promising drug combination targeting ERK1/2 and NFκB might reduce the effects of drug resistance in MM cells. This study provides a framework of a systems biology approach to studying drug resistance and drug combination selection. RPPA experimental Data and Matlab source codes of modularized factor graph for parameter estimation are freely available online at http://ctsb.is.wfubmc.edu/publications/modularized-factor-graph.php. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Predicting drug-disease interactions by semi-supervised graph cut algorithm and three-layer data integration.

PubMed

Wu, Guangsheng; Liu, Juan; Wang, Caihua

2017-12-28

Prediction of drug-disease interactions is promising for either drug repositioning or disease treatment fields. The discovery of novel drug-disease interactions, on one hand can help to find novel indictions for the approved drugs; on the other hand can provide new therapeutic approaches for the diseases. Recently, computational methods for finding drug-disease interactions have attracted lots of attention because of their far more higher efficiency and lower cost than the traditional wet experiment methods. However, they still face several challenges, such as the organization of the heterogeneous data, the performance of the model, and so on. In this work, we present to hierarchically integrate the heterogeneous data into three layers. The drug-drug and disease-disease similarities are first calculated separately in each layer, and then the similarities from three layers are linearly fused into comprehensive drug similarities and disease similarities, which can then be used to measure the similarities between two drug-disease pairs. We construct a novel weighted drug-disease pair network, where a node is a drug-disease pair with known or unknown treatment relation, an edge represents the node-node relation which is weighted with the similarity score between two pairs. Now that similar drug-disease pairs are supposed to show similar treatment patterns, we can find the optimal graph cut of the network. The drug-disease pair with unknown relation can then be considered to have similar treatment relation with that within the same cut. Therefore, we develop a semi-supervised graph cut algorithm, SSGC, to find the optimal graph cut, based on which we can identify the potential drug-disease treatment interactions. By comparing with three representative network-based methods, SSGC achieves the highest performances, in terms of both AUC score and the identification rates of true drug-disease pairs. The experiments with different integration strategies also demonstrate that considering several sources of data can improve the performances of the predictors. Further case studies on four diseases, the top-ranked drug-disease associations have been confirmed by KEGG, CTD database and the literature, illustrating the usefulness of SSGC. The proposed comprehensive similarity scores from multi-views and multiple layers and the graph-cut based algorithm can greatly improve the prediction performances of drug-disease associations.

Development times, clinical testing, postmarket follow-up, and safety risks for the new drugs approved by the US food and drug administration: the class of 2008.

PubMed

Moore, Thomas J; Furberg, Curt D

2014-01-01

The US Food and Drug Administration (FDA) has advanced multiple proposals to promote biomedical innovation by making new drugs available more quickly but with shorter, smaller, and more selective clinical trials and less rigorous end points. To inform the debate about appropriate standards, we studied the development times, clinical testing, postmarket follow-up, and safety risks for the new drugs approved by the FDA in 2008, when most provisions of current law, regulation, and policies were in effect. Descriptive study of the drugs classified as new molecular entities using preapproval FDA evaluation documents, agency drug information databases, prescribing information, and other primary data sources. Comparison of drugs that received standard review and those deemed sufficiently innovative to receive expedited review with regard to clinical development and FDA review time, the size and duration of efficacy trials, safety issues, and postmarket follow-up. In 2008, the FDA approved 20 therapeutic drugs, 8 with expedited review and 12 with standard review. The expedited drugs took a median of 5.1 years (range, 1.6-10.6 years) of clinical development to obtain marketing approval compared with 7.5 years (range, 4.7-19.4 years) for the standard review drugs (P = .05). The expedited drugs were tested for efficacy in a median of 104 patients receiving the active drug (range, 23-599), compared with a median of 580 patients (range, 75-1207) for standard review drugs (P = .003). Nonclinical testing showed that 6 therapeutic drugs were animal carcinogens, 5 were in vitro mutagens, and 14 were animal teratogens. Other safety concerns resulted in 5 Boxed Warnings; 8 drugs required risk management plans. The FDA required 85 postmarket commitments. By 2013, 5 drugs acquired a new or expanded Boxed Warning; 26 of 85 (31%) of the postmarketing study commitments had been fulfilled, and 8 (9%) had been submitted for agency review. For new drugs approved by the FDA in 2008, those that received expedited review were approved more rapidly than those that received standard review. However, considerably fewer patients were studied prior to approval, and many safety questions remained unanswered. By 2013, many postmarketing studies had not been completed.

The case for open-source software in drug discovery.

PubMed

DeLano, Warren L

2005-02-01

Widespread adoption of open-source software for network infrastructure, web servers, code development, and operating systems leads one to ask how far it can go. Will "open source" spread broadly, or will it be restricted to niches frequented by hopeful hobbyists and midnight hackers? Here we identify reasons for the success of open-source software and predict how consumers in drug discovery will benefit from new open-source products that address their needs with increased flexibility and in ways complementary to proprietary options.

Chemistry and Pharmacology of Citrus sinensis.

PubMed

Favela-Hernández, Juan Manuel J; González-Santiago, Omar; Ramírez-Cabrera, Mónica A; Esquivel-Ferriño, Patricia C; Camacho-Corona, María del Rayo

2016-02-22

Presently the search for new drugs from natural resources is of growing interest to the pharmaceutical industry. Natural products have been the source of new drugs since ancient times. Plants are a good source of secondary metabolites which have been found to have beneficial properties. The present study is a review of the chemistry and pharmacology of Citrus sinensis. This review reveals the therapeutic potential of C. sinensis as a source of natural compounds with important activities that are beneficial for human health that could be used to develop new drugs.

An evaluation of talker localization based on direction of arrival estimation and statistical sound source identification

NASA Astrophysics Data System (ADS)

Nishiura, Takanobu; Nakamura, Satoshi

2002-11-01

It is very important to capture distant-talking speech for a hands-free speech interface with high quality. A microphone array is an ideal candidate for this purpose. However, this approach requires localizing the target talker. Conventional talker localization algorithms in multiple sound source environments not only have difficulty localizing the multiple sound sources accurately, but also have difficulty localizing the target talker among known multiple sound source positions. To cope with these problems, we propose a new talker localization algorithm consisting of two algorithms. One is DOA (direction of arrival) estimation algorithm for multiple sound source localization based on CSP (cross-power spectrum phase) coefficient addition method. The other is statistical sound source identification algorithm based on GMM (Gaussian mixture model) for localizing the target talker position among localized multiple sound sources. In this paper, we particularly focus on the talker localization performance based on the combination of these two algorithms with a microphone array. We conducted evaluation experiments in real noisy reverberant environments. As a result, we confirmed that multiple sound signals can be identified accurately between ''speech'' or ''non-speech'' by the proposed algorithm. [Work supported by ATR, and MEXT of Japan.

Real-time quantitative fluorescence measurement of microscale cell culture analog systems

NASA Astrophysics Data System (ADS)

Oh, Taek-il; Kim, Donghyun; Tatosian, Daniel; Sung, Jong Hwan; Shuler, Michael

2007-02-01

A microscale cell culture analog (μCCA) is a cell-based lab-on-a-chip assay that, as an animal surrogate, is applied to pharmacological studies for toxicology tests. A μCCA typically comprises multiple chambers and microfluidics that connect the chambers, which represent animal organs and blood flow to mimic animal metabolism more realistically. A μCCA is expected to provide a tool for high-throughput drug discovery. Previously, a portable fluorescence detection system was investigated for a single μCCA device in real-time. In this study, we present a fluorescence-based imaging system that provides quantitative real-time data of the metabolic interactions in μCCAs with an emphasis on measuring multiple μCCA samples simultaneously for high-throughput screening. The detection system is based on discrete optics components, with a high-power LED and a charge-coupled device (CCD) camera as a light source and a detector, for monitoring cellular status on the chambers of each μCCA sample. Multiple samples are characterized mechanically on a motorized linear stage, which is fully-automated. Each μCCA sample has four chambers, where cell lines MES-SA/DX- 5, and MES-SA (tumor cells of human uterus) have been cultured. All cell-lines have been transfected to express the fusion protein H2B-GFP, which is a human histone protein fused at the amino terminus to EGFP. As a model cytotoxic drug, 10 μM doxorubicin (DOX) was used. Real-time quantitative data of the intensity loss of enhanced green fluorescent protein (EGFP) during cell death of target cells have been collected over several minutes to 40 hours. Design issues and improvements are also discussed.

Patterns of Drug Use, Risky Behavior, and Health Status Among Persons Who Inject Drugs Living in San Diego, California: A Latent Class Analysis

PubMed Central

Roth, Alexis M.; Armenta, Richard A.; Wagner, Karla D.; Roesch, Scott C.; Bluthenthal, Ricky N.; Cuevas-Mota, Jazmine; Garfein, Richard S.

2015-01-01

Background Among persons who inject drugs (PWID), polydrug use (the practice of mixing multiple drugs/alcohol sequentially or simultaneously) increases risk for HIV transmission and unintentional overdose deaths. Research has shown local drug markets influence drug use practices. However, little is known about the impact of drug mixing in markets dominated by black tar heroin and methamphetamine, such as the western United States. Methods Data were collected through an ongoing longitudinal study examining drug use, risk behavior, and health status among PWID. Latent class analysis (LCA) was used to identify patterns of substance use (heroin, methamphetamine, prescription drugs, alcohol, and marijuana) via multiple administration routes (injecting, smoking, and swallowing). Logistic regression was used to identify behaviors and health indicators associated with drug use class. Results The sample included 511 mostly white (51.5%) males (73.8%), with mean age of 43.5 years. Two distinct classes of drug users predominated: methamphetamine by multiple routes (51%) and heroin by injection (49%). In multivariable logistic regression, class membership was associated with age, race, and housing status. PWID who were HIV-seropositive and reported prior sexually transmitted infections had increased odds of belonging to the methamphetamine class. Those who were HCV positive and reported previous opioid overdose had an increased odds of being in the primarily heroin injection class (all P-values < .05). Conclusion Risk behaviors and health outcomes differed between PWID who primarily inject heroin vs. those who use methamphetamine. The findings suggest that in a region where PWID mainly use black tar heroin or methamphetamine, interventions tailored to sub-populations of PWID could improve effectiveness. PMID:25313832

21 CFR 874.4350 - Ear, nose, and throat fiberoptic light source and carrier.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Ear, nose, and throat fiberoptic light source and carrier. 874.4350 Section 874.4350 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND... of plastic fibers and that is intended to provide illumination at the tip of an ear, nose, or throat...

21 CFR 179.21 - Sources of radiation used for inspection of food, for inspection of packaged food, and for...

Code of Federal Regulations, 2014 CFR

2014-04-01

... 21 Food and Drugs 3 2014-04-01 2014-04-01 false Sources of radiation used for inspection of food, for inspection of packaged food, and for controlling food processing. 179.21 Section 179.21 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) IRRADIATION IN...

Adapting the Illicit Drug Reporting System (IDRS) to examine the feasibility of monitoring trends in the markets for 'party drugs'.

PubMed

Topp, Libby; Breen, Courtney; Kaye, Sharlene; Darke, Shane

2004-02-07

Since 1996, the Illicit Drug Reporting System (IDRS), Australia's strategic early warning system for illicit drug trends, has monitored annual trends in the markets for the four main illicit drug classes, cannabis, methamphetamine, cocaine and heroin. In 2000, a 2-year trial was implemented to examine the feasibility of using similar methodology to monitor trends in the markets for 'party drugs'. A triangulation of three data sources was sought: (1) quantitative interviews with a 'sentinel' population of drug users; (2) qualitative interviews with key informants (KIs), or those who have contact with drug users through their work; (3) extant indicator data sources such as the purity of illicit drugs seized by law enforcement agencies. The results suggested that the feasibility of collecting detailed, reliable and valid data about party drug markets is a direct function of the size of those markets. The trial demonstrated that the system would allow the successful monitoring of markets for party drugs that are relatively widely used, such as ecstasy, but would be less sensitive in monitoring markets for party drugs that are used by small proportions of the total population, such as gamma-hydroxy-butyrate (GHB) and ketamine. Methodological issues encountered during the conduct of this trial are discussed, including defining the appropriate sentinel population of drug users, identifying relevant key informants, and the relative absence of extant indicator data sources that could inform our understanding of party drug markets.

Improved statistical signal detection in pharmacovigilance by combining multiple strength-of-evidence aspects in vigiRank.

PubMed

Caster, Ola; Juhlin, Kristina; Watson, Sarah; Norén, G Niklas

2014-08-01

Detection of unknown risks with marketed medicines is key to securing the optimal care of individual patients and to reducing the societal burden from adverse drug reactions. Large collections of individual case reports remain the primary source of information and require effective analytics to guide clinical assessors towards likely drug safety signals. Disproportionality analysis is based solely on aggregate numbers of reports and naively disregards report quality and content. However, these latter features are the very fundament of the ensuing clinical assessment. Our objective was to develop and evaluate a data-driven screening algorithm for emerging drug safety signals that accounts for report quality and content. vigiRank is a predictive model for emerging safety signals, here implemented with shrinkage logistic regression to identify predictive variables and estimate their respective contributions. The variables considered for inclusion capture different aspects of strength of evidence, including quality and clinical content of individual reports, as well as trends in time and geographic spread. A reference set of 264 positive controls (historical safety signals from 2003 to 2007) and 5,280 negative controls (pairs of drugs and adverse events not listed in the Summary of Product Characteristics of that drug in 2012) was used for model fitting and evaluation; the latter used fivefold cross-validation to protect against over-fitting. All analyses were performed on a reconstructed version of VigiBase(®) as of 31 December 2004, at around which time most safety signals in our reference set were emerging. The following aspects of strength of evidence were selected for inclusion into vigiRank: the numbers of informative and recent reports, respectively; disproportional reporting; the number of reports with free-text descriptions of the case; and the geographic spread of reporting. vigiRank offered a statistically significant improvement in area under the receiver operating characteristics curve (AUC) over screening based on the Information Component (IC) and raw numbers of reports, respectively (0.775 vs. 0.736 and 0.707, cross-validated). Accounting for multiple aspects of strength of evidence has clear conceptual and empirical advantages over disproportionality analysis. vigiRank is a first-of-its-kind predictive model to factor in report quality and content in first-pass screening to better meet tomorrow's post-marketing drug safety surveillance needs.

A Phthalimide Derivative That Inhibits Centrosomal Clustering Is Effective on Multiple Myeloma

PubMed Central

Shiheido, Hirokazu; Terada, Fukiko; Tabata, Noriko; Hayakawa, Ichigo; Matsumura, Nobutaka; Takashima, Hideaki; Ogawa, Yoko; Du, Wenlin; Yamada, Taketo; Shoji, Mitsuru; Sugai, Takeshi; Doi, Nobuhide; Iijima, Shiro; Hattori, Yutaka; Yanagawa, Hiroshi

2012-01-01

Despite the introduction of newly developed drugs such as lenalidomide and bortezomib, patients with multiple myeloma are still difficult to treat and have a poor prognosis. In order to find novel drugs that are effective for multiple myeloma, we tested the antitumor activity of 29 phthalimide derivatives against several multiple myeloma cell lines. Among these derivatives, 2-(2,6-diisopropylphenyl)-5-amino-1H-isoindole-1,3- dione (TC11) was found to be a potent inhibitor of tumor cell proliferation and an inducer of apoptosis via activation of caspase-3, 8 and 9. This compound also showed in vivo activity against multiple myeloma cell line KMS34 tumor xenografts in ICR/SCID mice. By means of mRNA display selection on a microfluidic chip, the target protein of TC11 was identified as nucleophosmin 1 (NPM). Binding of TC11 and NPM monomer was confirmed by surface plasmon resonance. Immunofluorescence and NPM knockdown studies in HeLa cells suggested that TC11 inhibits centrosomal clustering by inhibiting the centrosomal-regulatory function of NPM, thereby inducing multipolar mitotic cells, which undergo apoptosis. NPM may become a novel target for development of antitumor drugs active against multiple myeloma. PMID:22761710

Dose finding with the sequential parallel comparison design.

PubMed

Wang, Jessie J; Ivanova, Anastasia

2014-01-01

The sequential parallel comparison design (SPCD) is a two-stage design recommended for trials with possibly high placebo response. A drug-placebo comparison in the first stage is followed in the second stage by placebo nonresponders being re-randomized between drug and placebo. We describe how SPCD can be used in trials where multiple doses of a drug or multiple treatments are compared with placebo and present two adaptive approaches. We detail how to analyze data in such trials and give recommendations about the allocation proportion to placebo in the two stages of SPCD.

Multiple Measures of Juvenile Drug Court Effectiveness: Results of a Quasi-Experimental Design

ERIC Educational Resources Information Center

Rodriguez, Nancy; Webb, Vincent J.

2004-01-01

Prior studies of juvenile drug courts have been constrained by small samples, inadequate comparison groups, or limited outcome measures. The authors report on a 3-year evaluation that examines the impact of juvenile drug court participation on recidivism and drug use. A quasi-experimental design is used to compare juveniles assigned to drug court…

Direct-to-consumer advertising skepticism and the use and perceived usefulness of prescription drug information sources.

PubMed

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

2009-01-01

This study investigates advertising skepticism in the context of consumers' prescription drug information seeking behavior. Results of a telephone survey found that: (a) the overall level of direct-to-consumer advertising (DTCA) skepticism among consumers was neutral; (b) DTCA skepticism was unrelated to age, positively related to education and income, and varied by race; (c) however, when all the antecedent variables were considered concurrently, only education emerged as a significant predictor (consumers with higher education were more skeptical of DTCA); (d) DTCA skepticism was not significantly related to perceived importance of prescription drug information; (e) DTCA skepticism was not associated with use of advertising and interpersonal sources of prescription drug information; and (f) DTCA skepticism was negatively related to perceived usefulness of advertising sources but unrelated to perceived usefulness of professional interpersonal sources (i.e., physicians and pharmacists). The article concludes with a discussion of findings and directions for future research.

Human Health Risk Implications of Multiple Sources of Faecal Indicator Bacteria in a Recreational Waterbody

EPA Science Inventory

We evaluate the influence of multiple sources of faecal indicator bacteria in recreational water bodies on potential human health risk by considering waters impacted by human and animal sources, human and non-pathogenic sources, and animal and non-pathogenic sources. We illustrat...

Experimental Design for Multi-drug Combination Studies Using Signaling Networks

PubMed Central

Huang, Hengzhen; Fang, Hong-Bin; Tan, Ming T.

2017-01-01

Summary Combinations of multiple drugs are an important approach to maximize the chance for therapeutic success by inhibiting multiple pathways/targets. Analytic methods for studying drug combinations have received increasing attention because major advances in biomedical research have made available large number of potential agents for testing. The preclinical experiment on multi-drug combinations plays a key role in (especially cancer) drug development because of the complex nature of the disease, the need to reduce development time and costs. Despite recent progresses in statistical methods for assessing drug interaction, there is an acute lack of methods for designing experiments on multi-drug combinations. The number of combinations grows exponentially with the number of drugs and dose-levels and it quickly precludes laboratory testing. Utilizing experimental dose-response data of single drugs and a few combinations along with pathway/network information to obtain an estimate of the functional structure of the dose-response relationship in silico, we propose an optimal design that allows exploration of the dose-effect surface with the smallest possible sample size in this paper. The simulation studies show our proposed methods perform well. PMID:28960231

Drug resistance in vectorborne parasites: multiple actors and scenarios for an evolutionary arms race.

