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1

Simultaneous confocal fluorescence microscopy and optical coherence tomography for drug distribution and tissue integrity assessment  

NASA Astrophysics Data System (ADS)

The effectiveness of microbicidal gels, topical products developed to prevent infection by sexually transmitted diseases including HIV/AIDS, is governed by extent of gel coverage, pharmacokinetics of active pharmaceutical ingredients (APIs), and integrity of vaginal epithelium. While biopsies provide localized information about drug delivery and tissue structure, in vivo measurements are preferable in providing objective data on API and gel coating distribution as well as tissue integrity. We are developing a system combining confocal fluorescence microscopy with optical coherence tomography (OCT) to simultaneously measure local concentrations and diffusion coefficients of APIs during transport from microbicidal gels into tissue, while assessing tissue integrity. The confocal module acquires 2-D images of fluorescent APIs multiple times per second allowing analysis of lateral diffusion kinetics. The custom Fourier domain OCT module has a maximum a-scan rate of 54 kHz and provides depth-resolved tissue integrity information coregistered with the confocal fluorescence measurements. The combined system is validated by imaging phantoms with a surrogate fluorophore. Time-resolved API concentration measured at fixed depths is analyzed for diffusion kinetics. This multimodal system will eventually be implemented in vivo for objective evaluation of microbicide product performance.

Rinehart, Matthew T.; LaCroix, Jeffrey; Henderson, Marcus; Katz, David; Wax, Adam

2011-03-01

2

Drug Threat Assessment Update: Minnesota.  

National Technical Information Service (NTIS)

This report is a brief update to the Minnesota Drug Threat Assessment, which is a strategic assessment of the status and outlook of the drug threat to Minnesota. Analytical judgment determined the threat posed by each drug type or category, taking into ac...

2002-01-01

3

Drug assessment: UK style.  

PubMed

Before medicines can be marketed in the UK, they are subject to a system of licensing and the granting of a marketing authorisation that describes the conditions and patient groups for which the medicinal product can be used within the terms of its licence.(1) The licensing process involves an assessment of data relating to the efficacy, safety and quality of the product. However, the marketing authorisation does not determine whether, or how, it will be used in clinical practice. In the UK, the National Institute for Health and Care Excellence (NICE), the Scottish Medicines Consortium (SMC) and the All Wales Medicines Strategy Group (AWMSG) publish recommendations on the use of medicines for health services in the United Kingdom. In this article we review their remit, work processes and the status of guidance published in England, Scotland, Wales and Northern Ireland. PMID:24336496

2013-12-01

4

Environmental assessment requirements for live biological drugs.  

PubMed

Marketing approval of biological products by the US Food and Drug Administration must comply with requirements of Code of Federal Regulations title 21 part 25, "Environmental Impact Considerations." An environmental impact statement is usually not required. Environmental assessment is required unless excluded. As naturally occurring substances, biological products qualify for categorical exclusion if manufacture and use do not significantly alter their concentration or distribution in the human environment. The manufacturing process and establishment descriptions in the license application should include enough detail to ensure that waste is controlled and inactivated. During clinical development of a live biotherapeutic product, data should be collected regarding the shedding of live organisms from treated patients. The ability of the live organism to persist in the environment should be assessed, and instructions for safe handling by health care providers and consumers should be incorporated into the package insert. PMID:18181713

Sutton, Ann

2008-02-01

5

Pricing, distribution, and use of antimalarial drugs.  

PubMed Central

Prices of new antimalarial drugs are targeted at the "travellers' market" in developed countries, which makes them unaffordable in malaria-endemic countries where the per capita annual drug expenditures are US$ 5 or less. Antimalarials are distributed through a variety of channels in both public and private sectors, the official malaria control programmes accounting for 25-30% of chloroquine distribution. The unofficial drug sellers in markets, streets, and village shops account for as much as half of antimalarials distributed in many developing countries. Use of antimalarials through the health services is often poor; drug shortages are common and overprescription and overuse of injections are significant problems. Anxiety over drug costs may prevent patients from getting the necessary treatment for malaria, especially because of the seasonal appearance of this disease when people's cash reserves are very low. The high costs may lead them to unofficial sources, which will sell a single tablet instead of a complete course of treatment, and subsequently to increased, often irrational demand for more drugs and more injections. Increasingly people are resorting to self-medication for malaria, which may cause delays in seeking proper treatment in cases of failure, especially in areas where chloroquine resistance has increased rapidly. Self-medication is now widespread, and measures to restrict the illicit sale of drugs have been unsuccessful. The "unofficial" channels thus represent an unacknowledged extension of the health services in many countries; suggestions are advanced to encourage better self-medication by increasing the knowledge base among the population at large (mothers, schoolchildren, market sellers, and shopkeepers), with an emphasis on correct dosing and on the importance of seeking further treatment without delay, if necessary. PMID:1893512

Foster, S. D.

1991-01-01

6

21 CFR 203.50 - Requirements for wholesale distribution of prescription drugs.  

Code of Federal Regulations, 2012 CFR

...for wholesale distribution of prescription drugs. 203.50 Section 203...CONTINUED) DRUGS: GENERAL PRESCRIPTION DRUG MARKETING Wholesale Distribution...for wholesale distribution of prescription drugs. (a) Identifying...

2012-04-01

7

21 CFR 203.50 - Requirements for wholesale distribution of prescription drugs.  

Code of Federal Regulations, 2011 CFR

...for wholesale distribution of prescription drugs. 203.50 Section 203...CONTINUED) DRUGS: GENERAL PRESCRIPTION DRUG MARKETING Wholesale Distribution...for wholesale distribution of prescription drugs. (a) Identifying...

2011-04-01

8

21 CFR 203.50 - Requirements for wholesale distribution of prescription drugs.  

...for wholesale distribution of prescription drugs. 203.50 Section 203...CONTINUED) DRUGS: GENERAL PRESCRIPTION DRUG MARKETING Wholesale Distribution...for wholesale distribution of prescription drugs. (a) Identifying...

2014-04-01

9

21 CFR 203.50 - Requirements for wholesale distribution of prescription drugs.  

Code of Federal Regulations, 2013 CFR

...for wholesale distribution of prescription drugs. 203.50 Section 203...CONTINUED) DRUGS: GENERAL PRESCRIPTION DRUG MARKETING Wholesale Distribution...for wholesale distribution of prescription drugs. (a) Identifying...

2013-04-01

10

[Update of the French drug reaction assessment method].  

PubMed

A tripartite group, entitled « CRI » (for Cercle de réflexion sur l'imputabilité), involving French pharmacovigilance staff from the French network of the Regional centers of pharmacovigilance, from pharmaceutical companies, and from French Health Authorities (Agence française de sécurité sanitaire des produits de santé) has worked to update the French drug reaction assessment method. Following assessment of strengths and weaknesses of the previous method, several points for improvement are proposed: a more precise wording and a more discriminating scale for some of the chronological and semiological criteria, a wider distribution of the intrinsic score from 5 to 7 levels, a new bibliographic scale for differentiating expected and unexpected adverse drug reactions, and a new informativness scale. This updated method would lead to a more relevant assessment of relationship between a drug and the occurrence of an adverse reaction. Furthermore, this method is a teaching tool to assess the level of relationship between a drug and the occurrence of an adverse reaction. PMID:22186077

Arimone, Yannick; Bidault, Irène; Dutertre, Jean-Paul; Gérardin, Marie; Guy, Claire; Haramburu, Françoise; Hillaire-Buys, Dominique; Meglio, Carmine; Penfornis, Catherine; Théophile, Hélène; Valnet-Rabier, Marie-Blanche

2011-01-01

11

Target assessment for antiparasitic drug discovery.  

PubMed

Drug discovery is a high-risk, expensive and lengthy process taking at least 12 years and costing upwards of US$500 million per drug to reach the clinic. For neglected diseases, the drug discovery process is driven by medical need and guided by pre-defined target product profiles. Assessment and prioritisation of the most promising targets for entry into screening programmes is crucial for maximising the chances of success. Here, we describe criteria used in our drug discovery unit for target assessment and introduce the 'traffic-light' system as a prioritisation and management tool. We hope this brief review will stimulate basic scientists to acquire additional information necessary for drug discovery. PMID:17962072

Frearson, Julie A; Wyatt, Paul G; Gilbert, Ian H; Fairlamb, Alan H

2007-12-01

12

Physiologically based pharmacokinetic modeling for assessing the clinical drug-drug interaction of alisporivir.  