PubMed

Vanaerschot, Manu; Huijben, Silvie; Van den Broeck, Frederik; Dujardin, Jean-Claude

2014-01-01

Drug-resistant pathogens emerge faster than new drugs come out of drug discovery pipelines. Current and future drug options should therefore be better protected, requiring a clear understanding of the factors that contribute to the natural history of drug resistance. Although many of these factors are relatively well understood for most bacteria, this proves to be more complex for vectorborne parasites. In this review, we discuss considering three key models (Plasmodium, Leishmania and Schistosoma) how drug resistance can emerge, spread and persist. We demonstrate a multiplicity of scenarios, clearly resulting from the biological diversity of the different organisms, but also from the different modes of action of the drugs used, the specific within- and between-host ecology of the parasites, and environmental factors that may have direct or indirect effects. We conclude that integrated control of drug-resistant vectorborne parasites is not dependent upon chemotherapy only, but also requires a better insight into the ecology of these parasites and how their transmission can be impaired. © 2013 Federation of European Microbiological Societies. Published by John Wiley & Sons Ltd. All rights reserved.

Incomplete Multisource Transfer Learning.

PubMed

Ding, Zhengming; Shao, Ming; Fu, Yun

2018-02-01

Transfer learning is generally exploited to adapt well-established source knowledge for learning tasks in weakly labeled or unlabeled target domain. Nowadays, it is common to see multiple sources available for knowledge transfer, each of which, however, may not include complete classes information of the target domain. Naively merging multiple sources together would lead to inferior results due to the large divergence among multiple sources. In this paper, we attempt to utilize incomplete multiple sources for effective knowledge transfer to facilitate the learning task in target domain. To this end, we propose an incomplete multisource transfer learning through two directional knowledge transfer, i.e., cross-domain transfer from each source to target, and cross-source transfer. In particular, in cross-domain direction, we deploy latent low-rank transfer learning guided by iterative structure learning to transfer knowledge from each single source to target domain. This practice reinforces to compensate for any missing data in each source by the complete target data. While in cross-source direction, unsupervised manifold regularizer and effective multisource alignment are explored to jointly compensate for missing data from one portion of source to another. In this way, both marginal and conditional distribution discrepancy in two directions would be mitigated. Experimental results on standard cross-domain benchmarks and synthetic data sets demonstrate the effectiveness of our proposed model in knowledge transfer from incomplete multiple sources.

Interspecies scaling and prediction of human clearance: comparison of small- and macro-molecule drugs

PubMed Central

Huh, Yeamin; Smith, David E.; Feng, Meihau Rose

2014-01-01

Human clearance prediction for small- and macro-molecule drugs was evaluated and compared using various scaling methods and statistical analysis.Human clearance is generally well predicted using single or multiple species simple allometry for macro- and small-molecule drugs excreted renally.The prediction error is higher for hepatically eliminated small-molecules using single or multiple species simple allometry scaling, and it appears that the prediction error is mainly associated with drugs with low hepatic extraction ratio (Eh). The error in human clearance prediction for hepatically eliminated small-molecules was reduced using scaling methods with a correction of maximum life span (MLP) or brain weight (BRW).Human clearance of both small- and macro-molecule drugs is well predicted using the monkey liver blood flow method. Predictions using liver blood flow from other species did not work as well, especially for the small-molecule drugs. PMID:21892879

Nanotechnology as a therapeutic tool to combat microbial resistance.

PubMed

Pelgrift, Robert Y; Friedman, Adam J

2013-11-01

Use of nanoparticles is among the most promising strategies to overcome microbial drug resistance. This review article consists of three parts. The first part discusses the epidemiology of microbial drug resistance. The second part describes mechanisms of drug resistance used by microbes. The third part explains how nanoparticles can overcome this resistance, including the following: Nitric oxide-releasing nanoparticles (NO NPs), chitosan-containing nanoparticles (chitosan NPs), and metal-containing nanoparticles all use multiple mechanisms simultaneously to combat microbes, thereby making development of resistance to these nanoparticles unlikely. Packaging multiple antimicrobial agents within the same nanoparticle also makes development of resistance unlikely. Nanoparticles can overcome existing drug resistance mechanisms, including decreased uptake and increased efflux of drug from the microbial cell, biofilm formation, and intracellular bacteria. Finally, nanoparticles can target antimicrobial agents to the site of infection, so that higher doses of drug are given at the infected site, thereby overcoming resistance. © 2013.

Isobaric metabolite interferences and the requirement for close examination of raw data in addition to stringent chromatographic separations in liquid chromatography/tandem mass spectrometric analysis of drugs in biological matrix.

PubMed

Yan, Zhengyin; Maher, Noureddine; Torres, Rhoda; Cotto, Carlos; Hastings, Becki; Dasgupta, Malini; Hyman, Rolanda; Huebert, Norman; Caldwell, Gary W

2008-07-01

In addition to matrix effects, common interferences observed in liquid chromatography/tandem mass spectrometry (LC/MS/MS) analyses can be caused by the response of drug-related metabolites to the multiple reaction monitoring (MRM) channel of a given drug, as a result of in-source reactions or decomposition of either phase I or II metabolites. However, it has been largely ignored that, for some drugs, metabolism can lead to the formation of isobaric or isomeric metabolites that exhibit the same MRM transitions as parent drugs. The present study describes two examples demonstrating that interference caused by isobaric or isomeric metabolites is a practical issue in analyzing biological samples by LC/MS/MS. In the first case, two sequential metabolic reactions, demethylation followed by oxidation of a primary alcohol moiety to a carboxylic acid, produced an isobaric metabolite that exhibits a MRM transition identical to the parent drug. Because the drug compound was rapidly metabolized in rats and completely disappeared in plasma samples, the isobaric metabolite appeared as a single peak in the total ion current (TIC) trace and could easily be quantified as the drug since it was eluted at a retention time very close to that of the drug in a 12-min LC run. In the second example, metabolism via the ring-opening of a substituted isoxazole moiety led to the formation of an isomeric product that showed an almost identical collision-induced dissociation (CID) MS spectrum as the original drug. Because two components were co-eluted, the isomeric product could be mistakenly quantified and reported by data processing software as the parent drug if the TIC trace was not carefully inspected. Nowadays, all LC/MS data are processed by computer software in a highly automated fashion, and some analysts may spend much less time to visually examine raw TIC traces than they used to do. Two examples described in this article remind us that quality data require both adequate chromatographic separations and close examination of raw data in LC/MS/MS analyses of drugs in biological matrix.

Determinants of orphan drugs prices in France: a regression analysis.

PubMed

Korchagina, Daria; Millier, Aurelie; Vataire, Anne-Lise; Aballea, Samuel; Falissard, Bruno; Toumi, Mondher

2017-04-21

The introduction of the orphan drug legislation led to the increase in the number of available orphan drugs, but the access to them is often limited due to the high price. Social preferences regarding funding orphan drugs as well as the criteria taken into consideration while setting the price remain unclear. The study aimed at identifying the determinant of orphan drug prices in France using a regression analysis. All drugs with a valid orphan designation at the moment of launch for which the price was available in France were included in the analysis. The selection of covariates was based on a literature review and included drug characteristics (Anatomical Therapeutic Chemical (ATC) class, treatment line, age of target population), diseases characteristics (severity, prevalence, availability of alternative therapeutic options), health technology assessment (HTA) details (actual benefit (AB) and improvement in actual benefit (IAB) scores, delay between the HTA and commercialisation), and study characteristics (type of study, comparator, type of endpoint). The main data sources were European public assessment reports, HTA reports, summaries of opinion on orphan designation of the European Medicines Agency, and the French insurance database of drugs and tariffs. A generalized regression model was developed to test the association between the annual treatment cost and selected covariates. A total of 68 drugs were included. The mean annual treatment cost was €96,518. In the univariate analysis, the ATC class (p = 0.01), availability of alternative treatment options (p = 0.02) and the prevalence (p = 0.02) showed a significant correlation with the annual cost. The multivariate analysis demonstrated significant association between the annual cost and availability of alternative treatment options, ATC class, IAB score, type of comparator in the pivotal clinical trial, as well as commercialisation date and delay between the HTA and commercialisation. The orphan drug pricing is a multivariate phenomenon. The complex association between drug prices and the studied attributes and shows that payers integrate multiple variables in decision making when setting orphan drug prices. The interpretation of the study results is limited by the small sample size and the complex data structure.

"Helpful People in Touch" Consumer Led Self Help Programs for People with Multiple Disorders, Mental Illness, Drug Addiction, and Alcoholism (MIDAA).

ERIC Educational Resources Information Center

Sciacca, Kathleen

This paper describes the consumer program, "Helpful People in Touch," a self-help treatment program for people with the multiple disorders of mental illness, drug addiction, and/or alcoholism. First, the terms, "Mentally Ill Chemical Abusers and Addicted" (MICAA) and "Chemical Abusing Mentally Ill" (CAMI) are defined…

The Documentation of Health Problems in Relation to Prescribed Medication in People with Profound Intellectual and Multiple Disabilities

ERIC Educational Resources Information Center

van der Heide, D. C.; van der Putten, A. A. J.; van den Berg, P. B.; Taxis, K.; Vlaskamp, C.

2009-01-01

Background: Persons with profound intellectual and multiple disabilities (PIMD) suffer from a wide range of health problems and use a wide range of different drugs. This study investigated for frequently used medication whether there was a health problem documented in the medical notes for the drug prescribed. Method: Persons with PIMD with an…

78 FR 35155 - Establishing a List of Qualifying Pathogens Under the Food and Drug Administration Safety and...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-06-12

... antibacterial activity for infections with multiple-drug-resistant Enterobacteriaceae. This means that...). GAIN is intended to encourage development of new antibacterial and antifungal drugs for the treatment... encourage development of new antibacterial and antifungal drugs for the treatment of serious or life...

Lessons Learned from Our Elders: How to Study Polypharmacy in Populations with Intellectual and Developmental Disabilities

ERIC Educational Resources Information Center

Stortz, Jessica N.; Lake, Johanna K.; Cobigo, Virginie; Ouellette-Kuntz, Hélène M. J.; Lunsky, Yona

2014-01-01

"Polypharmacy" is the concurrent use of multiple medications, including both psychotropic and non-psychotropic drugs. Although it may sometimes be clinically indicated, polypharmacy can have a number of negative consequences, including medication nonadherence, adverse drug reactions, and undesirable drug--drug interactions. The objective…

Animal Toxins as Therapeutic Tools to Treat Neurodegenerative Diseases

PubMed Central

de Souza, Jessica M.; Goncalves, Bruno D. C.; Gomez, Marcus V.; Vieira, Luciene B.; Ribeiro, Fabiola M.

2018-01-01

Neurodegenerative diseases affect millions of individuals worldwide. So far, no disease-modifying drug is available to treat patients, making the search for effective drugs an urgent need. Neurodegeneration is triggered by the activation of several cellular processes, including oxidative stress, mitochondrial impairment, neuroinflammation, aging, aggregate formation, glutamatergic excitotoxicity, and apoptosis. Therefore, many research groups aim to identify drugs that may inhibit one or more of these events leading to neuronal cell death. Venoms are fruitful natural sources of new molecules, which have been relentlessly enhanced by evolution through natural selection. Several studies indicate that venom components can exhibit selectivity and affinity for a wide variety of targets in mammalian systems. For instance, an expressive number of natural peptides identified in venoms from animals, such as snakes, scorpions, bees, and spiders, were shown to lessen inflammation, regulate glutamate release, modify neurotransmitter levels, block ion channel activation, decrease the number of protein aggregates, and increase the levels of neuroprotective factors. Thus, these venom components hold potential as therapeutic tools to slow or even halt neurodegeneration. However, there are many technological issues to overcome, as venom peptides are hard to obtain and characterize and the amount obtained from natural sources is insufficient to perform all the necessary experiments and tests. Fortunately, technological improvements regarding heterologous protein expression, as well as peptide chemical synthesis will help to provide enough quantities and allow chemical and pharmacological enhancements of these natural occurring compounds. Thus, the main focus of this review is to highlight the most promising studies evaluating animal toxins as therapeutic tools to treat a wide variety of neurodegenerative conditions, including Alzheimer’s disease, Parkinson’s disease, brain ischemia, glaucoma, amyotrophic lateral sclerosis, and multiple sclerosis. PMID:29527170

A new approach to identify, classify and count drugrelated events

PubMed Central

Bürkle, Thomas; Müller, Fabian; Patapovas, Andrius; Sonst, Anja; Pfistermeister, Barbara; Plank-Kiegele, Bettina; Dormann, Harald; Maas, Renke

2013-01-01

Aims The incidence of clinical events related to medication errors and/or adverse drug reactions reported in the literature varies by a degree that cannot solely be explained by the clinical setting, the varying scrutiny of investigators or varying definitions of drug-related events. Our hypothesis was that the individual complexity of many clinical cases may pose relevant limitations for current definitions and algorithms used to identify, classify and count adverse drug-related events. Methods Based on clinical cases derived from an observational study we identified and classified common clinical problems that cannot be adequately characterized by the currently used definitions and algorithms. Results It appears that some key models currently used to describe the relation of medication errors (MEs), adverse drug reactions (ADRs) and adverse drug events (ADEs) can easily be misinterpreted or contain logical inconsistencies that limit their accurate use to all but the simplest clinical cases. A key limitation of current models is the inability to deal with complex interactions such as one drug causing two clinically distinct side effects or multiple drugs contributing to a single clinical event. Using a large set of clinical cases we developed a revised model of the interdependence between MEs, ADEs and ADRs and extended current event definitions when multiple medications cause multiple types of problems. We propose algorithms that may help to improve the identification, classification and counting of drug-related events. Conclusions The new model may help to overcome some of the limitations that complex clinical cases pose to current paper- or software-based drug therapy safety. PMID:24007453

Prescriptive Oriented Drug Analysis of Multiple Sclerosis Disease by LC-UV in Whole Human Blood.

PubMed

Suneetha, A; Rajeswari, Raja K

2016-02-01

As a polytherapy treatment, multiple sclerosis disease demands prescriptions with more than one drug. Polytherapy is sometimes rational for drug combinations chosen to minimize adverse effects. Estimation of drugs that are concomitantly administered in polytherapy is acceptable as it shortens the analytical timepoints and also the usage of biological matrices. In clinical phase trials, the withdrawal of biofluids is a critical issue for each analysis. Estimating all the coadminsitered drugs in a single shot will be more effective and economical for pharmaceuticals. A single, simple, rapid and sensitive high-performance liquid chromatography assay method has been developed with UV detection and fully validated for the quantification of 14 drugs (at random combinations) used in the treatment of multiple sclerosis disease. The set of combinations was based on prescriptions to patients. Separations were achieved on an X-Terra MS C18 (100 × 3.9 mm, 5 µm) column. The analytes were extracted from 50 µL aliquots of whole human blood with protein precipitation using acetonitrile. All the drugs were sufficiently stable during storage for 24 h at room temperature and for 23 days at 2-8°C. The percentage recoveries of all drugs were between 90 and 115%, with RSD values <10.6%. This method has been shown to be reproducible and sensitive and can be applied to clinical samples from pharmacokinetic studies and also a useful tool in studying the drug interaction studies. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Designed multiple ligands in metabolic disease research: from concept to platform.

PubMed

Gattrell, W; Johnstone, C; Patel, S; Smith, C Sambrook; Scheel, A; Schindler, M

2013-08-01

Type 2 diabetes mellitus (T2DM) is a multifactorial disease, and drug monotherapy typically results in unsatisfactory treatment outcomes for patients. Even when used in combination, existing therapies lack efficacy in the long term. Designed multiple ligands (DMLs) are compounds developed to modulate multiple targets relevant to a disease. DMLs offer the potential to yield greater efficacy over monotherapies, either by modulating different biological pathways, or by boosting a single one. However, examples of DMLs progressing into clinical trials, or onto the market are rare; DML drug discovery is challenging, and perceived by some to be almost impossible. Nevertheless, with the judicious selection of biological targets, both from a biological and chemical perspective, it is possible to develop drug-like DMLs. Copyright © 2013 Elsevier Ltd. All rights reserved.

21 CFR 866.5660 - Multiple autoantibodies immunological test system.

Code of Federal Regulations, 2010 CFR

2010-04-01

... SERVICES (CONTINUED) MEDICAL DEVICES IMMUNOLOGY AND MICROBIOLOGY DEVICES Immunological Test Systems § 866.5660 Multiple autoantibodies immunological test system. (a) Identification. A multiple autoantibodies... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Multiple autoantibodies immunological test system...

A Randomized Pilot Study of the Engaging Moms Program for Family Drug Court

PubMed Central

Dakof, Gayle A.; Cohen, Jeri B.; Henderson, Craig E.; Duarte, Eliette; Boustani, Maya; Blackburn, Audra; Venzer, Ellen; Hawes, Sam

2010-01-01

In response to the need for effective drug court interventions, the effectiveness of the Engaging Moms Program (EMP) versus intensive case management services (ICMS) on multiple outcomes for mothers enrolled in family drug court was investigated. In this intent-to-treat study, mothers (N = 62) were randomly assigned to either usual drug court care or the Engaging Moms drug court program. Mothers were assessed at intake, and 3, 6, 12, and 18 months following intake. Results indicated that at 18 months post drug court enrollment, 77% of mothers assigned to EMP versus 55% of mothers assigned to ICMS had positive child welfare dispositions. There were statistically significant time effects for both intervention groups on multiple outcomes including substance use, mental health, parenting practices, and family functioning. EMP showed equal or better improvement than ICMS on all outcomes. The results suggest that EMP in family drug court is a viable and promising intervention approach to reduce maternal addiction and child maltreatment. PMID:20116961

Bioengineering Strategies for Designing Targeted Cancer Therapies

PubMed Central

Wen, Xuejun

2014-01-01

The goals of bioengineering strategies for targeted cancer therapies are (1) to deliver a high dose of an anticancer drug directly to a cancer tumor, (2) to enhance drug uptake by malignant cells, and (3) to minimize drug uptake by nonmalignant cells. Effective cancer-targeting therapies will require both passive- and active targeting strategies and a thorough understanding of physiologic barriers to targeted drug delivery. Designing a targeted therapy includes the selection and optimization of a nanoparticle delivery vehicle for passive accumulation in tumors, a targeting moiety for active receptor-mediated uptake, and stimuli-responsive polymers for control of drug release. The future direction of cancer targeting is a combinatorial approach, in which targeting therapies are designed to use multiple targeting strategies. The combinatorial approach will enable combination therapy for delivery of multiple drugs and dual ligand targeting to improve targeting specificity. Targeted cancer treatments in development and the new combinatorial approaches show promise for improving targeted anticancer drug delivery and improving treatment outcomes. PMID:23768509

[The decoration of Italian Renaissance drug jars after engravings].

PubMed

Drey, R E

1994-01-01

Although Italian drug jar painters generally devised original compositions for the ornamentation of their products, on occasion they derived their subjects from printed sources. Printed sources used by drug jar artists of the Renaissance include wood-engraved Italian tarot cards and wood-engraved illustrations by Hans Sebald Beham and Bernard Salomon in miniature bibles published in the sixteenth century in Frankfurt and in Lyons respectively.