PubMed

Alisporivir is a novel cyclophilin-binding molecule with potent anti-hepatitis C virus (HCV) activity. In vitro data from human liver microsomes suggest that alisporivir is a substrate and a time-dependent inhibitor (TDI) of CYP3A4. The aim of the current work was to develop a novel physiologically based pharmacokinetic (PBPK) model to quantitatively assess the magnitude of CYP3A4 mediated drug-drug interactions with alisporivir as the substrate or victim drug. Towards that, a Simcyp PBPK model was developed by integrating in vitro data with in vivo clinical findings to characterize the clinical pharmacokinetics of alisporivir and further assess the magnitude of drug-drug interactions. Incorporated with absorption, distribution, elimination, and TDI data, the model accurately predicted AUC, Cmax, and tmax values after single or multiple doses of alisporivir with a prediction deviation within ±32%. The model predicted an alisporivir AUC increase by 9.4-fold and a decrease by 86% when alisporivir was co-administrated with ketoconazole (CYP3A4 inhibitor) or rifampin (CYP3A4 inducer), respectively. Predictions were within ±20% of the observed changes. In conclusion, the PBPK model successfully predicted the alisporivir PK and the magnitude of drug-drug interactions. PMID:25008118

Xia, Binfeng; Barve, Avantika; Heimbach, Tycho; Zhang, Tao; Gu, Helen; Wang, Lai; Einolf, Heidi; Alexander, Natalya; Hanna, Imad; Ke, June; Mangold, James B; He, Handan; Sunkara, Gangadhar

2014-10-15

13

Assessing suicidal risk with antiepileptic drugs  

PubMed Central

Recently, the US Food and Drug Administration issued an alert about an increased risk for suicidality during treatment with antiepileptic drugs (AEDs) for different indications, including epilepsy. We discuss the issue of suicide in epilepsy with special attention to AEDs and the assessment of suicide in people with epilepsy. It has been suggested that early medical treatment with AEDs might potentially reduce suicide risk of people with epilepsy, but it is of great importance that the choice of drug is tailored to the mental state of the patient. The issue of suicidality in epilepsy is likely to represent an example of how the underdiagnosis of psychiatric symptoms, the lack of input from professionals (eg, psychologists, social workers, and psychiatrists), and the delay in an optimized AED therapy may worsen the prognosis of the condition with the occurrence of severe complications such as suicide. PMID:20957120

Mula, Marco; Bell, Gail S; Sander, Josemir W

2010-01-01

14

Assessing suicidal risk with antiepileptic drugs.  

PubMed

Recently, the US Food and Drug Administration issued an alert about an increased risk for suicidality during treatment with antiepileptic drugs (AEDs) for different indications, including epilepsy. We discuss the issue of suicide in epilepsy with special attention to AEDs and the assessment of suicide in people with epilepsy. It has been suggested that early medical treatment with AEDs might potentially reduce suicide risk of people with epilepsy, but it is of great importance that the choice of drug is tailored to the mental state of the patient. The issue of suicidality in epilepsy is likely to represent an example of how the underdiagnosis of psychiatric symptoms, the lack of input from professionals (eg, psychologists, social workers, and psychiatrists), and the delay in an optimized AED therapy may worsen the prognosis of the condition with the occurrence of severe complications such as suicide. PMID:20957120

Mula, Marco; Bell, Gail S; Sander, Josemir W

2010-01-01

15

Drug interactions evaluation: An integrated part of risk assessment of therapeutics  

SciTech Connect

Pharmacokinetic drug interactions can lead to serious adverse events or decreased drug efficacy. The evaluation of a new molecular entity's (NME's) drug-drug interaction potential is an integral part of risk assessment during drug development and regulatory review. Alteration of activities of enzymes or transporters involved in the absorption, distribution, metabolism, or excretion of a new molecular entity by concomitant drugs may alter drug exposure, which can impact response (safety or efficacy). The recent Food and Drug Administration (FDA) draft drug interaction guidance ( (http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm072101.pdf)) highlights the methodologies and criteria that may be used to guide drug interaction evaluation by industry and regulatory agencies and to construct informative labeling for health practitioner and patients. In addition, the Food and Drug Administration established a 'Drug Development and Drug Interactions' website to provide up-to-date information regarding evaluation of drug interactions ( (http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ucm080499.htm)). This review summarizes key elements in the FDA drug interaction guidance and new scientific developments that can guide the evaluation of drug-drug interactions during the drug development process.

Zhang, Lei; Reynolds, Kellie S.; Zhao, Ping [Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Building 51, Room 3188, 10903 New Hampshire Avenue, Silver Spring, MD 20993 (United States); Huang, Shiew-Mei, E-mail: shiewmei.huang@fda.hhs.go [Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Building 51, Room 3188, 10903 New Hampshire Avenue, Silver Spring, MD 20993 (United States)

2010-03-01

16

21 CFR 203.50 - Requirements for wholesale distribution of prescription drugs.  

Code of Federal Regulations, 2010 CFR

...Section 203.50 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT...HUMAN SERVICES (CONTINUED) DRUGS: GENERAL PRESCRIPTION DRUG MARKETING Wholesale Distribution...previous sales of the component drug or drugs. (d) List of...

2010-04-01

17

A reliability assessment methodology for distribution systems with distributed generation  

E-print Network

Reliability assessment is of primary importance in designing and planning distribution systems that operate in an economic manner with minimal interruption of customer loads. With the advances in renewable energy sources, Distributed Generation (DG...

Duttagupta, Suchismita Sujaya

2006-08-16

18

10 CFR 32.72 - Manufacture, preparation, or transfer for commercial distribution of radioactive drugs containing...  

...Manufacture, preparation, or transfer for commercial distribution of radioactive drugs containing...Manufacture, preparation, or transfer for commercial distribution of radioactive drugs containing...manufacture, prepare, or transfer for commercial distribution radioactive drugs...

2014-01-01

19

Interplay between mutational pathway and spatial drug distribution controls time to evolution of drug resistance  

E-print Network

Spatial gradients of drug concentration are believed to play an important role in the evolution of drug resistance. We use a stochastic model to show that in a growing population of malignant cells the effect of a spatially non-uniform drug distribution depends critically on the mutational pathway leading to resistance. A non-uniform drug concentration can strongly accelerate the emergence of resistance when the pathway involves a sequence of mutants with increasing resistance, but slows it down if the pathway crosses a fitness valley. Our results suggest that the design of better strategies to combat the emergence of resistance may require detailed knowledge of the mutational pathways involved.

Greulich, Philip; Allen, Rosalind J

2012-01-01

20

21 CFR 1310.10 - Removal of the exemption of drugs distributed under the Food, Drug and Cosmetic Act.  

Code of Federal Regulations, 2011 CFR

21 Food and Drugs 9 2011-04-01 2011-04-01 false Removal of the exemption of drugs distributed under the Food, Drug and Cosmetic Act. 1310.10 Section 1310.10 Food and Drugs DRUG ENFORCEMENT ADMINISTRATION,...

2011-04-01

21

31 CFR 20.210 - To whom must I distribute my drug-free workplace statement?  

... To whom must I distribute my drug-free workplace statement? 20.210 Section...GOVERNMENTWIDE REQUIREMENTS FOR DRUG-FREE WORKPLACE (FINANCIAL ASSISTANCE) ...To whom must I distribute my drug-free workplace statement? You must...

2014-07-01

22

36 CFR 1212.210 - To whom must I distribute my drug-free workplace statement?  

... To whom must I distribute my drug-free workplace statement? 1212.210 ...GOVERNMENTWIDE REQUIREMENTS FOR DRUG-FREE WORKPLACE (FINANCIAL ASSISTANCE) ...To whom must I distribute my drug-free workplace statement? You must...