Multiscale Modelling of Cancer Progression and Treatment Control: The Role of Intracellular Heterogeneities in Chemotherapy Treatment

NASA Astrophysics Data System (ADS)

Chaplain, Mark A. J.; Powathil, Gibin G.

Cancer is a complex, multiscale process involving interactions at intracellular, intercellular and tissue scales that are in turn susceptible to microenvironmental changes. Each individual cancer cell within a cancer cell mass is unique, with its own internal cellular pathways and biochemical interactions. These interactions contribute to the functional changes at the cellular and tissue scale, creating a heterogenous cancer cell population. Anticancer drugs are effective in controlling cancer growth by inflicting damage to various target molecules and thereby triggering multiple cellular and intracellular pathways, leading to cell death or cell-cycle arrest. One of the major impediments in the chemotherapy treatment of cancer is drug resistance driven by multiple mechanisms, including multi-drug and cell-cycle mediated resistance to chemotherapy drugs. In this article, we discuss two hybrid multiscale modelling approaches, incorporating multiple interactions involved in the sub-cellular, cellular and microenvironmental levels to study the effects of cell-cycle, phase-specific chemotherapy on the growth and progression of cancer cells.

Multiscale Modelling of Cancer Progression and Treatment Control: The Role of Intracellular Heterogeneities in Chemotherapy Treatment

NASA Astrophysics Data System (ADS)

Chaplain, Mark A. J.; Powathil, Gibin G.

2015-04-01

Cancer is a complex, multiscale process involving interactions at intracellular, intercellular and tissue scales that are in turn susceptible to microenvironmental changes. Each individual cancer cell within a cancer cell mass is unique, with its own internal cellular pathways and biochemical interactions. These interactions contribute to the functional changes at the cellular and tissue scale, creating a heterogenous cancer cell population. Anticancer drugs are effective in controlling cancer growth by inflicting damage to various target molecules and thereby triggering multiple cellular and intracellular pathways, leading to cell death or cell-cycle arrest. One of the major impediments in the chemotherapy treatment of cancer is drug resistance driven by multiple mechanisms, including multi-drug and cell-cycle mediated resistance to chemotherapy drugs. In this article, we discuss two hybrid multiscale modelling approaches, incorporating multiple interactions involved in the sub-cellular, cellular and microenvironmental levels to study the effects of cell-cycle, phase-specific chemotherapy on the growth and progression of cancer cells.

Report of Increasing Overdose Deaths that include Acetyl Fentanyl in Multiple Counties of the Southwestern Region of the Commonwealth of Pennsylvania in 2015-2016.

PubMed

Dwyer, Jessica B; Janssen, Jennifer; Luckasevic, Todd M; Williams, Karl E

2018-01-01

Acetyl fentanyl is a Schedule I controlled synthetic opioid that is becoming an increasingly detected "designer drug." Routine drug screening procedures in local forensic toxicology laboratories identified a total of 41 overdose deaths associated with acetyl fentanyl within multiple counties of the southwestern region of the state of Pennsylvania. The range, median, mean, and standard deviation of blood acetyl fentanyl concentrations for these 41 cases were 0.13-2100 ng/mL, 11 ng/mL, 169.3 ng/mL, and 405.3 ng/mL, respectively. Thirty-six individuals (88%) had a confirmed history of substance abuse, and all but one case (96%) were ruled multiple drug toxicities. This report characterizes this localized trend of overdose deaths associated with acetyl fentanyl and provides further evidence supporting an alarmingly concentrated opiate and opioid epidemic of both traditional and novel drugs within this region of the United States. © 2017 American Academy of Forensic Sciences.

Bowling alone, dying together: The role of social capital in mitigating the drug overdose epidemic in the United States.

PubMed

Zoorob, Michael J; Salemi, Jason L

2017-04-01

Drug overdose deaths have risen precipitously over the last fifteen years. Substantial geographic variation, beyond a simple rural-urban dichotomy, exists in the concentration of overdose deaths, suggesting the existence of as-yet unidentified environmental variables that predict resilience (or vulnerability) to drug overdoses. Motivated by reports highlighting the role of community fragility in the opioid epidemic, we explore whether social capital attenuates overdose death rates. We conducted an ecologic temporal trends study from 1999 to 2014 to investigate the association between mortality due to drug overdose and social capital. Data from multiple sources were compiled at the county-level to produce an analytic dataset comprising overdose mortality, social capital, and a host of potentially confounding variables indicated by the literature (N=49,664 county-years). Multinomial logistic regression was used to estimate the likelihood that a county falls in low (<4 deaths per 100,000), moderate, or high (>16 deaths per 100,000) categories of annual overdose morality. We observed a strong and statistically significant inverse association between county-level social capital and age-adjusted mortality due to drug overdose (p<0.01). Compared to the lowest quintile of social capital, counties at the highest quintile were 83% less likely to fall in the "high-overdose" category and 75% less likely to fall in the "moderate-overdose" category. This study finds large-sample evidence that social capital protects communities against drug overdose. This finding could help guide policymakers in identifying where overdose epidemics are likely to occur and how to ameliorate them. Copyright © 2017 Elsevier B.V. All rights reserved.

Measuring research influence on drug policy: a case example of two epidemiological monitoring systems.

PubMed

Ritter, Alison; Lancaster, Kari

2013-01-01

Assessing the extent to which drug research influences and impacts upon policy decision-making needs to go beyond bibliometric analysis of academic citations. Policy makers do not necessarily access the academic literature, and policy processes are largely iterative and rely on interactions and relationships. Furthermore, media representation of research contributes to public opinion and can influence policy uptake. In this context, assessing research influence involves examining the extent to which a research project is taken up in policy documents, used within policy processes, and disseminated via the media. This three component approach is demonstrated using a case example of two ongoing illicit drug monitoring systems: the Illicit Drug Reporting System (IDRS) and the Ecstasy and related Drugs Reporting System (EDRS). Systematic searches for reference to the IDRS and/or EDRS within policy documents, across multiple policy processes (such as parliamentary inquiries) and in the media, in conjunction with analysis of the types of mentions in these three sources, enables an analysis of policy influence. The context for the research is also described as the foundation for the approach. The application of the three component approach to the case study demonstrates a practical and systematic retrospective approach to measure drug research influence. For example, the ways in which the IDRS and EDRS were mentioned in policy documents demonstrated research utilisation. Policy processes were inclusive of IDRS and EDRS findings, while the media analysis revealed only a small contribution in the context of wider media reporting. Consistent with theories of policy processes, assessing the extent of research influence requires a systematic analysis of policy documents and processes. Development of such analyses and associated methods will better equip researchers to evaluate the impact of research. Copyright © 2012 Elsevier B.V. All rights reserved.

Assumptions made when preparing drug exposure data for analysis have an impact on results: An unreported step in pharmacoepidemiology studies.

PubMed

Pye, Stephen R; Sheppard, Thérèse; Joseph, Rebecca M; Lunt, Mark; Girard, Nadyne; Haas, Jennifer S; Bates, David W; Buckeridge, David L; van Staa, Tjeerd P; Tamblyn, Robyn; Dixon, William G

2018-04-17

Real-world data for observational research commonly require formatting and cleaning prior to analysis. Data preparation steps are rarely reported adequately and are likely to vary between research groups. Variation in methodology could potentially affect study outcomes. This study aimed to develop a framework to define and document drug data preparation and to examine the impact of different assumptions on results. An algorithm for processing prescription data was developed and tested using data from the Clinical Practice Research Datalink (CPRD). The impact of varying assumptions was examined by estimating the association between 2 exemplar medications (oral hypoglycaemic drugs and glucocorticoids) and cardiovascular events after preparing multiple datasets derived from the same source prescription data. Each dataset was analysed using Cox proportional hazards modelling. The algorithm included 10 decision nodes and 54 possible unique assumptions. Over 11 000 possible pathways through the algorithm were identified. In both exemplar studies, similar hazard ratios and standard errors were found for the majority of pathways; however, certain assumptions had a greater influence on results. For example, in the hypoglycaemic analysis, choosing a different variable to define prescription end date altered the hazard ratios (95% confidence intervals) from 1.77 (1.56-2.00) to 2.83 (1.59-5.04). The framework offers a transparent and efficient way to perform and report drug data preparation steps. Assumptions made during data preparation can impact the results of analyses. Improving transparency regarding drug data preparation would increase the repeatability, reproducibility, and comparability of published results. © 2018 The Authors. Pharmacoepidemiology & Drug Safety Published by John Wiley & Sons Ltd.

Systemic Analysis of Foodborne Disease Outbreak in Korea.

PubMed

Lee, Jong-Kyung; Kwak, No-Seong; Kim, Hyun Jung

2016-02-01

This study systemically analyzed data on the prevalence of foodborne pathogens and foodborne disease outbreaks to identify the priorities of foodborne infection risk management in Korea. Multiple correspondence analysis was applied to three variables: origin of food source, phase of food supply chain, and 12 pathogens using 358 cases from 76 original papers and official reports published in 1998-2012. In addition, correspondence analysis of two variables--place and pathogen--was conducted based on epidemiological data of 2357 foodborne outbreaks in 2002-2011 provided by the Korean Ministry of Food and Drug Safety. The results of this study revealed three distinct areas of food monitoring: (1) livestock-derived raw food contaminated with Campylobacter spp., pathogenic Escherichia coli, Salmonella spp., and Listeria monocytogenes; (2) multi-ingredient and ready-to-eat food related to Staphylococcus aureus; and (3) water associated with norovirus. Our findings emphasize the need to track the sources and contamination pathways of foodborne pathogens for more effective risk management.

The income-generating behaviour of injecting drug-users in Oslo.

PubMed

Bretteville-Jensen, A L; Sutton, M

1996-01-01

Drug users' income-generating behaviours, such as prostitution, acquisitive crime and small-scale dealing, have a major influence on the harm caused to the non-using population. Using data on the drug use and income sources of 900 drug-injectors in Oslo, this paper has two aims: to present data on Oslo income-generating behaviours and compare these with those in the Netherlands and Scotland; and to explore conceptual issues in the comparison of self-reported dealing income with other sources. Eighty-three per cent of respondents reported income from social benefit, and 43% had sold drugs in the last month. Half the females reported income from prostitution. The income-generation differences found in the comparisons section do not seem to reflect variations in drug and other social policies, but may relate to differences in the profitability of dealing. Using self-reported dealing income to compare the contributions of different income sources may be misleading, however, since it does not reflect financial profit or the value of dealers' drug consumption. Adjusted figures show that theft accounts for 23% of total drugs expenditure, while the corresponding figures for dealing and prostitution are 42% and 21%, respectively.

QSAR of phytochemicals for the design of better drugs.

PubMed

Kar, Supratik; Roy, Kunal

2012-10-01

Phytochemicals have been the single most prolific source of leads for the development of new drug entities from the dawn of the drug discovery. They cover a wide range of therapeutic indications with a great diversity of chemical structures. The research fraternity still believes in exploring the phytochemicals for new drug discovery. Application of molecular biological techniques has increased the availability of novel compounds that can be conveniently isolated from natural sources. Combinatorial chemistry approaches are being applied based on phytochemical scaffolds to create screening libraries that closely resemble drug-like compounds. In silico techniques like quantitative structure-activity relationships (QSAR), pharmacophore and virtual screening are playing crucial and rate accelerating steps for the better drug design in modern era. QSAR models of different classes of phytochemicals covering different therapeutic areas are thoroughly discussed in the review. Further, the authors have enlisted all the available phytochemical databases for the convenience of researchers working in the area. This review justifies the need to develop more QSAR models for the design of better drugs from phytochemicals. Technical drawbacks associated with phytochemical research have been lessened, and there are better opportunities to explore the biological activity of previously inaccessible sources of phytochemicals although there is still the need to reduce the time and cost involvement in such exercise. The future possibilities for the integration of ethnopharmacology with QSAR, place us at an exciting stage that will allow us to explore plant sources worldwide and design better drugs.

Thiolated alginate-based multiple layer mucoadhesive films of metformin forintra-pocket local delivery: in vitro characterization and clinical assessment.

PubMed

Kassem, Abeer Ahmed; Issa, Doaa Ahmed Elsayed; Kotry, Gehan Sherif; Farid, Ragwa Mohamed

2017-01-01

Periodontal disease broadly defines group of conditions in which the supportive structure of the tooth (periodontium) is destroyed. Recent studies suggested that the anti-diabetic drug metformin hydrochloride (MF) has an osteogenic effect and is beneficial for the management of periodontitis. Development of strong mucoadhesive multiple layer film loading small dose of MF for intra-pocket application. Multiple layer film was developed by double casting followed by compression method. Either 6% carboxy methyl cellulose sodium (CMC) or sodium alginate (ALG) constituted the inner drug (0.6%) loaded layer. Thiolated sodium alginate (TSA; 2 or 4%) constituted the outer drug free layers to enhance mucoadhesion and achieve controlled drug release. Optimized formulation was assessed clinically on 20 subjects. Films were uniform, thin and hard enough for easy insertion into periodontal pockets. Based on water uptake and in vitro drug release, CMC based film with 4% TSA as an outer layer was the optimized formulation with enhanced mucoadhesion and controlled drug release (83.73% over 12 h). SEM showed the effective fabrication of the triple layer film in which connective lines between the layers could be observed. FTIR examination suggests possibility of hydrogen bonding between the -NH groups of metformin and -OH groups of CMC. DSC revealed the presence of MF mainly in the amorphous form. Clinical results indicated improvement of all clinical parameters six months post treatment. The results suggested that local application of the mucoadhesive multiple layer films loaded with metformin hydrochloride was able to manage moderate chronic periodontitis.

Influence of the Supramolecular Micro-Assembly of Multiple Emulsions on their Biopharmaceutical Features and In vivo Therapeutic Response.

PubMed

Cilurzo, Felisa; Cristiano, Maria Chiara; Di Marzio, Luisa; Cosco, Donato; Carafa, Maria; Ventura, Cinzia Anna; Fresta, Massimo; Paolino, Donatella

2015-01-01

The ability of some surfactants to self-assemble in a water/oil bi-phase environment thus forming supramolecular structure leading to the formation of w/o/w multiple emulsions was investigated. The w/o/w multiple emulsions obtained by self-assembling (one-step preparation method) were compared with those prepared following the traditional two-step procedure. Methyl-nicotinate was used as a hydrophilic model drug. The formation of the multiple emulsion structure was evidenced by optical microscopy, which showed a mean size of the inner oil droplets of 6 μm and 10 μm for one-step and two-step multiple emulsions, respectively. The in vitrobiopharmaceutical features of the various w/o/w multiple emulsion formulations were evaluated by means of viscosimetry studies, drug release and in vitro percutaneous permeation experiments through human stratum corneum and viable epidermis membranes. The self-assembled multiple emulsions allowed a more gradual percutaneous permeation (a zero-order permeation rate) than the two-step ones. The in vivotopical carrier properties of the two different multiple emulsions were evaluated on healthy human volunteers by using the spectrophotometry of reflectance, an in vivonon invasive method. These multiple emulsion systems were also compared with conventional emulsion formulations. Our findings demonstrated that the multiple emulsions obtained by self-assembling were able to provide a more sustained drug delivery into the skin and hence a longer therapeutic action than two-step multiple emulsions and conventional emulsion formulations. Finally, our findings showed that the supramolecular micro-assembly of multiple emulsions was able to influence not only the biopharmaceutical characteristics but also the potential in vivotherapeutic response.

Alcoholism, Drug Addiction, and the Road to Recovery: Life on the Edge.

ERIC Educational Resources Information Center

Stimmel, Barry

Originally published in 1992 as The Facts About Drug Use, this updated edition contains new information about the effects of alcohol and recreational, mood-altering drugs on the body. The multiple causes of drug use and the options available to those dependent on drugs as a way of life are thoroughly described. Knowledge of the adverse effects of…

Myocardial Drug Distribution Generated from Local Epicardial Application: Potential Impact of Cardiac Capillary Perfusion in a Swine Model Using Epinephrine

PubMed Central

Maslov, Mikhail Y.; Edelman, Elazer R.; Pezone, Matthew J.; Wei, Abraham E.; Wakim, Matthew G.; Murray, Michael R.; Tsukada, Hisashi; Gerogiannis, Iraklis S.; Groothuis, Adam; Lovich, Mark A.

2014-01-01

Prior studies in small mammals have shown that local epicardial application of inotropic compounds drives myocardial contractility without systemic side effects. Myocardial capillary blood flow, however, may be more significant in larger species than in small animals. We hypothesized that bulk perfusion in capillary beds of the large mammalian heart enhances drug distribution after local release, but also clears more drug from the tissue target than in small animals. Epicardial (EC) drug releasing systems were used to apply epinephrine to the anterior surface of the left heart of swine in either point-sourced or distributed configurations. Following local application or intravenous (IV) infusion at the same dose rates, hemodynamic responses, epinephrine levels in the coronary sinus and systemic circulation, and drug deposition across the ventricular wall, around the circumference and down the axis, were measured. EC delivery via point-source release generated transmural epinephrine gradients directly beneath the site of application extending into the middle third of the myocardial thickness. Gradients in drug deposition were also observed down the length of the heart and around the circumference toward the lateral wall, but not the interventricular septum. These gradients extended further than might be predicted from simple diffusion. The circumferential distribution following local epinephrine delivery from a distributed source to the entire anterior wall drove drug toward the inferior wall, further than with point-source release, but again, not to the septum. This augmented drug distribution away from the release source, down the axis of the left ventricle, and selectively towards the left heart follows the direction of capillary perfusion away from the anterior descending and circumflex arteries, suggesting a role for the coronary circulation in determining local drug deposition and clearance. The dominant role of the coronary vasculature is further suggested by the elevated drug levels in the coronary sinus effluent. Indeed, plasma levels, hemodynamic responses, and myocardial deposition remote from the point of release were similar following local EC or IV delivery. Therefore, the coronary vasculature shapes the pharmacokinetics of local myocardial delivery of small catecholamine drugs in large animal models. Optimal design of epicardial drug delivery systems must consider the underlying bulk capillary perfusion currents within the tissue to deliver drug to tissue targets and may favor therapeutic molecules with better potential retention in myocardial tissue. PMID:25234821

Traditional and systems biology based drug discovery for the rare tumor syndrome neurofibromatosis type 2

PubMed Central

Angus, Steve P.; Beauchamp, Roberta L.; Blakeley, Jaishri O.; Bott, Marga; Burns, Sarah S.; Carlstedt, Annemarie; Chang, Long-Sheng; Chen, Xin; Clapp, D. Wade; Desouza, Patrick A.; Erdin, Serkan; Fernandez-Valle, Cristina; Guinney, Justin; Gusella, James F.; Haggarty, Stephen J.; Johnson, Gary L.; Morrison, Helen; Petrilli, Alejandra M.; Plotkin, Scott R.; Pratap, Abhishek; Ramesh, Vijaya; Sciaky, Noah; Stemmer-Rachamimov, Anat; Stuhlmiller, Tim J.; Talkowski, Michael E.; Yates, Charles W.; Zawistowski, Jon S.; Zhao, Wen-Ning

2018-01-01

Neurofibromatosis 2 (NF2) is a rare tumor suppressor syndrome that manifests with multiple schwannomas and meningiomas. There are no effective drug therapies for these benign tumors and conventional therapies have limited efficacy. Various model systems have been created and several drug targets have been implicated in NF2-driven tumorigenesis based on known effects of the absence of merlin, the product of the NF2 gene. We tested priority compounds based on known biology with traditional dose-concentration studies in meningioma and schwann cell systems. Concurrently, we studied functional kinome and gene expression in these cells pre- and post-treatment to determine merlin deficient molecular phenotypes. Cell viability results showed that three agents (GSK2126458, Panobinostat, CUDC-907) had the greatest activity across schwannoma and meningioma cell systems, but merlin status did not significantly influence response. In vivo, drug effect was tumor specific with meningioma, but not schwannoma, showing response to GSK2126458 and Panobinostat. In culture, changes in both the transcriptome and kinome in response to treatment clustered predominantly based on tumor type. However, there were differences in both gene expression and functional kinome at baseline between meningioma and schwannoma cell systems that may form the basis for future selective therapies. This work has created an openly accessible resource (www.synapse.org/SynodosNF2) of fully characterized isogenic schwannoma and meningioma cell systems as well as a rich data source of kinome and transcriptome data from these assay systems before and after treatment that enables single and combination drug discovery based on molecular phenotype. PMID:29897904

Traditional and systems biology based drug discovery for the rare tumor syndrome neurofibromatosis type 2.