2014-07-01

23

77 FR 20025 - Draft Guidance for Industry on Compliance Policy for Reporting Drug Sample Distribution...  

Federal Register 2010, 2011, 2012, 2013

...on Compliance Policy for Reporting Drug Sample Distribution Information; Availability...Compliance Policy on Reporting Drug Sample Distribution Information Under the Affordable...Agency's implementation of the drug sample transparency reporting provisions of...

2012-04-03

24

45 CFR 156.295 - Prescription drug distribution and cost reporting.  

Code of Federal Regulations, 2012 CFR

...2012-10-01 false Prescription drug distribution and cost reporting...Standards § 156.295 Prescription drug distribution and cost reporting...and the percentage of prescriptions for which a generic drug was available and...

2012-10-01

25

45 CFR 156.295 - Prescription drug distribution and cost reporting.  

Code of Federal Regulations, 2013 CFR

...2013-10-01 false Prescription drug distribution and cost reporting...Standards § 156.295 Prescription drug distribution and cost reporting...and the percentage of prescriptions for which a generic drug was available and...

2013-10-01

26

38 CFR 48.210 - To whom must I distribute my drug-free workplace statement?  

...false To whom must I distribute my drug-free workplace statement? 48.210 Section... GOVERNMENTWIDE REQUIREMENTS FOR DRUG-FREE WORKPLACE (FINANCIAL ASSISTANCE) Requirements...210 To whom must I distribute my drug-free workplace statement? You must...

2014-07-01

27

Quantitative detection of drug dose and spatial distribution in the lung revealed by Cryoslicing Imaging.  

PubMed

Administration of drugs via inhalation is an attractive route for pulmonary and systemic drug delivery. The therapeutic outcome of inhalation therapy depends not only on the dose of the lung-delivered drug, but also on its bioactivity and regional distribution. Fluorescence imaging has the potential to monitor these aspects already during preclinical development of inhaled drugs, but quantitative methods of analysis are lacking. In this proof-of-concept study, we demonstrate that Cryoslicing Imaging allows for 3D quantitative fluorescence imaging on ex vivo murine lungs. Known amounts of fluorescent substance (nanoparticles or fluorophore-drug conjugate) were instilled in the lungs of mice. The excised lungs were measured by Cryoslicing Imaging. Herein, white light and fluorescence images are obtained from the face of a gradually sliced frozen organ block. A quantitative representation of the fluorescence intensity throughout the lung was inferred from the images by accounting for instrument noise, tissue autofluorescence and out-of-plane fluorescence. Importantly, the out-of-plane fluorescence correction is based on the experimentally determined effective light attenuation coefficient of frozen murine lung tissue (10.0±0.6cm(-1) at 716nm). The linear correlation between pulmonary total fluorescence intensity and pulmonary fluorophore dose indicates the validity of this method and allows direct fluorophore dose assessment. The pulmonary dose of a fluorescence-labeled drug (Fc?R-Alexa750) could be assessed with an estimated accuracy of 9% and the limit of detection in ng regime. Hence, Cryoslicing Imaging can be used for quantitative assessment of dose and 3D distribution of fluorescence-labeled drugs or drug carriers in the lungs of mice. PMID:25262414

Barapatre, Nirav; Symvoulidis, Panagiotis; Möller, Winfried; Prade, Friedrich; Deliolanis, Nikolaos C; Hertel, Sebastian; Winter, Gerhard; Yildirim, Ali Ö; Stoeger, Tobias; Eickelberg, Oliver; Ntziachristos, Vasilis; Schmid, Otmar

2015-01-01

28

21 CFR 1310.11 - Reinstatement of exemption for drug products distributed under the Food, Drug and Cosmetic Act.  

Code of Federal Regulations, 2012 CFR

...RECORDS AND REPORTS OF LISTED CHEMICALS AND CERTAIN MACHINES § 1310...possession or distribution of listed chemicals contained in the exempt drug product. (c) Changes in exempt drug product compositions: Any change in the quantitative or...