PubMed

Allaway, Robert; Angus, Steve P; Beauchamp, Roberta L; Blakeley, Jaishri O; Bott, Marga; Burns, Sarah S; Carlstedt, Annemarie; Chang, Long-Sheng; Chen, Xin; Clapp, D Wade; Desouza, Patrick A; Erdin, Serkan; Fernandez-Valle, Cristina; Guinney, Justin; Gusella, James F; Haggarty, Stephen J; Johnson, Gary L; La Rosa, Salvatore; Morrison, Helen; Petrilli, Alejandra M; Plotkin, Scott R; Pratap, Abhishek; Ramesh, Vijaya; Sciaky, Noah; Stemmer-Rachamimov, Anat; Stuhlmiller, Tim J; Talkowski, Michael E; Welling, D Bradley; Yates, Charles W; Zawistowski, Jon S; Zhao, Wen-Ning

2018-01-01

Neurofibromatosis 2 (NF2) is a rare tumor suppressor syndrome that manifests with multiple schwannomas and meningiomas. There are no effective drug therapies for these benign tumors and conventional therapies have limited efficacy. Various model systems have been created and several drug targets have been implicated in NF2-driven tumorigenesis based on known effects of the absence of merlin, the product of the NF2 gene. We tested priority compounds based on known biology with traditional dose-concentration studies in meningioma and schwann cell systems. Concurrently, we studied functional kinome and gene expression in these cells pre- and post-treatment to determine merlin deficient molecular phenotypes. Cell viability results showed that three agents (GSK2126458, Panobinostat, CUDC-907) had the greatest activity across schwannoma and meningioma cell systems, but merlin status did not significantly influence response. In vivo, drug effect was tumor specific with meningioma, but not schwannoma, showing response to GSK2126458 and Panobinostat. In culture, changes in both the transcriptome and kinome in response to treatment clustered predominantly based on tumor type. However, there were differences in both gene expression and functional kinome at baseline between meningioma and schwannoma cell systems that may form the basis for future selective therapies. This work has created an openly accessible resource (www.synapse.org/SynodosNF2) of fully characterized isogenic schwannoma and meningioma cell systems as well as a rich data source of kinome and transcriptome data from these assay systems before and after treatment that enables single and combination drug discovery based on molecular phenotype.

Identification of agents effective against multiple toxins and viruses by host-oriented cell targeting.

PubMed

Zilbermintz, Leeor; Leonardi, William; Jeong, Sun-Young; Sjodt, Megan; McComb, Ryan; Ho, Chi-Lee C; Retterer, Cary; Gharaibeh, Dima; Zamani, Rouzbeh; Soloveva, Veronica; Bavari, Sina; Levitin, Anastasia; West, Joel; Bradley, Kenneth A; Clubb, Robert T; Cohen, Stanley N; Gupta, Vivek; Martchenko, Mikhail

2015-08-27

A longstanding and still-increasing threat to the effective treatment of infectious diseases is resistance to antimicrobial countermeasures. Potentially, the targeting of host proteins and pathways essential for the detrimental effects of pathogens offers an approach that may discover broad-spectrum anti-pathogen countermeasures and circumvent the effects of pathogen mutations leading to resistance. Here we report implementation of a strategy for discovering broad-spectrum host-oriented therapies against multiple pathogenic agents by multiplex screening of drugs for protection against the detrimental effects of multiple pathogens, identification of host cell pathways inhibited by the drug, and screening for effects of the agent on other pathogens exploiting the same pathway. We show that a clinically used antimalarial drug, Amodiaquine, discovered by this strategy, protects host cells against infection by multiple toxins and viruses by inhibiting host cathepsin B. Our results reveal the practicality of discovering broadly acting anti-pathogen countermeasures that target host proteins exploited by pathogens.

Consensus statement on the treatment of multiple sclerosis by the Spanish Society of Neurology in 2016.

PubMed

García Merino, A; Ramón Ara Callizo, J; Fernández Fernández, O; Landete Pascual, L; Moral Torres, E; Rodríguez-Antigüedad Zarrantz, A

2017-03-01

With the advent of new disease-modifying drugs, the treatment of multiple sclerosis is becoming increasingly complex. Using consensus statements is therefore advisable. The present consensus statement, which was drawn up by the Spanish Society of Neurology's study group for demyelinating diseases, updates previous consensus statements on the disease. The present study lists the medications currently approved for multiple sclerosis and their official indications, and analyses such treatment-related aspects as activity, early treatment, maintenance, follow-up, treatment failure, changes in medication, and special therapeutic situations. This consensus statement includes treatment recommendations for a wide range of demyelinating diseases, from isolated demyelinating syndromes to the different forms of multiple sclerosis, as well as recommendations for initial therapy and changes in drug medication, and additional comments on induction and combined therapy and practical aspects of the use of these drugs. Copyright © 2016 Sociedad Española de Neurología. Publicado por Elsevier España, S.L.U. All rights reserved.

[Construction of multiple drug release system based on components of traditional Chinese medicine].

PubMed

Liu, Dan; Jia, Xiaobin; Yu, Danhong; Zhang, Zhenhai; Sun, E

2012-08-01

With the development of the modernization drive of traditional Chinese medicine (TCM) preparations, new-type TCM dosage forms research have become a hot spot in the field. Because of complexity of TCM components as well as uncertainty of material base, there is still not a scientific system for modern TCM dosage forms so far. Modern TCM preparations inevitably take the nature of the multi-component and the general function characteristics of multi-link and multi-target into account. The author suggests building a multiple drug release system for TCM using diverse preparation techniques and drug release methods at levels on the basis the nature and function characteristics of TCM components. This essay expounds elaborates the ideas to build the multiple traditional Chinese medicine release system, theoretical basis, preparation techniques and assessment system, current problems and solutions, in order to build a multiple TCM release system with a view of enhancing the bioavailability of TCM components and provide a new form for TCM preparations.

A statistical approach for evaluating the effectiveness of heartworm preventive drugs: what does 100% efficacy really mean?

PubMed

Vidyashankar, Anand N; Jimenez Castro, Pablo D; Kaplan, Ray M

2017-11-09

Initial studies of heartworm preventive drugs all yielded an observed efficacy of 100% with a single dose, and based on these data the US Food and Drug Administration (FDA) required all products to meet this standard for approval. Those initial studies, however, were based on just a few strains of parasites, and therefore were not representative of the full assortment of circulating biotypes. This issue has come to light in recent years, where it has become common for studies to yield less than 100% efficacy. This has changed the landscape for the testing of new products because heartworm efficacy studies lack the statistical power to conclude that finding zero worms is different from finding a few worms. To address this issue, we developed a novel statistical model, based on a hierarchical modeling and parametric bootstrap approach that provides new insights to assess multiple sources of variability encountered in heartworm drug efficacy studies. Using the newly established metrics we performed both data simulations and analyzed actual experimental data. Our results suggest that an important source of modeling variability arises from variability in the parasite establishment rate between dogs; not accounting for this can overestimate the efficacy in more than 40% of cases. We provide strong evidence that ZoeMo-2012 and JYD-34, which both were established from the same source dog, have differing levels of susceptibility to moxidectin. In addition, we provide strong evidence that the differences in efficacy seen in two published studies using the MP3 strain were not due to randomness, and thus must be biological in nature. Our results demonstrate how statistical modeling can improve the interpretation of data from heartworm efficacy studies by providing a means to identify the true efficacy range based on the observed data. Importantly, these new insights should help to inform regulators on how to move forward in establishing new statistically and scientifically valid requirements for efficacy in the registration of new heartworm preventative products. Furthermore, our results provide strong evidence that heartworm 'strains' can change their susceptibility phenotype over short periods of time, providing further evidence that a wide diversity of susceptibility phenotypes exists among naturally circulating biotypes of D. immitis.

Exploring sex differences in drug use, health and service use characteristics among young urban crack users in Brazil.

PubMed

Bertoni, Neilane; Burnett, Chantal; Cruz, Marcelo Santos; Andrade, Tarcisio; Bastos, Francisco I; Leal, Erotildes; Fischer, Benedikt

2014-08-28

Studies have shown important gender differences among drug (including crack) users related to: drug use patterns; health risks and consequences; criminal involvement; and service needs/use. Crack use is prevalent in Brazil; however, few comparative data by sex exist. We examined and compared by sex key drug use, health, socio-economic indicators and service use in a bi-city sample of young (18-24 years), regular and marginalized crack users in Brazil. Study participants (total n = 159; n = 124 males and n = 35 females) were recruited by community-based methods from impoverished neighborhoods in Rio de Janeiro and Salvador. Assessments occurred by an anonymous interviewer-administered questionnaire and serum collection for blood-borne virus testing between November 2010 and June 2011. Descriptive statistics and differences for key variables by sex were computed; in addition, a 'chi-squared automatic interaction detector' ('CHAID') analysis explored potential primary factors differentiating male and female participants. Most participants were non-white, and had low education and multiple income sources. More women had unstable housing and income from sex work and/or panhandling/begging, whereas more men were employed. Both groups indicated multi-year histories of and frequent daily crack use, but virtually no drug injection histories. Men reported more co-use of other drugs. More women were: involved in sex-for-drug exchanges; blood-borne virus (BBV) tested and HIV+. Both groups reported similar physical and mental health patterns; however women more commonly utilized social or health services. The CHAID analysis identified sex work; paid work; begging/panhandling; as well as physical and mental health status (all at p < 0.05) as primary differentiating factors by sex. Crack users in our study showed notable differences by sex, including socio-economic indicators, drug co-use patterns, sex risks/work, BBV testing and status, and service utilization. Results emphasize the need for targeted special interventions and services for males and female crack users in Brazil.

Dose-specific adverse drug reaction identification in electronic patient records: temporal data mining in an inpatient psychiatric population.

PubMed

Eriksson, Robert; Werge, Thomas; Jensen, Lars Juhl; Brunak, Søren

2014-04-01

Data collected for medical, filing and administrative purposes in electronic patient records (EPRs) represent a rich source of individualised clinical data, which has great potential for improved detection of patients experiencing adverse drug reactions (ADRs), across all approved drugs and across all indication areas. The aim of this study was to take advantage of techniques for temporal data mining of EPRs in order to detect ADRs in a patient- and dose-specific manner. We used a psychiatric hospital's EPR system to investigate undesired drug effects. Within one workflow the method identified patient-specific adverse events (AEs) and links these to specific drugs and dosages in a temporal manner, based on integration of text mining results and structured data. The structured data contained precise information on drug identity, dosage and strength. When applying the method to the 3,394 patients in the cohort, we identified AEs linked with a drug in 2,402 patients (70.8 %). Of the 43,528 patient-specific drug substances prescribed, 14,736 (33.9 %) were linked with AEs. From these links we identified multiple ADRs (p < 0.05) and found them to occur at similar frequencies, as stated by the manufacturer and in the literature. We showed that drugs displaying similar ADR profiles share targets, and we compared submitted spontaneous AE reports with our findings. For nine of the ten most prescribed antipsychotics in the patient population, larger doses were prescribed to sedated patients than non-sedated patients; five antipsychotics [corrected] exhibited a significant difference (p<0.05). Finally, we present two cases (p < 0.05) identified by the workflow. The method identified the potentially fatal AE QT prolongation caused by methadone, and a non-described likely ADR between levomepromazine and nightmares found among the hundreds of identified novel links between drugs and AEs (p < 0.05). The developed method can be used to extract dose-dependent ADR information from already collected EPR data. Large-scale AE extraction from EPRs may complement or even replace current drug safety monitoring methods in the future, reducing or eliminating manual reporting and enabling much faster ADR detection.

Gene-gene-environment interactions between drugs, transporters, receptors, and metabolizing enzymes: Statins, SLCO1B1, and CYP3A4 as an example.

PubMed

Sadee, Wolfgang

2013-09-01

Pharmacogenetic biomarker tests include mostly specific single gene-drug pairs, capable of accounting for a portion of interindividual variability in drug response and toxicity. However, multiple genes are likely to contribute, either acting independently or epistatically, with the CYP2C9-VKORC1-warfarin test panel, an example of a clinically used gene-gene-dug interaction. I discuss here further instances of gene-gene-drug interactions, including a proposed dynamic effect on statin therapy by genetic variants in both a transporter (SLCO1B1) and a metabolizing enzyme (CYP3A4) in liver cells, the main target site where statins block cholesterol synthesis. These examples set a conceptual framework for developing diagnostic panels involving multiple gene-drug combinations. Copyright © 2013 Wiley Periodicals, Inc.

The Microphysiology Systems Database for Analyzing and Modeling Compound Interactions with Human and Animal Organ Models

PubMed Central

Vernetti, Lawrence; Bergenthal, Luke; Shun, Tong Ying; Taylor, D. Lansing

2016-01-01

Abstract Microfluidic human organ models, microphysiology systems (MPS), are currently being developed as predictive models of drug safety and efficacy in humans. To design and validate MPS as predictive of human safety liabilities requires safety data for a reference set of compounds, combined with in vitro data from the human organ models. To address this need, we have developed an internet database, the MPS database (MPS-Db), as a powerful platform for experimental design, data management, and analysis, and to combine experimental data with reference data, to enable computational modeling. The present study demonstrates the capability of the MPS-Db in early safety testing using a human liver MPS to relate the effects of tolcapone and entacapone in the in vitro model to human in vivo effects. These two compounds were chosen to be evaluated as a representative pair of marketed drugs because they are structurally similar, have the same target, and were found safe or had an acceptable risk in preclinical and clinical trials, yet tolcapone induced unacceptable levels of hepatotoxicity while entacapone was found to be safe. Results demonstrate the utility of the MPS-Db as an essential resource for relating in vitro organ model data to the multiple biochemical, preclinical, and clinical data sources on in vivo drug effects. PMID:28781990

Exploiting nature's rich source of proteasome inhibitors as starting points in drug development.

PubMed

Gräwert, Melissa Ann; Groll, Michael

2012-02-01

Cancer is the No. 2 cause of death in the Western world and one of the most expensive diseases to treat. Thus, it is not surprising, that every major pharmaceutical and biotechnology company has a blockbuster oncology product. In 2003, Millennium Pharmaceuticals entered the race with Velcade®, a first-in-class proteasome inhibitor that has been approved by the FDA for treatment of multiple myeloma and its sales have passed the billion dollar mark. Velcade®'s extremely toxic boronic acid pharmacophore, however, contributes to a number of severe side effects. Nevertheless, the launching of this product has validated the proteasome as a target in fighting cancer and further proteasome inhibitors have entered the market as anti-cancer drugs. Additionally, proteasome inhibitors have found application as crop protection agents, anti-parasitics, immunosuppressives, as well as in new therapies for muscular dystrophies and inflammation. Many of these compounds are based on microbial metabolites. In this review, we emphasize the important role of the structural elucidation of the various unique binding mechanisms of these compounds that have been optimized throughout evolution to target the proteasome. Based on this knowledge, medicinal chemists have further optimized these natural products, resulting in potential drugs with reduced off-target activities. This journal is © The Royal Society of Chemistry 2012

Biosynthesis of Drug Glucuronide Metabolites in the Budding Yeast Saccharomyces cerevisiae.

PubMed

Ikushiro, Shinichi; Nishikawa, Miyu; Masuyama, Yuuka; Shouji, Tadashi; Fujii, Miharu; Hamada, Masahiro; Nakajima, Noriyuki; Finel, Moshe; Yasuda, Kaori; Kamakura, Masaki; Sakaki, Toshiyuki

2016-07-05

Glucuronidation is one of the most common pathways in mammals for detoxification and elimination of hydrophobic xenobiotic compounds, including many drugs. Metabolites, however, can form active or toxic compounds, such as acyl glucuronides, and their safety assessment is often needed. The absence of efficient means for in vitro synthesis of correct glucuronide metabolites frequently limits such toxicological analyses. To overcome this hurdle we have developed a new approach, the essence of which is a coexpression system containing a human, or another mammalian UDP-glucuronosyltransferases (UGTs), as well as UDP-glucose-6-dehydrogenase (UGDH), within the budding yeast, Saccharomyces cerevisiae. The system was first tested using resting yeast cells coexpressing UGDH and human UGT1A6, 7-hydroxycoumarin as the substrate, in a reaction medium containing 8% glucose, serving as a source of UDP-glucuronic acid. Glucuronides were readily formed and recovered from the medium. Subsequently, by selecting suitable mammalian UGT enzyme for the coexpression system we could obtain the desired glucuronides of various compounds, including molecules with multiple conjugation sites and acyl glucuronides of several carboxylic acid containing drugs, namely, mefenamic acid, flufenamic acid, and zomepirac. In conclusion, a new and flexible yeast system with mammalian UGTs has been developed that exhibits a capacity for efficient production of various glucuronides, including acyl glucuronides.

Not lost in translation: Emerging clinical importance of the G protein-coupled estrogen receptor GPER.

PubMed

Barton, Matthias

2016-07-01

It has been 20years that the G protein-coupled estrogen receptor (GPER) was cloned as the orphan receptor GPR30 from multiple cellular sources, including vascular endothelial cells. Here, I will provide an overview of estrogen biology and the historical background leading to the discovery of rapid vascular estrogen signaling. I will also review the recent advances in the understanding of the mechanisms underlying GPER function, its role in physiology and disease, some of the currently available GPER-targeting drugs approved for clinical use such as SERMs (selective estrogen receptor modulators) and SERDs (selective estrogen receptor downregulators). Many of currently used drugs such as tamoxifen, raloxifene, or faslodex™/fulvestrant were discovered targeting GPER many years after they had been introduced to the clinics for entirely different purposes. This has important implications for the clinical use of these drugs and their modes of action, which I have termed 'reverse translational medicine'. In addition, environmental pollutants known as 'endocrine disruptors' have been found to bind to GPER. This article also discusses recent evidence in these areas as well as opportunities in translational clinical medicine and GPER research, including medical genetics, personalized medicine, prevention, and its theranostic use. Copyright © 2016 Elsevier Inc. All rights reserved.

Inhaled nano- and microparticles for drug delivery

PubMed Central

El-Sherbiny, Ibrahim M.; El-Baz, Nancy M.; Yacoub, Magdi H.

2015-01-01

The 21st century has seen a paradigm shift to inhaled therapy, for both systemic and local drug delivery, due to the lung's favourable properties of a large surface area and high permeability. Pulmonary drug delivery possesses many advantages, including non-invasive route of administration, low metabolic activity, control environment for systemic absorption and avoids first bypass metabolism. However, because the lung is one of the major ports of entry, it has multiple clearance mechanisms, which prevent foreign particles from entering the body. Although these clearance mechanisms maintain the sterility of the lung, clearance mechanisms can also act as barriers to the therapeutic effectiveness of inhaled drugs. This effectiveness is also influenced by the deposition site and delivered dose. Particulate-based drug delivery systems have emerged as an innovative and promising alternative to conventional inhaled drugs to circumvent pulmonary clearance mechanisms and provide enhanced therapeutic efficiency and controlled drug release. The principle of multiple pulmonary clearance mechanisms is reviewed, including mucociliary, alveolar macrophages, absorptive, and metabolic degradation. This review also discusses the current approaches and formulations developed to achieve optimal pulmonary drug delivery systems. PMID:26779496

Ignition probability of polymer-bonded explosives accounting for multiple sources of material stochasticity

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

Kim, S.; Barua, A.; Zhou, M., E-mail: min.zhou@me.gatech.edu

2014-05-07

Accounting for the combined effect of multiple sources of stochasticity in material attributes, we develop an approach that computationally predicts the probability of ignition of polymer-bonded explosives (PBXs) under impact loading. The probabilistic nature of the specific ignition processes is assumed to arise from two sources of stochasticity. The first source involves random variations in material microstructural morphology; the second source involves random fluctuations in grain-binder interfacial bonding strength. The effect of the first source of stochasticity is analyzed with multiple sets of statistically similar microstructures and constant interfacial bonding strength. Subsequently, each of the microstructures in the multiple setsmore » is assigned multiple instantiations of randomly varying grain-binder interfacial strengths to analyze the effect of the second source of stochasticity. Critical hotspot size-temperature states reaching the threshold for ignition are calculated through finite element simulations that explicitly account for microstructure and bulk and interfacial dissipation to quantify the time to criticality (t{sub c}) of individual samples, allowing the probability distribution of the time to criticality that results from each source of stochastic variation for a material to be analyzed. Two probability superposition models are considered to combine the effects of the multiple sources of stochasticity. The first is a parallel and series combination model, and the second is a nested probability function model. Results show that the nested Weibull distribution provides an accurate description of the combined ignition probability. The approach developed here represents a general framework for analyzing the stochasticity in the material behavior that arises out of multiple types of uncertainty associated with the structure, design, synthesis and processing of materials.« less

Influences on the prescribing of new drugs.

PubMed

Tobin, Luke; de Almedia Neto, Abelio C; Wutzke, Sonia; Patterson, Craig; Mackson, Judith; Weekes, Lynn; Williamson, Margaret

2008-01-01

The aim of this study was to identify the factors that influence prescribing of new drugs among general practitioners, endocrinologists and psychiatrists. Four focus groups were conducted with GPs, endocrinologists and psychiatrists on sources of awareness and influences on prescribing of new drugs. Pharmaceutical companies were the most important source for becoming aware of new drugs. There were many influences on the decision to prescribe a new drug, the most important being efficacy, safety, cost and advantage over existing therapies. Endocrinologists placed greater emphasis on evidence from clinical trials and scientific conferences, and psychiatrists and GPs placed more weight on pharmaceutical representatives, colleagues and specialists. New drug prescribing occurs in a complex environment with many influences. Effective interventions to promote rational, safe and effective prescribing of new drugs will need to be cognisant of these factors.

21 CFR 179.21 - Sources of radiation used for inspection of food, for inspection of packaged food, and for...

Code of Federal Regulations, 2010 CFR

2010-04-01

... 21 Food and Drugs 3 2010-04-01 2009-04-01 true Sources of radiation used for inspection of food, for inspection of packaged food, and for controlling food processing. 179.21 Section 179.21 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) FOOD FOR HUMAN CONSUMPTION (CONTINUED) IRRADIATION IN THE...

DGIdb 3.0: a redesign and expansion of the drug-gene interaction database.

PubMed

Cotto, Kelsy C; Wagner, Alex H; Feng, Yang-Yang; Kiwala, Susanna; Coffman, Adam C; Spies, Gregory; Wollam, Alex; Spies, Nicholas C; Griffith, Obi L; Griffith, Malachi

2018-01-04

The drug-gene interaction database (DGIdb, www.dgidb.org) consolidates, organizes and presents drug-gene interactions and gene druggability information from papers, databases and web resources. DGIdb normalizes content from 30 disparate sources and allows for user-friendly advanced browsing, searching and filtering for ease of access through an intuitive web user interface, application programming interface (API) and public cloud-based server image. DGIdb v3.0 represents a major update of the database. Nine of the previously included 24 sources were updated. Six new resources were added, bringing the total number of sources to 30. These updates and additions of sources have cumulatively resulted in 56 309 interaction claims. This has also substantially expanded the comprehensive catalogue of druggable genes and anti-neoplastic drug-gene interactions included in the DGIdb. Along with these content updates, v3.0 has received a major overhaul of its codebase, including an updated user interface, preset interaction search filters, consolidation of interaction information into interaction groups, greatly improved search response times and upgrading the underlying web application framework. In addition, the expanded API features new endpoints which allow users to extract more detailed information about queried drugs, genes and drug-gene interactions, including listings of PubMed IDs, interaction type and other interaction metadata.

Cardiotoxicity screening: a review of rapid-throughput in vitro approaches.

PubMed

Li, Xichun; Zhang, Rui; Zhao, Bin; Lossin, Christoph; Cao, Zhengyu

2016-08-01

Cardiac toxicity represents one of the leading causes of drug failure along different stages of drug development. Multiple very successful pharmaceuticals had to be pulled from the market or labeled with strict usage warnings due to adverse cardiac effects. In order to protect clinical trial participants and patients, the International Conference on Harmonization published guidelines to recommend that all new drugs to be tested preclinically for hERG (Kv11.1) channel sensitivity before submitting for regulatory reviews. However, extensive studies have demonstrated that measurement of hERG activity has limitations due to the multiple molecular targets of drug compound through which it may mitigate or abolish a potential arrhythmia, and therefore, a model measuring multiple ion channel effects is likely to be more predictive. Several phenotypic rapid-throughput methods have been developed to predict the potential cardiac toxic compounds in the early stages of drug development using embryonic stem cells- or human induced pluripotent stem cell-derived cardiomyocytes. These rapid-throughput methods include microelectrode array-based field potential assay, impedance-based or Ca(2+) dynamics-based cardiomyocytes contractility assays. This review aims to discuss advantages and limitations of these phenotypic assays for cardiac toxicity assessment.

Multidrug-resistant bacteria infection and nursing quality management application in the department of physical examination.

PubMed

Xu, Li; Luo, Qiang; Chen, Liangzhen; Jiao, Lingmei

2017-09-01

The main problem of clinical prevention and control of multi drug resistant bacteria infection is to strengthen the monitoring of pathogenic bacteria spectrum, this study research on the multi drug-resistant bacteria infection and nursing quality management application in the department of physical examination. The results of this study showed that the number of patients with multiple drug resistant infections showed an increasing trend. Therefore, once the patients with multiple drug-resistant bacteria infection are found, the prevention and control of the patients with multiple drug-resistant bacteria should be strictly followed, and the patient's medication care should be highly valued. Also, the nurses need to be classified based on the knowledge and skill characteristics of the nurses in the department of physical examination, and compare the nursing effect before and after classification and grouping. The physicians and individuals receiving physical examinations in the department of physical examination had a higher degree of satisfaction for nursing effect after classification compared with those before classification. Classification and grouping management helps improve the nursing quality and overall quality of the nurses in the department of physical examination.

Electrophysiological correlates of cocktail-party listening.

PubMed

Lewald, Jörg; Getzmann, Stephan

2015-10-01

Detecting, localizing, and selectively attending to a particular sound source of interest in complex auditory scenes composed of multiple competing sources is a remarkable capacity of the human auditory system. The neural basis of this so-called "cocktail-party effect" has remained largely unknown. Here, we studied the cortical network engaged in solving the "cocktail-party" problem, using event-related potentials (ERPs) in combination with two tasks demanding horizontal localization of a naturalistic target sound presented either in silence or in the presence of multiple competing sound sources. Presentation of multiple sound sources, as compared to single sources, induced an increased P1 amplitude, a reduction in N1, and a strong N2 component, resulting in a pronounced negativity in the ERP difference waveform (N2d) around 260 ms after stimulus onset. About 100 ms later, the anterior contralateral N2 subcomponent (N2ac) occurred in the multiple-sources condition, as computed from the amplitude difference for targets in the left minus right hemispaces. Cortical source analyses of the ERP modulation, resulting from the contrast of multiple vs. single sources, generally revealed an initial enhancement of electrical activity in right temporo-parietal areas, including auditory cortex, by multiple sources (at P1) that is followed by a reduction, with the primary sources shifting from right inferior parietal lobule (at N1) to left dorso-frontal cortex (at N2d). Thus, cocktail-party listening, as compared to single-source localization, appears to be based on a complex chronology of successive electrical activities within a specific cortical network involved in spatial hearing in complex situations. Copyright © 2015 Elsevier B.V. All rights reserved.

Predicting drug-target interactions using restricted Boltzmann machines.

PubMed

Wang, Yuhao; Zeng, Jianyang

2013-07-01

In silico prediction of drug-target interactions plays an important role toward identifying and developing new uses of existing or abandoned drugs. Network-based approaches have recently become a popular tool for discovering new drug-target interactions (DTIs). Unfortunately, most of these network-based approaches can only predict binary interactions between drugs and targets, and information about different types of interactions has not been well exploited for DTI prediction in previous studies. On the other hand, incorporating additional information about drug-target relationships or drug modes of action can improve prediction of DTIs. Furthermore, the predicted types of DTIs can broaden our understanding about the molecular basis of drug action. We propose a first machine learning approach to integrate multiple types of DTIs and predict unknown drug-target relationships or drug modes of action. We cast the new DTI prediction problem into a two-layer graphical model, called restricted Boltzmann machine, and apply a practical learning algorithm to train our model and make predictions. Tests on two public databases show that our restricted Boltzmann machine model can effectively capture the latent features of a DTI network and achieve excellent performance on predicting different types of DTIs, with the area under precision-recall curve up to 89.6. In addition, we demonstrate that integrating multiple types of DTIs can significantly outperform other predictions either by simply mixing multiple types of interactions without distinction or using only a single interaction type. Further tests show that our approach can infer a high fraction of novel DTIs that has been validated by known experiments in the literature or other databases. These results indicate that our approach can have highly practical relevance to DTI prediction and drug repositioning, and hence advance the drug discovery process. Software and datasets are available on request. Supplementary data are available at Bioinformatics online.

Multiplicative Effects of Social and Psychological Risk Factors on College Students' Suicidal Behaviors.

PubMed

Assari, Shervin

2018-05-17

Less is known about the multiplicative effects of social and psychological risk and protective factors of suicidality on college campuses. The current study aimed to investigate the multiplicative effects of social (identifying oneself as gay/lesbian, financial difficulty, violence victimization, and religiosity) and psychological (anxiety, depression, problem alcohol use, drug use) and risk/protective factors on suicidal behaviors among college students in the United States. Using a cross-sectional design, the Healthy Mind Study (HMS; 2016⁻2017), is a national online survey of college students in the United States. Social (identifying oneself as gay/lesbian, violence victimization, financial difficulty, and religiosity) and psychological (anxiety, depression, problem alcohol use, and drug use) risk/protective factors were assessed among 27,961 individuals. Three aspects of suicidality, including ideation, plan, and attempt, were also assessed. Logistic regression models were used for data analysis. Financial difficulty, violence victimization, identifying oneself as gay/lesbian, anxiety, depression, and drug use increased, while religiosity reduced the odds of suicidal behaviors. Multiplicative effects were found between the following social and psychological risk factors: (1) financial difficulty and anxiety; (2) financial difficulty and depression; (3) depression and drug use; (4) problem alcohol use and drug use; and (5) depression and problem alcohol use. There is a considerable overlap in the social and psychological processes, such as financial stress, mood disorders, and substance use problems, on risk of suicide in college students. As social and psychological risk factors do not operate independently, comprehensive suicidal risk evaluations that simultaneously address multiple social and psychological risk factors may be superior to programs that only address a single risk factor.

Drug effects on multiple and concurrent schedules of ethanol- and food-maintained behaviour: context-dependent selectivity

PubMed Central

Ginsburg, B C; Lamb, R J

2014-01-01

BACKGROUND AND PURPOSE Drugs that more potently or effectively reduce ethanol-maintained behaviour versus an alternative are considered selective and are considered promising pharmacotherapies for alcoholism. Such results are often obtained using separate groups or multiple schedules where ethanol and the alternative are available alone or sequentially. Recently, we observed that when ethanol and food were available sequentially under a multiple schedule, fluvoxamine and varenicline were selective; yet this selectivity disappeared when ethanol and food were concurrently available. EXPERIMENTAL APPROACH We examined the generality of these findings by comparing doses of several drugs required to decrease ethanol- and food-maintained responding under a multiple schedule and under a concurrent schedule. Effects were determined for chlordiazepoxide, 2,5-dimethoxy-4-iodoamphetamine (DOI), meta-chlorophenylpiperazine (mCPP), morphine, naltrexone and d-amphetamine. KEY RESULTS Under the multiple schedule, ED50 values for decreases in ethanol-maintained responding were significantly different and lower than ED50s for decreases in food-maintained responding (demonstrating selectivity) for each drug except for chlordiazepoxide (which was equipotent) and naltrexone (which did not affect responding). However, this selectivity vanished or even inverted under the concurrent schedule, such that ED50 values for decreasing ethanol- and food-maintained responding were not different (or, following DOI, the ED50 for food-maintained responding was lower than for ethanol-maintained responding). CONCLUSIONS AND IMPLICATIONS Results are consistent with those seen following fluvoxamine and varenicline administration, and suggest that selectivity is assay-dependent. These results indicate the need for careful interpretation of selective drug effects, especially when obtained in situations where ethanol or the alternative is the only programmed reinforcement available. PMID:24697498

Drug effects on multiple and concurrent schedules of ethanol- and food-maintained behaviour: context-dependent selectivity.

PubMed

Ginsburg, B C; Lamb, R J

2014-07-01

Drugs that more potently or effectively reduce ethanol-maintained behaviour versus an alternative are considered selective and are considered promising pharmacotherapies for alcoholism. Such results are often obtained using separate groups or multiple schedules where ethanol and the alternative are available alone or sequentially. Recently, we observed that when ethanol and food were available sequentially under a multiple schedule, fluvoxamine and varenicline were selective; yet this selectivity disappeared when ethanol and food were concurrently available. We examined the generality of these findings by comparing doses of several drugs required to decrease ethanol- and food-maintained responding under a multiple schedule and under a concurrent schedule. Effects were determined for chlordiazepoxide, 2,5-dimethoxy-4-iodoamphetamine (DOI), meta-chlorophenylpiperazine (mCPP), morphine, naltrexone and d-amphetamine. Under the multiple schedule, ED50 values for decreases in ethanol-maintained responding were significantly different and lower than ED50 s for decreases in food-maintained responding (demonstrating selectivity) for each drug except for chlordiazepoxide (which was equipotent) and naltrexone (which did not affect responding). However, this selectivity vanished or even inverted under the concurrent schedule, such that ED50 values for decreasing ethanol- and food-maintained responding were not different (or, following DOI, the ED50 for food-maintained responding was lower than for ethanol-maintained responding). Results are consistent with those seen following fluvoxamine and varenicline administration, and suggest that selectivity is assay-dependent. These results indicate the need for careful interpretation of selective drug effects, especially when obtained in situations where ethanol or the alternative is the only programmed reinforcement available. © 2014 The British Pharmacological Society.

Cold Atom Source Containing Multiple Magneto-Optical Traps

NASA Technical Reports Server (NTRS)

Ramirez-Serrano, Jaime; Kohel, James; Kellogg, James; Lim, Lawrence; Yu, Nan; Maleki, Lute

2007-01-01

An apparatus that serves as a source of a cold beam of atoms contains multiple two-dimensional (2D) magneto-optical traps (MOTs). (Cold beams of atoms are used in atomic clocks and in diverse scientific experiments and applications.) The multiple-2D-MOT design of this cold atom source stands in contrast to single-2D-MOT designs of prior cold atom sources of the same type. The advantages afforded by the present design are that this apparatus is smaller than prior designs.

Fingolimod Prescribed for the Treatment of Multiple Sclerosis in Patients Younger Than Age 18 Years.

PubMed

Fragoso, Yara Dadalti; Alves-Leon, Soniza Vieira; Barreira, Amilton Antunes; Callegaro, Dagoberto; Brito Ferreira, Maria Lucia; Finkelsztejn, Alessandro; Gomes, Sidney; Magno Goncalves, Marcus Vinicius; Moraes Machado, Maria Iris; Marques, Vanessa Daccach; Cunha Matta, Andre Palma; Papais-Alvarenga, Regina Maria; Apostolos Pereira, Samira Luisa; Tauil, Carlos Bernardo

2015-08-01

There have been no clinical trials for approval of medications for treating multiple sclerosis in patients younger than age 18 years. All treatments are based on personal experience and data from open observational studies. Fingolimod is an oral drug for multiple sclerosis that has been shown to be efficient and safe in adults. The aim of our study is to describe patients with multiple sclerosis who started treatment with fingolimod before the age of 18 years. Seventeen patients treated with fingolimod were identified in the Brazilian database of children and adolescents with multiple sclerosis. The average time of use of the drug was 8.6 months. Fingolimod showed a good safety and efficacy profile in these patients, all of whom had very active multiple sclerosis. After starting treatment with fingolimod, only one patient had a relapse and a new lesion on magnetic resonance imaging. The patients' degree of disability did not progress. No major adverse events were reported in relation to the first dose of the drug, nor in the short- and medium-term treatment. No patient has been followed for longer than 18 months, thus limiting long-term conclusions. Off-label use of fingolimod in patients younger than age 18 years may be a good therapeutic option for multiple sclerosis control. Copyright © 2015 Elsevier Inc. All rights reserved.

Multifaceted role of lipids in Mycobacterium leprae.

PubMed

Kaur, Gurkamaljit; Kaur, Jagdeep

2017-03-01

Mycobacterium leprae must adopt a metabolic strategy and undergo various metabolic alterations upon infection to survive inside the human body for years in a dormant state. A change in lipid homeostasis upon infection is highly pronounced in Mycobacterium leprae. Lipids play an essential role in the survival and pathogenesis of mycobacteria. Lipids are present in several forms and serve multiple roles from being a source of nutrition, providing rigidity, evading the host immune response to serving as virulence factors, etc. The synthesis and degradation of lipids is a highly regulated process and is the key to future drug designing and diagnosis for mycobacteria. In the current review, an account of the distinct roles served by lipids, the mechanism of their synthesis and degradation has been elucidated.