2012-04-01

29

21 CFR 1310.11 - Reinstatement of exemption for drug products distributed under the Food, Drug and Cosmetic Act.  

Code of Federal Regulations, 2010 CFR

...RECORDS AND REPORTS OF LISTED CHEMICALS AND CERTAIN MACHINES § 1310...possession or distribution of listed chemicals contained in the exempt drug product. (c) Changes in exempt drug product compositions: Any change in the quantitative or...

2010-04-01

30

21 CFR 1310.11 - Reinstatement of exemption for drug products distributed under the Food, Drug and Cosmetic Act.  

Code of Federal Regulations, 2013 CFR

...RECORDS AND REPORTS OF LISTED CHEMICALS AND CERTAIN MACHINES § 1310...possession or distribution of listed chemicals contained in the exempt drug product. (c) Changes in exempt drug product compositions: Any change in the quantitative or...

2013-04-01

31

21 CFR 1310.11 - Reinstatement of exemption for drug products distributed under the Food, Drug and Cosmetic Act.  

...RECORDS AND REPORTS OF LISTED CHEMICALS AND CERTAIN MACHINES § 1310...possession or distribution of listed chemicals contained in the exempt drug product. (c) Changes in exempt drug product compositions: Any change in the quantitative or...

2014-04-01

32

21 CFR 1310.11 - Reinstatement of exemption for drug products distributed under the Food, Drug and Cosmetic Act.  

Code of Federal Regulations, 2011 CFR

...RECORDS AND REPORTS OF LISTED CHEMICALS AND CERTAIN MACHINES § 1310...possession or distribution of listed chemicals contained in the exempt drug product. (c) Changes in exempt drug product compositions: Any change in the quantitative or...

2011-04-01

33

A hybrid approach to advancing quantitative prediction of tissue distribution of basic drugs in human  

SciTech Connect

A general toxicity of basic drugs is related to phospholipidosis in tissues. Therefore, it is essential to predict the tissue distribution of basic drugs to facilitate an initial estimate of that toxicity. The objective of the present study was to further assess the original prediction method that consisted of using the binding to red blood cells measured in vitro for the unbound drug (RBCu) as a surrogate for tissue distribution, by correlating it to unbound tissue:plasma partition coefficients (Kpu) of several tissues, and finally to predict volume of distribution at steady-state (V{sub ss}) in humans under in vivo conditions. This correlation method demonstrated inaccurate predictions of V{sub ss} for particular basic drugs that did not follow the original correlation principle. Therefore, the novelty of this study is to provide clarity on the actual hypotheses to identify i) the impact of pharmacological mode of action on the generic correlation of RBCu-Kpu, ii) additional mechanisms of tissue distribution for the outlier drugs, iii) molecular features and properties that differentiate compounds as outliers in the original correlation analysis in order to facilitate its applicability domain alongside the properties already used so far, and finally iv) to present a novel and refined correlation method that is superior to what has been previously published for the prediction of human V{sub ss} of basic drugs. Applying a refined correlation method after identifying outliers would facilitate the prediction of more accurate distribution parameters as key inputs used in physiologically based pharmacokinetic (PBPK) and phospholipidosis models.

Poulin, Patrick, E-mail: patrick-poulin@videotron.ca [Quebec City, Quebec (Canada); Ekins, Sean [Collaborations in Chemistry, 601 Runnymede Avenue, Jenkintown, PA 19046 (United States); Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, 20 Penn Street, Baltimore, MD 21201 (United States); Department of Pharmacology, University of Medicine and Dentistry of New Jersey (UMDNJ)-Robert Wood Johnson Medical School, 675 Hoes Lane, Piscataway, NJ 08854 (United States); Theil, Frank-Peter [Genentech, South San Francisco (United States)

2011-01-15

34

A hybrid approach to advancing quantitative prediction of tissue distribution of basic drugs in human.  