Clinical development of imatinib: an anticancer drug

PubMed Central

Goswami, Dipanjan; Gurule, Sanjay; Lahiry, Abhiroop; Anand, Amit; Khuroo, Arshad; Monif, Tausif

2016-01-01

Background: A novel and accurate high-throughput tandem mass spectroscopic method has been developed and validated for determination of imatinib, a protein-tyrosine kinase inhibitor against chronic myeloid leukemia. Materials & methods: Chromatographic separation was carried on XTerra® RP18 column (150 mm × 4.6 mm, 5 µm particle size) manufactured by Waters Corporation, MA, USA. The detection was performed on a triple quadruple tandem mass spectrometer by multiple reactions monitoring mode via electrospray ionization source. Results: The selective and sensitive method was linear in the concentration range of 9.57–4513.29 ng/ml and reported no matrix effect. Conclusion: The mean Cmax was found to be 10–15% lower in European subjects as compared with Indian subjects. PMID:28031942

Demyelinating disease in patients treated with TNF antagonists in rheumatology: data from BIOBADASER, a pharmacovigilance database, and a systematic review.

PubMed

Cruz Fernández-Espartero, María; Pérez-Zafrilla, Beatriz; Naranjo, Antonio; Esteban, Carmen; Ortiz, Ana M; Gómez-Reino, Juan J; Carmona, Loreto

2011-12-01

To estimate the rate of demyelinating diseases in patients with rheumatic diseases treated with tumor necrosis factor (TNF) antagonists and to describe the cases reported to 3 different pharmacovigilance sources. All confirmed cases of demyelinating disease, optic neuritis, and multiple sclerosis (MS) in patients with rheumatic diseases treated with TNF-antagonists were reviewed from 3 different sources: (1) the Spanish Registry of biological therapies in rheumatic diseases (BIOBADASER); (2) the Spanish Pharmacovigilance Database of Adverse Drug Reactions (FEDRA); and (3) a systematic review (PubMed, EMBASE, and the Cochrane Library). In BIOBADASER, the incidence rate per 1000 patients was estimated with a 95% confidence interval (95% CI). In 21,425 patient-years in BIOBADASER, there were 9 patients with confirmed demyelinating disease, 4 with optic neuritis, and 1 with MS. In addition, 22 patients presented polyneuropathies, paresthesias, dysesthesias, facial palsy, or vocal cord paralysis without confirmed demyelination. The incidence rate of demyelinating disease in patients with rheumatic diseases exposed to TNF-antagonists in BIOBADASER was 0.65 per 1000 patient-years (95% CI: 0.39-1.1). The incidence of MS in BIOBADASER was 0.05 (95% CI: 0.01-0.33), while the incidence in the general Spanish population was 0.02 to 0.04 cases per 1000. Compared with BIOBADASER, cases in FEDRA (n = 19) and in the literature (n = 48) tend to be younger, have shorter exposure to TNF-antagonists, and recover after discontinuation of the drug. It is not clear whether TNF antagonists increase the incidence of demyelinating diseases in patients with rheumatic diseases. Differences between cases depending on the pharmacovigilance source could be explained by selective reporting bias outside registries. Copyright © 2011. Published by Elsevier Inc.

Demyelinating disease in patients treated with TNF antagonists in rheumatology: data from BIOBADASER, a pharmacovigilance database, and a systematic review.

PubMed

Fernández-Espartero, María Cruz; Pérez-Zafrilla, Beatriz; Naranjo, Antonio; Esteban, Carmen; Ortiz, Ana M; Gómez-Reino, Juan J; Carmona, Loreto

2011-02-01

To estimate the rate of demyelinating diseases in patients with rheumatic diseases treated with tumor necrosis factor (TNF) antagonists and to describe the cases reported to 3 different pharmacovigilance sources. All confirmed cases of demyelinating disease, optic neuritis, and multiple sclerosis (MS) in patients with rheumatic diseases treated with TNF-antagonists were reviewed from 3 different sources: (1) the Spanish Registry of biological therapies in rheumatic diseases (BIOBADASER); (2) the Spanish Pharmacovigilance Database of Adverse Drug Reactions (FEDRA); and (3) a systematic review (PubMed, EMBASE, and the Cochrane Library). In BIOBADASER, the incidence rate per 1000 patients was estimated with a 95% confidence interval (95%CI). In 21,425 patient-years in BIOBADASER, there were 9 patients with confirmed demyelinating disease, 4 with optic neuritis, and 1 with MS. In addition, 22 patients presented polyneuropathies, paresthesias, dysesthesias, facial palsy, or vocal cord paralysis without confirmed demyelination. The incidence rate of demyelinating disease in patients with rheumatic diseases exposed to TNF antagonists in BIOBADASER was 0.65 per 1000 patient-years (95%CI: 0.39-1.1). The incidence of MS in BIOBADASER was 0.05 (95%CI: 0.01-0.33), while the incidence in the general Spanish population was 0.02 to 0.04 cases per 1000. Compared with BIOBADASER, cases in FEDRA (n = 19) and in the literature (n = 48) tend to be younger, have shorter exposure to TNF-antagonists, and recover after discontinuation of the drug. It is not clear whether TNF antagonists increase the incidence of demyelinating diseases in patients with rheumatic diseases. Differences between cases depending on the pharmacovigilance source could be explained by selective reporting bias outside registries. Copyright © 2011 Elsevier Inc. All rights reserved.

W/O/W multiple emulsions with diclofenac sodium.

PubMed

Lindenstruth, Kai; Müller, Bernd W

2004-11-01

The disperse oil droplets of W/O/W multiple emulsions contain small water droplets, in which drugs could be incorporated, but the structure of these emulsions is also the reason for possible instability. Due to the middle oil phase which acts as a 'semipermeable' membrane the passage of water across the oil phase can take place. However, the emulsions have been produced in a two-step-production process so not only the leakage of encapsulated drug molecules out of the inner water phase during storage but also a production-induced reduction of the encapsulation rate should be considered. The aim of this study was to ascertain how far the production-induced reduction of the encapsulation rate relates to the size of inner water droplets and to evaluate the relevance of multiple emulsions as drug carrier for diclofenac sodium. Therefore multiple emulsions were produced according to a central composite design. During the second production step it was observed that the parameters pressure and temperature have an influence on the size of the oil droplets in the W/O/W multiple emulsions. Further experiments with different W/O emulsions resulted in W/O/W multiple emulsions with different encapsulation rates of diclofenac sodium, due to the different sizes of the inner water droplets, which were obtained in the first production step.

Factors influencing consumer purchasing patterns of generic versus brand name over-the-counter drugs.

PubMed

Kohli, Erol; Buller, Allison

2013-02-01

US consumers spend more than $20 billion/year on over-the-counter (OTC) drugs. Although generic and brand name OTC drugs share the same active ingredients and undergo the same rigorous Food and Drug Administration approval process, brand name formulations continue to lead the OTC drug market with a higher market share. There is a limited amount of publicly available information regarding consumer perceptions and awareness about generic and brand name OTC drugs. The main objective of this research was to understand what factors influence US consumers to purchase generic versus brand name OTC drugs. The researchers used a 20-question, self-administered, multiple-choice survey to collect data on the factors influencing consumers' preferences for generic versus brand name OTC drugs. Results revealed that the single most influential factor for participants when purchasing OTC drugs was lower cost. Although economic factors play an important role in influencing consumers to choose generic formulations, a variety of other factors including advertisements, duration of the OTC effectiveness, severity of sickness, preferable form of OTC medication, safety of the OTC, relief of multiple symptoms, and preferred company will persuade others to pay more for brand name drugs. Ultimately, increased awareness and use of generic OTC drugs may result in substantial cost savings for consumers.

Identification of precision treatment strategies for relapsed/refractory multiple myeloma by functional drug sensitivity testing.

PubMed

Majumder, Muntasir Mamun; Silvennoinen, Raija; Anttila, Pekka; Tamborero, David; Eldfors, Samuli; Yadav, Bhagwan; Karjalainen, Riikka; Kuusanmäki, Heikki; Lievonen, Juha; Parsons, Alun; Suvela, Minna; Jantunen, Esa; Porkka, Kimmo; Heckman, Caroline A

2017-08-22

Novel agents have increased survival of multiple myeloma (MM) patients, however high-risk and relapsed/refractory patients remain challenging to treat and their outcome is poor. To identify novel therapies and aid treatment selection for MM, we assessed the ex vivo sensitivity of 50 MM patient samples to 308 approved and investigational drugs. With the results we i) classified patients based on their ex vivo drug response profile; ii) identified and matched potential drug candidates to recurrent cytogenetic alterations; and iii) correlated ex vivo drug sensitivity to patient outcome. Based on their drug sensitivity profiles, MM patients were stratified into four distinct subgroups with varied survival outcomes. Patients with progressive disease and poor survival clustered in a drug response group exhibiting high sensitivity to signal transduction inhibitors. Del(17p) positive samples were resistant to most drugs tested with the exception of histone deacetylase and BCL2 inhibitors. Samples positive for t(4;14) were highly sensitive to immunomodulatory drugs, proteasome inhibitors and several targeted drugs. Three patients treated based on the ex vivo results showed good response to the selected treatments. Our results demonstrate that ex vivo drug testing may potentially be applied to optimize treatment selection and achieve therapeutic benefit for relapsed/refractory MM.

[Effect of preventive treatment on cognitive performance in patients with multiple sclerosis].

PubMed

Shorobura, Maria S

2018-01-01

Introduction: cognitive, emotional and psychopathological changes play a significant role in the clinical picture of multiple sclerosis and influence the effectiveness of drug therapy, working capacity, quality of life, and the process of rehabilitation of patients with multiple sclerosis. The aim: investigate the changes in cognitive function in patients with multiple sclerosis, such as information processing speed and working memory of patients before and after treatment with immunomodulating drug. Materials and methods:33 patients examined reliably diagnosed with multiple sclerosis who were treated with preventive examinations and treatment from 2012 to 2016. For all patients with multiple sclerosis had clinical-neurological examination (neurological status using the EDSS scale) and the cognitive status was evaluated using the PASAT auditory test. Patient screening was performed before, during and after the therapy. Statistical analysis of the results was performed in the system Statistica 8.0. We used Student's t-test (t), Mann-Whitney test (Z). Person evaluated the correlation coefficients and Spearman (r, R), Wilcoxon criterion (T), Chi-square (X²). Results: The age of patients with multiple sclerosis affects the growth and EDSS scale score decrease PASAT to treatment. Duration of illness affects the EDSS scale score and performance PASAT. Indicators PASAT not significantly decreased throughout the treatment. Conclusions: glatiramer acetate has a positive effect on cognitive function, information processing speed and working memory patients with multiple sclerosis, which is one of the important components of the therapeutic effect of this drug.

Preventing the Consequences of Alcohol Abuse: Identification of Soldiers at High Risk for Fatal and Serious Injuries

DTIC Science & Technology

2005-07-01

Drug/Alcohol Combo: 1980-1985 1986-1988 303.1 - Alcohol dependence with drug abuse 303.07 - Alcohol dependence syndrome - acute alcohol intoxication...with single drug use 303.10 - Alcohol dependence with drug abuse, unspecified 303.08 - Alcohol dependence syndrome - acute alcohol intoxication, with...multiple drug use 303.11 - Alcohol dependence with drug abuse, 303.97 - Alcohol dependence syndrome - other and continuous/habitual unspecified alcohol

Mycobacterium abscessus post-injection abscesses from extrinsic contamination of multiple-dose bottles of normal saline in a rural clinic.

PubMed

Yuan, Jun; Liu, Yufei; Yang, Zhicong; Cai, Yanshan; Deng, Zhiai; Qin, Pengzhe; Li, Tiegang; Dong, Zhiqiang; Yan, Ziqiang; Zhou, Duanhua; Luo, Huiming; Ma, Huilai; Pang, Xinglin; Fontaine, Robert E

2009-09-01

We investigated an outbreak of gluteal abscesses following intramuscular (IM) injections given at a clinic in rural China to identify the causative agent, source, and method of exposure. We defined a case as an abscess that appeared at the site of an injection given since June 1, 2006. We compared case rates by injection route, medication, and diluents. We reviewed injection practices, and cultured abscesses and environmental sites for mycobacteria. From October through December 2006, 5.8% (n=35) of 604 persons who had received injections at the clinic developed a case. All 35 cases occurred in 184 patients (attack rate=19.0%) who had received IM injections with various drugs that had been mixed with normal saline (NS); risk ratio=infinity; p<0.0001. No cases occurred in the absence of NS exposure. We identified Mycobacterium abscessus from eight abscesses and from the clinic water supply, and observed the inappropriate reuse of a 16-gauge needle left in the rubber septum of 100 ml multiple-dose bottles of NS in the clinic. Fourteen percent (n=527) of the 3887 registered residents of this village had been treated with IM drugs over a three-month period, often for minor illnesses. This outbreak of M. abscessus occurred from exposure to extrinsically contaminated NS through improper injection practices. Frequent treatment of minor illnesses with IM injections of antibiotics was likely an important contributing factor to the size of this outbreak.

Dynamic enhancement of drug product labels to support drug safety, efficacy, and effectiveness.

PubMed

Boyce, Richard D; Horn, John R; Hassanzadeh, Oktie; Waard, Anita de; Schneider, Jodi; Luciano, Joanne S; Rastegar-Mojarad, Majid; Liakata, Maria

2013-01-26

Out-of-date or incomplete drug product labeling information may increase the risk of otherwise preventable adverse drug events. In recognition of these concerns, the United States Federal Drug Administration (FDA) requires drug product labels to include specific information. Unfortunately, several studies have found that drug product labeling fails to keep current with the scientific literature. We present a novel approach to addressing this issue. The primary goal of this novel approach is to better meet the information needs of persons who consult the drug product label for information on a drug's efficacy, effectiveness, and safety. Using FDA product label regulations as a guide, the approach links drug claims present in drug information sources available on the Semantic Web with specific product label sections. Here we report on pilot work that establishes the baseline performance characteristics of a proof-of-concept system implementing the novel approach. Claims from three drug information sources were linked to the Clinical Studies, Drug Interactions, and Clinical Pharmacology sections of the labels for drug products that contain one of 29 psychotropic drugs. The resulting Linked Data set maps 409 efficacy/effectiveness study results, 784 drug-drug interactions, and 112 metabolic pathway assertions derived from three clinically-oriented drug information sources (ClinicalTrials.gov, the National Drug File - Reference Terminology, and the Drug Interaction Knowledge Base) to the sections of 1,102 product labels. Proof-of-concept web pages were created for all 1,102 drug product labels that demonstrate one possible approach to presenting information that dynamically enhances drug product labeling. We found that approximately one in five efficacy/effectiveness claims were relevant to the Clinical Studies section of a psychotropic drug product, with most relevant claims providing new information. We also identified several cases where all of the drug-drug interaction claims linked to the Drug Interactions section for a drug were potentially novel. The baseline performance characteristics of the proof-of-concept will enable further technical and user-centered research on robust methods for scaling the approach to the many thousands of product labels currently on the market.

An integrative system biology approach to unravel potential drug candidates for multiple age related disorders.

PubMed

Srivastava, Isha; Khurana, Pooja; Yadav, Mohini; Hasija, Yasha

2017-12-01

Aging, though an inevitable part of life, is becoming a worldwide social and economic problem. Healthy aging is usually marked by low probability of age related disorders. Good therapeutic approaches are still in need to cure age related disorders. Occurrence of more than one ARD in an individual, expresses the need of discovery of such target proteins, which can affect multiple ARDs. Advanced scientific and medical research technologies throughout last three decades have arrived to the point where lots of key molecular determinants affect human disorders can be examined thoroughly. In this study, we designed and executed an approach to prioritize drugs that may target multiple age related disorders. Our methodology, focused on the analysis of biological pathways and protein protein interaction networks that may contribute to the pharmacology of age related disorders, included various steps such as retrieval and analysis of data, protein-protein interaction network analysis, and statistical and comparative analysis of topological coefficients, pathway, and functional enrichment analysis, and identification of drug-target proteins. We assume that the identified molecular determinants may be prioritized for further screening as novel drug targets to cure multiple ARDs. Based on the analysis, an online tool named as 'ARDnet' has been developed to construct and demonstrate ARD interactions at the level of PPI, ARDs and ARDs protein interaction, ARDs pathway interaction and drug-target interaction. The tool is freely made available at http://genomeinformatics.dtu.ac.in/ARDNet/Index.html. Copyright © 2017 Elsevier B.V. All rights reserved.

Patient and Physician Perceptions of Drug Safety Information for Sleep Aids: A Qualitative Study.

PubMed

Kesselheim, Aaron S; McGraw, Sarah A; Dejene, Sara Z; Rausch, Paula; Dal Pan, Gerald J; Lappin, Brian M; Zhou, Esther H; Avorn, Jerry; Campbell, Eric G

2017-06-01

The US Food and Drug Administration uses drug safety communications (DSCs) to release emerging information regarding post-market safety issues, but it is unclear the extent of awareness by patients and providers of these communications and their specific recommendations. We conducted semi-structured interviews with patients and physicians to evaluate their awareness and understanding of emerging drug safety information related to two sleep aids: zolpidem or eszopiclone. We conducted interviews with 40 patients and ten physicians recruited from a combination of insurer claims databases and online sources. We evaluated (1) sources of drug safety information; (2) discussions between patients and physicians about the two medications; (3) their knowledge of the DSC; and (4) preferences for learning about future drug safety information. Interviews were transcribed and analyzed thematically. Patients cited their physicians, pharmacy inserts, and the Internet as sources of drug safety information. Physicians often referred to medical journals and online medical sources. Most patients reported being aware of information contained in the DSC summaries they were read. Almost all patients and physicians reported discussing side effects during patient-provider conversations, but almost no patients mentioned that physicians had communicated with them key messaging from the DSCs at issue: the risk of next-morning impairment with zolpidem and the lower recommended initial dose for women. Some risks of medications are effectively communicated to patients and physicians; however, there is still a noticeable gap between information issued by the Food and Drug Administration and patient and physician awareness of this knowledge, as well as patients' decisions to act on this information. Disseminators of emerging drug safety information should explore ways of providing user-friendly resources to patients and healthcare professionals that can update them on new risks in a timely manner.

Risk perception by healthcare professionals related to drug use during pregnancy: a Swiss survey.

PubMed

Csajka, Chantal; Jaquet, Aurélie; Winterfeld, Ursula; Meyer, Yvonne; Einarson, Adrienne; Panchaud, Alice

2014-03-07

Healthcare professionals' (HCPs') perception of risk associated with drug use in pregnancy may have an impact on the pharmacological treatment of some women. The aim of this study was to examine this risk perception in a sample of Swiss HCPs with a special focus on their knowledge and use of available specialised information sources. An online, French and German, questionnaire was e-mailed to 7,136 members of four Swiss professional societies (gynaecologists, paediatricians, midwives and pharmacists). The questionnaire was designed (a) to collect demographic characteristics, (b) to evaluate the frequency of use of several specialised sources of information on drugs in pregnancy in their daily practice, and (c) to examine the perception of risk associated with drug use during pregnancy. A total of 1,310 questionnaires were collected (response rate of 18.4%). More than 80% of the respondent HCPs use the Swiss Drug Reference Book (Compendium) to assess the risk associated with drugs during pregnancy and are not aware of available specialised information sources (books, websites or information centres). Despite some disparities between HPCs, the risk related to drug intake was overall highly misperceived. Blinded reading of three product monographs in the Compendium was associated with an overestimated perception of risk (e.g., after reading the "paracetamol" monograph, 38% of the participants stated they would probably not advise the use of this drug to a pregnant patient). Overall, an overestimation of the risk associated with drug use during pregnancy has been observed in our sample of HCPs, which might be related to the underuse of specialised information source among other factors. These findings evidenced the need for increased training for HCPs in order to optimise medication use during pregnancy. Further studies are needed to confirm these results and identify causes.