PubMed

A general toxicity of basic drugs is related to phospholipidosis in tissues. Therefore, it is essential to predict the tissue distribution of basic drugs to facilitate an initial estimate of that toxicity. The objective of the present study was to further assess the original prediction method that consisted of using the binding to red blood cells measured in vitro for the unbound drug (RBCu) as a surrogate for tissue distribution, by correlating it to unbound tissue:plasma partition coefficients (Kpu) of several tissues, and finally to predict volume of distribution at steady-state (V(ss)) in humans under in vivo conditions. This correlation method demonstrated inaccurate predictions of V(ss) for particular basic drugs that did not follow the original correlation principle. Therefore, the novelty of this study is to provide clarity on the actual hypotheses to identify i) the impact of pharmacological mode of action on the generic correlation of RBCu-Kpu, ii) additional mechanisms of tissue distribution for the outlier drugs, iii) molecular features and properties that differentiate compounds as outliers in the original correlation analysis in order to facilitate its applicability domain alongside the properties already used so far, and finally iv) to present a novel and refined correlation method that is superior to what has been previously published for the prediction of human V(ss) of basic drugs. Applying a refined correlation method after identifying outliers would facilitate the prediction of more accurate distribution parameters as key inputs used in physiologically based pharmacokinetic (PBPK) and phospholipidosis models. PMID:21034759

Poulin, Patrick; Ekins, Sean; Theil, Frank-Peter

2011-01-15

35

Assessment of drug information resource preferences of pharmacy students and faculty.  

PubMed

A 39-item survey instrument was distributed to faculty and students at Wingate University School of Pharmacy to assess student and faculty drug information (DI) resource use and access preferences. The response rate was 81% (n?=?289). Faculty and professional year 2 to 4 students preferred access on laptop or desktop computers (67% and 75%, respectively), followed by smartphones (27% and 22%, respectively). Most faculty and students preferred using Lexicomp Online for drug information (53% and 74%, respectively). Results indicate that DI resources use is similar between students and faculty; laptop or desktop computers are the preferred platforms for accessing drug information. PMID:24860270

Hanrahan, Conor T; Cole, Sabrina W

2014-04-01

36

Assessment of drug information resource preferences of pharmacy students and faculty  

PubMed Central

A 39-item survey instrument was distributed to faculty and students at Wingate University School of Pharmacy to assess student and faculty drug information (DI) resource use and access preferences. The response rate was 81% (n?=?289). Faculty and professional year 2 to 4 students preferred access on laptop or desktop computers (67% and 75%, respectively), followed by smartphones (27% and 22%, respectively). Most faculty and students preferred using Lexicomp Online for drug information (53% and 74%, respectively). Results indicate that DI resources use is similar between students and faculty; laptop or desktop computers are the preferred platforms for accessing drug information. PMID:24860270

Hanrahan, Conor T.; Cole, Sabrina W.

2014-01-01

37

Microdialysis for assessing intratumoral drug disposition in brain cancers: a tool for rational drug development  

PubMed Central

Importance of the field: Many promising targeted agents and combination therapies are being investigated for brain cancer. However, the results from recent clinical trials have been disappointing. A better understanding of the disposition of drug in the brain early in drug development would facilitate appropriate channeling of new drugs into brain cancer clinical trials. Areas covered in this review: Barriers to successful drug activity against brain cancer and issues affecting intratumoral drug concentrations are reviewed. The use of the microdialysis technique for extracellular fluid (ECF) sampling and its application to drug distribution studies in brain are reviewed using published literature from 1995 to the present. The benefits and limitations of microdialysis for performing neuorpharmacokinetic (nPK) and neuropharmacodynamic (nPD) studies are discussed. What the reader will gain: The reader will gain an appreciation of the challenges involved in identifying agents likely to have efficacy in brain cancer, an understanding of the general principles of microdialysis, and the power and limitations of using this technique in early drug development for brain cancer therapies. Take home message: A major factor preventing efficacy of anti-brain cancer drugs is limited access to tumor. Intracerebral microdialysis allows sampling of drug in the brain ECF. The resulting nPK/nPD data can aid in the rational selection of drugs for investigation in brain tumor clinical trials. PMID:20969450

Blakeley, Jaishri; Portnow, Jana

2014-01-01

38

Managed care pharmacy, socioeconomic assessments and drug adoption decisions  

Microsoft Academic Search

A telephone survey of a representative national sample of 51 large managed care organizations in the U.S. (> 50,000 enrollees) was undertaken (1) to understand the role of socioeconomic assessments on drug adoption decisions; (2) to determine the sources of these assessments and the reliance of managed care pharmacy on each; and (3) to determine the resources for internally versus

Alan Lyles; Bryan R. Luce; Anne M. Rentz

1997-01-01

39

Risk-benefit assessment of tocolytic drugs.  