The development of multiple drug use among anabolic-androgenic steroid users: six subjective case reports

PubMed Central

Skårberg, Kurt; Nyberg, Fred; Engström, Ingemar

2008-01-01

Background The inappropriate use of anabolic androgenic steroids (AAS) was originally a problem among athletes but AAS are now often used in nonsport situations and by patients attending regular addiction clinics. The aim of this study was to improve understanding of the development of multiple drug use in patients seeking treatment at an addiction clinic for AAS-related problems. Methods We interviewed six patients (four men and two women) with experience of AAS use who were attending an addiction clinic for what they believed were AAS-related problems. The patients were interviewed in-depth about their life stories, with special emphasis on social background, substance use, the development of total drug use and subjective experienced psychological and physical side effects. Results There was significant variation in the development of drug use in relation to social background, onset of drug use, relationship to AAS use and experience of AAS effects. All patients had initially experienced positive effects from AAS but, over time, the negative experiences had outweighed the positive effects. All patients were dedicated to excess training and took AAS in combination with gym training, indicating that the use of these drugs is closely related to this form of training. Use of multiple drugs was common either in parallel with AAS use or serially. Conclusion The study shows the importance of understanding how AAS use can develop either with or without the concomitant use of other drugs of abuse. The use of AAS can, however, progress to the use of other drugs. The study also indicates the importance of obtaining accurate, comprehensive information about the development of AAS use in designing treatment programmes and prevention strategies in this area. PMID:19040748

The development of multiple drug use among anabolic-androgenic steroid users: six subjective case reports.

PubMed

Skårberg, Kurt; Nyberg, Fred; Engström, Ingemar

2008-11-28

The inappropriate use of anabolic androgenic steroids (AAS) was originally a problem among athletes but AAS are now often used in nonsport situations and by patients attending regular addiction clinics. The aim of this study was to improve understanding of the development of multiple drug use in patients seeking treatment at an addiction clinic for AAS-related problems. We interviewed six patients (four men and two women) with experience of AAS use who were attending an addiction clinic for what they believed were AAS-related problems. The patients were interviewed in-depth about their life stories, with special emphasis on social background, substance use, the development of total drug use and subjective experienced psychological and physical side effects. There was significant variation in the development of drug use in relation to social background, onset of drug use, relationship to AAS use and experience of AAS effects. All patients had initially experienced positive effects from AAS but, over time, the negative experiences had outweighed the positive effects. All patients were dedicated to excess training and took AAS in combination with gym training, indicating that the use of these drugs is closely related to this form of training. Use of multiple drugs was common either in parallel with AAS use or serially. The study shows the importance of understanding how AAS use can develop either with or without the concomitant use of other drugs of abuse. The use of AAS can, however, progress to the use of other drugs. The study also indicates the importance of obtaining accurate, comprehensive information about the development of AAS use in designing treatment programmes and prevention strategies in this area.

Precursor medications as a source of methamphetamine and/or amphetamine positive drug testing results.

PubMed

Cody, John T

2002-05-01

Medical Review Officer interpretation of laboratory results is an important component of drug testing programs. The clinical evaluation of laboratory results to assess the possibility of appropriate medical use of a drug is a task with many different facets, depending on the drug class considered. This intercession prevents the reporting of positive results unless it is apparent that drugs were used illicitly. In addition to the commonly encountered prescribed drugs that yield positive drug testing results, other sources of positive results must be considered. This review describes a series of compounds referred to as "precursor" drugs that are metabolized by the body to amphetamine and/or methamphetamine. These compounds lead to positive results for amphetamines even though neither amphetamine nor methamphetamine were used, a possibility that must be considered in the review of laboratory results. Description of the drugs, their clinical indications, and results seen following administration are provided. This information allows for the informed evaluation of results with regard to the potential involvement of these drugs.

ADVANCED TOOLS FOR ASSESSING SELECTED PRESCRIPTION AND ILLICIT DRUGS IN TREATED SEWAGE EFFLUENTS AND SOURCE WATERS

EPA Science Inventory

The purpose of this poster is to present the application and assessment of advanced technologies in a real-world environment - wastewater effluent and source waters - for detecting six drugs (azithromycin, fluoxetine, omeprazole, levothyroxine, methamphetamine, and methylenedioxy...

Modification of c and n sources for enhanced production of cyclosporin ‘a’ by Aspergillus Terreus

PubMed Central

Tanseer, Sundas; Anjum, Tehmina

2011-01-01

Most of the studies regarding cyclosporin ‘A’ production through fungi concentrate around Tolypocladium inflatum. This is mainly due to lower reported production of this drug in other fungi. The present study was therefore conducted to explore indigenous isolates of Aspergillus terreus for synthesis of this drug and defining a production medium for obtaining high yield of cyclosporin ‘A’. For this purpose carbon and nitrogen sources were optimized for the selected best strain of A. terreus. Overall results depicted that the best cyclosporin ‘A’ yield from selected Aspergillus terreus (FCBP58) could be obtained by using production medium containing glucose 10% as carbon source and peptone 0.5% as nitrogen source. This modification in production medium enhanced drug synthesis by selected fungi significantly. The production capabilities when compared with biomass of fungi there was found no relationship between the two confirming that the medium modification increased overall drug synthesis powers of the fungi. PMID:24031766

Multilevel analysis of the influence of patients' and general practitioners' characteristics on patented versus multiple-sourced statin prescribing in France.

PubMed

Pichetti, Sylvain; Sermet, Catherine; Godman, Brian; Campbell, Stephen M; Gustafsson, Lars L

2013-06-01

The French National Health Insurance and the Ministry of Health have introduced multiple reforms in recent years to increase prescribing efficiency. These include guidelines, academic detailing, financial incentives for the prescribing and dispensing of generics drugs as well as a voluntary pay-for-performance programme. However, the quality and efficiency of prescribing could be enhanced potentially if there was better understanding of the dynamics of prescribing behaviour in France. To analyse the patient and general practitioner characteristics that influence patented versus multiple-sourced statin prescribing in France. Statistical analysis was performed on the statin prescribing habits from 341 general practitioners (GPs) that were included in the IMS-Health Permanent Survey on Medical Prescription in France, which was conducted between 2009 and 2010 and involved 14,360 patients. Patient characteristics included their age and gender as well as five medical profiles that were constructed from the diagnoses obtained during consultations. These were (1) disorders of lipoprotein metabolism, (2) heart disease, (3) diabetes, (4) complex profiles and (5) profiles based on other diagnoses. Physician characteristics included their age, gender, solo or group practice, weekly workload and payment scheme. Patient age had a statistically significant impact on statin prescribing for patients in profile 1 (disorders of lipoprotein metabolism) and profile 3 (complex profiles) with a greater number of patented statins being prescribed for the youngest patients. For instance, patients older than 76 years with a complex profile were prescribed fewer patented statins than patients aged 68-76 years old with the same medical profile (coefficient: -0.225; p = 0.0008). By contrast, regardless of the patient's age, the medical profile did not affect the probability of prescribing a patented statin except in young patients with heart diseases who were prescribed a greater number of patented statins (coefficient: 0.3992; p = 0.0007). Prescribing was also statistically influenced by physician features, e.g., older male physicians were more likely to prescribe patented statins (coefficient: 0.245; p = 0.0417) and GPs practicing in groups were more likely to prescribe multiple sourced statins (coefficient: -0.178; p = 0.0338), which is an important finding of the study. GPs with a lower workload prescribed a greater number of patented statins. There is significant variability in the prescribing of different statins among patient and physician profiles as well as between solo and group practices. Consequently, there are opportunities to target demand-side measures to enhance the prescribing of multiple-sourced statins. Further studies are warranted, in particular in other therapeutic classes, to provide a counter-balance to the considerable marketing activities of pharmaceutical companies.

A hyaluronic acid nanogel for photo-chemo theranostics of lung cancer with simultaneous light-responsive controlled release of doxorubicin

NASA Astrophysics Data System (ADS)

Khatun, Zehedina; Nurunnabi, Md; Nafiujjaman, Md; Reeck, Gerald R.; Khan, Haseeb A.; Cho, Kwang Jae; Lee, Yong-Kyu

2015-06-01

The combined delivery of photo- and chemo-therapeutic agents is an emerging strategy to overcome drug resistance in treating cancer, and controlled light-responsive drug release is a proven tactic to produce a continuous therapeutic effect for a prolonged duration. Here, a combination of light-responsive graphene, chemo-agent doxorubicin and pH-sensitive disulfide-bond linked hyaluronic acid form a nanogel (called a graphene-doxorubicin conjugate in a hyaluronic acid nanogel) that exerts an activity with multiple effects: thermo and chemotherapeutic, real-time noninvasive imaging, and light-glutathione-responsive controlled drug release. The nanogel is mono-dispersed with an average diameter of 120 nm as observed by using TEM and a hydrodynamic size analyzer. It has excellent photo-luminescence properties and good stability in buffer and serum solutions. Graphene itself, being photoluminescent, can be considered an optical imaging contrast agent as well as a heat source when excited by laser irradiation. Thus the nanogel shows simultaneous thermo-chemotherapeutic effects on noninvasive optical imaging. We have also found that irradiation enhances the release of doxorubicin in a controlled manner. This release synergizes therapeutic activity of the nanogel in killing tumor cells. Our findings demonstrate that the graphene-doxorubicin conjugate in the hyaluronic acid nanogel is very effective in killing the human lung cancer cell line (A549) with limited toxicity in the non-cancerous cell line (MDCK).The combined delivery of photo- and chemo-therapeutic agents is an emerging strategy to overcome drug resistance in treating cancer, and controlled light-responsive drug release is a proven tactic to produce a continuous therapeutic effect for a prolonged duration. Here, a combination of light-responsive graphene, chemo-agent doxorubicin and pH-sensitive disulfide-bond linked hyaluronic acid form a nanogel (called a graphene-doxorubicin conjugate in a hyaluronic acid nanogel) that exerts an activity with multiple effects: thermo and chemotherapeutic, real-time noninvasive imaging, and light-glutathione-responsive controlled drug release. The nanogel is mono-dispersed with an average diameter of 120 nm as observed by using TEM and a hydrodynamic size analyzer. It has excellent photo-luminescence properties and good stability in buffer and serum solutions. Graphene itself, being photoluminescent, can be considered an optical imaging contrast agent as well as a heat source when excited by laser irradiation. Thus the nanogel shows simultaneous thermo-chemotherapeutic effects on noninvasive optical imaging. We have also found that irradiation enhances the release of doxorubicin in a controlled manner. This release synergizes therapeutic activity of the nanogel in killing tumor cells. Our findings demonstrate that the graphene-doxorubicin conjugate in the hyaluronic acid nanogel is very effective in killing the human lung cancer cell line (A549) with limited toxicity in the non-cancerous cell line (MDCK). Electronic supplementary information (ESI) available: In vitro stability study method and results, FT-IR data, optical properties and thermal stability (TGA and DTA), cell image and in vivo optical image and histological images. See DOI: 10.1039/c5nr01075f

Traditional Medicine Collection Tracking System (TM-CTS): a database for ethnobotanically driven drug-discovery programs.

PubMed

Harris, Eric S J; Erickson, Sean D; Tolopko, Andrew N; Cao, Shugeng; Craycroft, Jane A; Scholten, Robert; Fu, Yanling; Wang, Wenquan; Liu, Yong; Zhao, Zhongzhen; Clardy, Jon; Shamu, Caroline E; Eisenberg, David M

2011-05-17

Ethnobotanically driven drug-discovery programs include data related to many aspects of the preparation of botanical medicines, from initial plant collection to chemical extraction and fractionation. The Traditional Medicine Collection Tracking System (TM-CTS) was created to organize and store data of this type for an international collaborative project involving the systematic evaluation of commonly used Traditional Chinese Medicinal plants. The system was developed using domain-driven design techniques, and is implemented using Java, Hibernate, PostgreSQL, Business Intelligence and Reporting Tools (BIRT), and Apache Tomcat. The TM-CTS relational database schema contains over 70 data types, comprising over 500 data fields. The system incorporates a number of unique features that are useful in the context of ethnobotanical projects such as support for information about botanical collection, method of processing, quality tests for plants with existing pharmacopoeia standards, chemical extraction and fractionation, and historical uses of the plants. The database also accommodates data provided in multiple languages and integration with a database system built to support high throughput screening based drug discovery efforts. It is accessed via a web-based application that provides extensive, multi-format reporting capabilities. This new database system was designed to support a project evaluating the bioactivity of Chinese medicinal plants. The software used to create the database is open source, freely available, and could potentially be applied to other ethnobotanically driven natural product collection and drug-discovery programs. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

Traditional Medicine Collection Tracking System (TM-CTS): A Database for Ethnobotanically-Driven Drug-Discovery Programs

PubMed Central

Harris, Eric S. J.; Erickson, Sean D.; Tolopko, Andrew N.; Cao, Shugeng; Craycroft, Jane A.; Scholten, Robert; Fu, Yanling; Wang, Wenquan; Liu, Yong; Zhao, Zhongzhen; Clardy, Jon; Shamu, Caroline E.; Eisenberg, David M.

2011-01-01

Aim of the study. Ethnobotanically-driven drug-discovery programs include data related to many aspects of the preparation of botanical medicines, from initial plant collection to chemical extraction and fractionation. The Traditional Medicine-Collection Tracking System (TM-CTS) was created to organize and store data of this type for an international collaborative project involving the systematic evaluation of commonly used Traditional Chinese Medicinal plants. Materials and Methods. The system was developed using domain-driven design techniques, and is implemented using Java, Hibernate, PostgreSQL, Business Intelligence and Reporting Tools (BIRT), and Apache Tomcat. Results. The TM-CTS relational database schema contains over 70 data types, comprising over 500 data fields. The system incorporates a number of unique features that are useful in the context of ethnobotanical projects such as support for information about botanical collection, method of processing, quality tests for plants with existing pharmacopoeia standards, chemical extraction and fractionation, and historical uses of the plants. The database also accommodates data provided in multiple languages and integration with a database system built to support high throughput screening based drug discovery efforts. It is accessed via a web-based application that provides extensive, multi-format reporting capabilities. Conclusions. This new database system was designed to support a project evaluating the bioactivity of Chinese medicinal plants. The software used to create the database is open source, freely available, and could potentially be applied to other ethnobotanically-driven natural product collection and drug-discovery programs. PMID:21420479

Pharmacokinetic–pharmacodynamic modelling in anaesthesia

PubMed Central

Gambús, Pedro L; Trocóniz, Iñaki F

2015-01-01

Anaesthesiologists adjust drug dosing, administration system and kind of drug to the characteristics of the patient. They then observe the expected response and adjust dosing to the specific requirements according to the difference between observed response, expected response and the context of the surgery and the patient. The approach above can be achieved because on one hand quantification technology has made significant advances allowing the anaesthesiologist to measure almost any effect by using noninvasive, continuous measuring systems. On the other the knowledge on the relations between dosing, concentration, biophase dynamics and effect as well as detection of variability sources has been achieved as being the benchmark specialty for pharmacokinetic–pharmacodynamic (PKPD) modelling. The aim of the review is to revisit the most common PKPD models applied in the field of anaesthesia (i.e. effect compartmental, turnover, drug–receptor binding and drug interaction models) through representative examples. The effect compartmental model has been widely used in this field and there are multiple applications and examples. The use of turnover models has been limited mainly to describe respiratory effects. Similarly, cases in which the dissociation process of the drug–receptor complex is slow compared with other processes relevant to the time course of the anaesthetic effect are not frequent in anaesthesia, where in addition to a rapid onset, a fast offset of the response is required. With respect to the characterization of PD drug interactions different response surface models are discussed. Relevant applications that have changed the way modern anaesthesia is practiced are also provided. PMID:24251846

Integration of phytochemicals and phytotherapy into cancer precision medicine.

PubMed

Efferth, Thomas; Saeed, Mohamed E M; Mirghani, Elhaj; Alim, Awadh; Yassin, Zahir; Saeed, Elfatih; Khalid, Hassan E; Daak, Salah

2017-07-25

Concepts of individualized therapy in the 1970s and 1980s attempted to develop predictive in vitro tests for individual drug responsiveness without reaching clinical routine. Precision medicine attempts to device novel individual cancer therapy strategies. Using bioinformatics, relevant knowledge is extracted from huge data amounts. However, tumor heterogeneity challenges chemotherapy due to genetically and phenotypically different cell subpopulations, which may lead to refractory tumors. Natural products always served as vital resources for cancer therapy (e.g., Vinca alkaloids, camptothecin, paclitaxel, etc.) and are also sources for novel drugs. Targeted drugs developed to specifically address tumor-related proteins represent the basis of precision medicine. Natural products from plants represent excellent resource for targeted therapies. Phytochemicals and herbal mixtures act multi-specifically, i.e. they attack multiple targets at the same time. Network pharmacology facilitates the identification of the complexity of pharmacogenomic networks and new signaling networks that are distorted in tumors. In the present review, we give a conceptual overview, how the problem of drug resistance may be approached by integrating phytochemicals and phytotherapy into academic western medicine. Modern technology platforms (e.g. "-omics" technologies, DNA/RNA sequencing, and network pharmacology) can be applied for diverse treatment modalities such as cytotoxic and targeted chemotherapy as well as phytochemicals and phytotherapy. Thereby, these technologies represent an integrative momentum to merge the best of two worlds: clinical oncology and traditional medicine. In conclusion, the integration of phytochemicals and phytotherapy into cancer precision medicine represents a valuable asset to chemically synthesized chemicals and therapeutic antibodies.

The “Black Box” of Prescription Drug Diversion

PubMed Central

Inciardi, James A.; Surratt, Hilary L.; Cicero, Theodore J.; Kurtz, Steven P.; Martin, Steven S.; Parrino, Mark W.

2009-01-01

A variety of surveys and studies are examined in an effort to better understand the scope of prescription drug diversion and to determine if there are consistent patterns of diversion among various populations of prescription drug abusers. Data are drawn from the RADARS® System, the National Survey of Drug Use and Health (NSDUH), the Delaware School Survey, and a series of quantitative and qualitative studies conducted in Miami, Florida. The data suggest that the major sources of diversion include drug dealers, friends and relatives, smugglers, pain patients, and the elderly, but these vary by the population being targeted. In all of the studies examined, the use of the Internet as a source for prescription drugs is insignificant. Little is known about where drug dealers are obtaining their supplies, and as such, prescription drug diversion is a “black box” requiring concentrated systematic study. PMID:20155603

Does mechanism of drug action matter to inform rational polytherapy in epilepsy?

PubMed

Giussani, Giorgia; Beghi, Ettore

2013-05-01

When monotherapy for epilepsy fails, add-on therapy is an alternative option. There are several possible antiepileptic drug combinations based on their different and multiple mechanisms of action and pharmacokinetic interactions. However, only when benefits of drug combinations outweigh the harms, polytherapy can be defined as "rational". In the past 20 years, second generation AEDs have been marketed, some of which have better defined mechanisms of action and better pharmacokinetic profile. The mechanisms of action of AEDs involve, among others, blockade of voltage-gated sodium channels, blockade of voltage-gated calcium channel, activation of the ionotropic GABAA receptor and increase of GABA levels at the synaptic cleft, blockade of glutamate receptors, binding to synaptic vesicle protein 2A, and opening of KCNQ (Kv7) potassium channels. Aim of this review was to examine published reports on AEDs combinations in animal models and humans focusing on mechanisms of action and pharmacokinetic interactions. Studies in animals have shown that AED combinations are more effective when using drugs with different mechanisms of action. The most effective combination was found using a drug with a single mechanism of action and another with multiple mechanisms of action. In humans some combinations between a blocker of voltage-gated sodium channels and a drug with multiple mechanisms of action may be synergistic. Future studies are necessary to better define rational combinations and complementary mechanisms of action, considering also pharmacokinetic interactions and measures of toxicity and not only drug efficacy.

A New Era for Cancer Target Therapies: Applying Systems Biology and Computer-Aided Drug Design to Cancer Therapies.

PubMed

Wong, Yung-Hao; Chiu, Chia-Chiun; Lin, Chih-Lung; Chen, Ting-Shou; Jheng, Bo-Ren; Lee, Yu-Ching; Chen, Jeremy; Chen, Bor-Sen

In recent years, many systems biology approaches have been used with various cancers. The materials described here can be used to build bases to discover novel cancer therapy targets in connection with computer-aided drug design (CADD). A deeper understanding of the mechanisms of cancer will provide more choices and correct strategies in the development of multiple target drug therapies, which is quite different from the traditional cancer single target therapy. Targeted therapy is one of the most powerful strategies against cancer and can also be applied to other diseases. Due to the large amount of progress in computer hardware and the theories of computational chemistry and physics, CADD has been the main strategy for developing novel drugs for cancer therapy. In contrast to traditional single target therapies, in this review we will emphasize the future direction of the field, i.e., multiple target therapies. Structure-based and ligand-based drug designs are the two main topics of CADD. The former needs both 3D protein structures and ligand structures, while the latter only needs ligand structures. Ordinarily it is estimated to take more than 14 years and 800 million dollars to develop a new drug. Many new CADD software programs and techniques have been developed in recent decades. We conclude with an example where we combined and applied systems biology and CADD to the core networks of four cancers and successfully developed a novel cocktail for drug therapy that treats multiple targets.

21 CFR 888.3030 - Single/multiple component metallic bone fixation appliances and accessories.

Code of Federal Regulations, 2014 CFR

2014-04-01

... 21 Food and Drugs 8 2014-04-01 2014-04-01 false Single/multiple component metallic bone fixation....3030 Single/multiple component metallic bone fixation appliances and accessories. (a) Identification. Single/multiple component metallic bone fixation appliances and accessories are devices intended to be...

21 CFR 888.3030 - Single/multiple component metallic bone fixation appliances and accessories.

Code of Federal Regulations, 2012 CFR

2012-04-01

... 21 Food and Drugs 8 2012-04-01 2012-04-01 false Single/multiple component metallic bone fixation....3030 Single/multiple component metallic bone fixation appliances and accessories. (a) Identification. Single/multiple component metallic bone fixation appliances and accessories are devices intended to be...

21 CFR 888.3030 - Single/multiple component metallic bone fixation appliances and accessories.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 21 Food and Drugs 8 2011-04-01 2011-04-01 false Single/multiple component metallic bone fixation....3030 Single/multiple component metallic bone fixation appliances and accessories. (a) Identification. Single/multiple component metallic bone fixation appliances and accessories are devices intended to be...

21 CFR 888.3030 - Single/multiple component metallic bone fixation appliances and accessories.

Code of Federal Regulations, 2013 CFR

2013-04-01

... 21 Food and Drugs 8 2013-04-01 2013-04-01 false Single/multiple component metallic bone fixation....3030 Single/multiple component metallic bone fixation appliances and accessories. (a) Identification. Single/multiple component metallic bone fixation appliances and accessories are devices intended to be...

21 CFR 888.3030 - Single/multiple component metallic bone fixation appliances and accessories.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Single/multiple component metallic bone fixation....3030 Single/multiple component metallic bone fixation appliances and accessories. (a) Identification. Single/multiple component metallic bone fixation appliances and accessories are devices intended to be...

Differences among practitioners in patterns of preference for information sources in the adoption of new drugs.

PubMed

Peay, M Y; Peay, E R

1984-01-01

The major aim of this study was to identify coherent patterns in doctors' preferences for potential sources of information about new drugs and the characteristics of the doctors who display them. One hundred twenty-four general practitioners and specialists evaluated and reported their use of a number of potential sources. Overall, commercial sources were cited more often than professional ones for providing first information about a new drug, but the reverse was the case when the doctor was actively considering prescribing it. The primary professional sources received more favourable evaluation than any of the commercial sources, but results suggest that usage does not necessarily follow the doctor's opinion of a source. Relationships between reported use and evaluation reveal two coherent patterns of source preference: 'journal' and 'commercial'. The commercial pattern is particularly sharply defined, identifying a subset of doctors who can be designated justifiably as 'commercially-oriented'. Evaluation and use of particular sources varied with age and differed between specialists and general practitioners. Results indicate that differences in patterns of preference are systematically related to characteristics of the doctor in combination with the stage of the adoption process.

A decline in the prevalence of injecting drug users in Estonia, 2005–2009

PubMed Central

Uusküla, A; Rajaleid, K; Talu, A; Abel-Ollo, K; Des Jarlais, DC

2013-01-01

Aims and setting Descriptions of behavioural epidemics have received little attention compared with infectious disease epidemics in Eastern Europe. Here we report a study aimed at estimating trends in the prevalence of injection drug use between 2005 and 2009 in Estonia. Design and methods The number of injection drug users (IDUs) aged 15–44 each year between 2005 and 2009 was estimated using capture-recapture methodology based on 4 data sources (2 treatment data bases: drug abuse and non-fatal overdose treatment; criminal justice (drug related offences) and mortality (injection drug use related deaths) data). Poisson log-linear regression models were applied to the matched data, with interactions between data sources fitted to replicate the dependencies between the data sources. Linear regression was used to estimate average change over time. Findings there were 24305, 12292, 238, 545 records and 8100, 1655, 155, 545 individual IDUs identified in the four capture sources (Police, drug treatment, overdose, and death registry, accordingly) over the period 2005 – 2009. The estimated prevalence of IDUs among the population aged 15–44 declined from 2.7% (1.8–7.9%) in 2005 to 2.0% (1.4–5.0%) in 2008, and 0.9% (0.7–1.7%) in 2009. Regression analysis indicated an average reduction of over 1700 injectors per year. Conclusion While the capture-recapture method has known limitations, the results are consistent with other data from Estonia. Identifying the drivers of change in the prevalence of injection drug use warrants further research. PMID:23290632

A Simple Assay to Screen Antimicrobial Compounds Potentiating the Activity of Current Antibiotics

PubMed Central

Iqbal, Junaid; Kazmi, Shahana Urooj; Khan, Naveed Ahmed

2013-01-01

Antibiotic resistance continues to pose a significant problem in the management of bacterial infections, despite advances in antimicrobial chemotherapy and supportive care. Here, we suggest a simple, inexpensive, and easy-to-perform assay to screen antimicrobial compounds from natural products or synthetic chemical libraries for their potential to work in tandem with the available antibiotics against multiple drug-resistant bacteria. The aqueous extract of Juglans regia tree bark was tested against representative multiple drug-resistant bacteria in the aforementioned assay to determine whether it potentiates the activity of selected antibiotics. The aqueous extract of J. regia bark was added to Mueller-Hinton agar, followed by a lawn of multiple drug-resistant bacteria, Salmonella typhi or enteropathogenic E. coli. Next, filter paper discs impregnated with different classes of antibiotics were placed on the agar surface. Bacteria incubated with extract or antibiotics alone were used as controls. The results showed a significant increase (>30%) in the zone of inhibition around the aztreonam, cefuroxime, and ampicillin discs compared with bacteria incubated with the antibiotics/extract alone. In conclusion, our assay is able to detect either synergistic or additive action of J. regia extract against multiple drug-resistant bacteria when tested with a range of antibiotics. PMID:23865073

Safer scoring? Cryptomarkets, social supply and drug market violence.

PubMed

Barratt, Monica J; Ferris, Jason A; Winstock, Adam R

2016-09-01

Cryptomarkets are digital platforms that use anonymising software (e.g. Tor) and cryptocurrencies (e.g. Bitcoin) to facilitate trade of goods and services, most notably illicit drugs. Cryptomarkets may reduce systemic violence compared with in-person drug trading because no face-to-face contact is required and disputes can be resolved through a neutral third party. In this paper, we describe the purchasing behaviour of cryptomarket users and then compare the self-reported experiences of threats, violence and other drug-market concerns when obtaining drugs from cryptomarkets with obtaining drugs through friends, known dealers and strangers. The Global Drug Survey was completed in late 2014 by a self-selected sample who reported accessing drugs through cryptomarkets in the last 12 months (N=3794). Their median age was 22 years and 82% were male. The drug types most commonly obtained through cryptomarkets were MDMA/Ecstasy (55%), cannabis (43%) and LSD (35%). Cryptomarket users reported using a median of 2 sources in addition to cryptomarkets to access drugs, the most common being in-person friendships (74%), in-person dealers (57%) and open markets/strangers (26%). When asked to nominate the main source they would use if cryptomarkets were unavailable, 49% nominated friends, 34% known dealers and 4% strangers. 'Threats to personal safety' (3%) and 'experiencing physical violence' (1%) were less often reported when using cryptomarkets compared with sourcing through friends (14%; 6%), known dealers (24%; 10%) or strangers (35%; 15%). Concerns about drug impurities and law enforcement were reported more often when using the alternative source, while loss of money, waiting too long and not receiving the product were more often reported when using cryptomarkets. Cryptomarkets are associated with substantially less threats and violence than alternative market types used by cryptomarket customers, even though a large majority of these alternatives were closed networks where violence should be relatively less common. Copyright © 2016 Elsevier B.V. All rights reserved.

Dynamic enhancement of drug product labels to support drug safety, efficacy, and effectiveness

PubMed Central

2013-01-01

Out-of-date or incomplete drug product labeling information may increase the risk of otherwise preventable adverse drug events. In recognition of these concerns, the United States Federal Drug Administration (FDA) requires drug product labels to include specific information. Unfortunately, several studies have found that drug product labeling fails to keep current with the scientific literature. We present a novel approach to addressing this issue. The primary goal of this novel approach is to better meet the information needs of persons who consult the drug product label for information on a drug’s efficacy, effectiveness, and safety. Using FDA product label regulations as a guide, the approach links drug claims present in drug information sources available on the Semantic Web with specific product label sections. Here we report on pilot work that establishes the baseline performance characteristics of a proof-of-concept system implementing the novel approach. Claims from three drug information sources were linked to the Clinical Studies, Drug Interactions, and Clinical Pharmacology sections of the labels for drug products that contain one of 29 psychotropic drugs. The resulting Linked Data set maps 409 efficacy/effectiveness study results, 784 drug-drug interactions, and 112 metabolic pathway assertions derived from three clinically-oriented drug information sources (ClinicalTrials.gov, the National Drug File – Reference Terminology, and the Drug Interaction Knowledge Base) to the sections of 1,102 product labels. Proof-of-concept web pages were created for all 1,102 drug product labels that demonstrate one possible approach to presenting information that dynamically enhances drug product labeling. We found that approximately one in five efficacy/effectiveness claims were relevant to the Clinical Studies section of a psychotropic drug product, with most relevant claims providing new information. We also identified several cases where all of the drug-drug interaction claims linked to the Drug Interactions section for a drug were potentially novel. The baseline performance characteristics of the proof-of-concept will enable further technical and user-centered research on robust methods for scaling the approach to the many thousands of product labels currently on the market. PMID:23351881

Accidental Overdose Intoxication: A Hazard of Drug Smuggling

PubMed Central

Arora, Sudhir; Tafreshi, Michael; Sobo, Steven; Krochmal, Paul; Alexander, Leslie L.

1982-01-01

Three patients involved in illicit drug smuggling via the swallowing of high dose, high purity drugs packed in multiple condoms are reported. Two of these patients experienced drug overdose symptoms due to leakage or rupture of the condoms in the GI tract. They were treated successfully. ImagesFigure 1Figure 2Figure 3Figure 4 PMID:7120497

42 CFR 2.34 - Disclosures to prevent multiple enrollments in detoxification and maintenance treatment programs.

Code of Federal Regulations, 2013 CFR

2013-10-01

..., DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL PROVISIONS CONFIDENTIALITY OF ALCOHOL AND DRUG ABUSE PATIENT... means the dispensing of a narcotic drug in decreasing doses to an individual in order to reduce or... narcotic drug. Maintenance treatment means the dispensing of a narcotic drug in the treatment of an...

42 CFR 2.34 - Disclosures to prevent multiple enrollments in detoxification and maintenance treatment programs.

Code of Federal Regulations, 2011 CFR

2011-10-01

..., DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL PROVISIONS CONFIDENTIALITY OF ALCOHOL AND DRUG ABUSE PATIENT... means the dispensing of a narcotic drug in decreasing doses to an individual in order to reduce or... narcotic drug. Maintenance treatment means the dispensing of a narcotic drug in the treatment of an...

42 CFR 2.34 - Disclosures to prevent multiple enrollments in detoxification and maintenance treatment programs.

Code of Federal Regulations, 2012 CFR

2012-10-01

..., DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL PROVISIONS CONFIDENTIALITY OF ALCOHOL AND DRUG ABUSE PATIENT... means the dispensing of a narcotic drug in decreasing doses to an individual in order to reduce or... narcotic drug. Maintenance treatment means the dispensing of a narcotic drug in the treatment of an...

42 CFR 2.34 - Disclosures to prevent multiple enrollments in detoxification and maintenance treatment programs.

Code of Federal Regulations, 2014 CFR

2014-10-01

..., DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL PROVISIONS CONFIDENTIALITY OF ALCOHOL AND DRUG ABUSE PATIENT... means the dispensing of a narcotic drug in decreasing doses to an individual in order to reduce or... narcotic drug. Maintenance treatment means the dispensing of a narcotic drug in the treatment of an...

Use of ultrasonic array method for positioning multiple partial discharge sources in transformer oil.

PubMed

Xie, Qing; Tao, Junhan; Wang, Yongqiang; Geng, Jianghai; Cheng, Shuyi; Lü, Fangcheng

2014-08-01

Fast and accurate positioning of partial discharge (PD) sources in transformer oil is very important for the safe, stable operation of power systems because it allows timely elimination of insulation faults. There is usually more than one PD source once an insulation fault occurs in the transformer oil. This study, which has both theoretical and practical significance, proposes a method of identifying multiple PD sources in the transformer oil. The method combines the two-sided correlation transformation algorithm in the broadband signal focusing and the modified Gerschgorin disk estimator. The method of classification of multiple signals is used to determine the directions of arrival of signals from multiple PD sources. The ultrasonic array positioning method is based on the multi-platform direction finding and the global optimization searching. Both the 4 × 4 square planar ultrasonic sensor array and the ultrasonic array detection platform are built to test the method of identifying and positioning multiple PD sources. The obtained results verify the validity and the engineering practicability of this method.

Common source-multiple load vs. separate source-individual load photovoltaic system

NASA Technical Reports Server (NTRS)

Appelbaum, Joseph

1989-01-01

A comparison of system performance is made for two possible system setups: (1) individual loads powered by separate solar cell sources; and (2) multiple loads powered by a common solar cell source. A proof for resistive loads is given that shows the advantage of a common source over a separate source photovoltaic system for a large range of loads. For identical loads, both systems perform the same.

Vigi4Med Scraper: A Framework for Web Forum Structured Data Extraction and Semantic Representation

PubMed Central

Audeh, Bissan; Beigbeder, Michel; Zimmermann, Antoine; Jaillon, Philippe; Bousquet, Cédric

2017-01-01

The extraction of information from social media is an essential yet complicated step for data analysis in multiple domains. In this paper, we present Vigi4Med Scraper, a generic open source framework for extracting structured data from web forums. Our framework is highly configurable; using a configuration file, the user can freely choose the data to extract from any web forum. The extracted data are anonymized and represented in a semantic structure using Resource Description Framework (RDF) graphs. This representation enables efficient manipulation by data analysis algorithms and allows the collected data to be directly linked to any existing semantic resource. To avoid server overload, an integrated proxy with caching functionality imposes a minimal delay between sequential requests. Vigi4Med Scraper represents the first step of Vigi4Med, a project to detect adverse drug reactions (ADRs) from social networks founded by the French drug safety agency Agence Nationale de Sécurité du Médicament (ANSM). Vigi4Med Scraper has successfully extracted greater than 200 gigabytes of data from the web forums of over 20 different websites. PMID:28122056

Effect of sertraline on proliferation and neurogenic differentiation of human adipose-derived stem cells

PubMed Central

Razavi, Shahnaz; Jahromi, Maliheh; Amirpour, Nushin; Khosravizadeh, Zahra

2014-01-01

Background: Antidepressant drugs are commonly employed for anxiety and mood disorders. Sertraline is extensively used as antidepressant in clinic. In addition, adipose tissue represents an abundant and accessible source of adult stem cells with the ability to differentiate in to multiple lineages. Therefore, human adipose-derived stem cells (hADSCs) may be useful for autologous transplantation. Materials and Methods: In the present study, we assessed the effect of antidepressant drug Sertraline on the proliferation and neurogenic differentiation of hADSCs using MTT assay and immunofluorescence technique respectively. Results: MTT assay analysis showed that 0.5 μM Sertraline significantly increased the proliferation rate of hADSCs induced cells (P < 0.05), while immunofluorescent staining indicated that Sertraline treatment during neurogenic differentiation could be decreased the percentage of glial fibrillary acidic protein and Nestin-positive cells, but did not significantly effect on the percentage of MAP2 positive cells. Conclusion: Overall, our data show that Sertraline can be promoting proliferation rate during neurogenic differentiation of hADSCs after 6 days post-induction, while Sertraline inhibits gliogenesis of induced hADSCs. PMID:24800186

UPLC-MS/MS method for therapeutic drug monitoring of 10 antibiotics used in intensive care units.

PubMed

El-Najjar, Nahed; Hösl, Julian; Holzmann, Thomas; Jantsch, Jonathan; Gessner, André

2018-03-01

A large variation in the levels of different ß-lactams and other antibiotics used in critically ill patients has been documented. The aim of this study is to establish and validate a fast, ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method for the simultaneous analysis of ten antibiotics (Meropenem, Cefepime, Ceftazidime, Piperacillin, Benzylpenicillin, Ampicillin, Flucloxacillin, Linezolid, and Sulfamethoxazole/Trimethoprim) in human plasma according to European Medicines Agency (EMA) guidelines. Protein precipitation with ice-cold methanol containing 9 isotopically labeled internal standards was used for sample clean up. Antibiotics were detected, following a 4-minute gradient separation, in multiple reactions monitoring (MRM) using API 4000 instrument equipped with electrospray source operating in positive ion mode. The lower limit of quantification was 0.1 mg/L for Meropenem, Ceftazidime, Piperacillin, Ampicillin, Flucloxacillin, and Sulfamethoxazole; 0.05 mg/L for Cefepime, Benzylpenicillin, and Trimethoprim; and 0.02 mg/L for Linezolid. The method proved to be precise and accurate and applicable for therapeutic drug monitoring and other pharmacokinetic studies. Copyright © 2017 John Wiley & Sons, Ltd.