PubMed

beta 2-Mimetics are the principal agents used for myometrial relaxation. As all the available drugs also have beta 1-stimulant effects, the various side effects (cardiovascular, pulmonary and metabolic) require a critical consideration of the clinical indications, thorough supervision and combined therapeutic concepts. With regard to clinical indications, 'prophylactic tocolysis' frequently turns out to be unnecessary, as does the treatment of physiological uterine contractions during pregnacy which have no effect on the cervix. The benefit of tocolysis must be seen not so much in a reduction of preterm labour but in enabling the obstetrician and neonatologist to optimise the handling of the premature baby, e.g. by allowing lung maturation or by enabling the patient to reach a centre for perinatal medicine before the birth. Labour-dependent fetal distress situations during birth at term can also be managed successfully. Supervision involves thorough control of both mother (especially of cardiovascular and metabolic parameters, electrolyte and water balance) and fetus (cardiotocography, fetometry) in order to decide individually when possible benefits are outweighed by maternal or fetal risks. Combination of beta 2-mimetic treatment with magnesium therapy reduces the beta-mimetic dosage required, has a cardioprotective action, and reduces the development of drug tolerance and the risk of lung oedema. This combination, therefore, should become routine in tocolytic therapy. If further protection against cardiovascular and risk of lung oedema is required, administration of beta 1-blockers is advisable. PMID:1930743

Wischnik, A

1991-01-01

40

Assessment of Alcohol and Other Drug Use by Runaway Youths  

Microsoft Academic Search

While excellent adolescent alcohol and drug screening tools are available, there are relatively few, if any, psychometrically validated measures to use in the assessment of adolescent treatment outcome. This study conducted a test-retest exercise of the Form 90 Drug and Alcohol (Form 90 DnA) to determine the stability of adolescent responses when administering the day-by-day calendar\\/grid approach. Homeless youth (N

Natasha Slesnick; J. Scott Tonigan

2004-01-01

41

Mathematical modeling and finite element simulation of slow release of drugs using hydrogels as carriers with various drug concentration distributions.  

PubMed

In drug release systems using hydrogels as carriers, the presence of the polymer network will reduce the drug release rate, which can extend the release period. For a controlled-release process of drug, usually the ideal situation is to get a zero-order drug release rate. In this paper, the mathematical model of hydrogel swelling processes is constructed on the basis of a biphasic theory, and then an integrated equation that considers both water convection and drug diffusion phenomena is used to describe the drug release process. The effects of the initial drug concentration with nonuniform distributions along the radial direction of hydrogel carriers on the release of drugs are studied through simulating two-dimensional hydrogel swelling processes by means of the COMSOL Multiphysics software. The simulation results show that along with the hydrogel swelling, the drug release rate is changing, and the major influencing factors of the drug release rate are water convection and drug diffusion coefficient, which are affected by water volume fraction, drug concentration distribution in matrix, and carrier radius. The results also indicate that the initial drug concentration distribution following a sine curve can result in an ideal zero-order release process. PMID:23526640

Xu, Yihan; Jia, Yuxi; Wang, Zhao; Wang, Zhaojing

2013-05-01

42

Adverse cutaneous drug reactions: Eight year assessment in hospitalized patients  

PubMed Central

Background: Adverse cutaneous drug reactions (ACDRs) are the most commonly reported adverse drug events. The causative drugs and clinical patterns of ACDRs are different in various populations. This study was conducted to identify the clinical patterns, causative drugs and reasons for drug administration in patients hospitalized due to ACDR. Materials and Methods: This retrospective study was carried out in a referral university hospital, Isfahan, Iran. The medical records of all patients who were hospitalized in the Dermatology Department due to ACDRs were reviewed covering an 8-year period between December 2006 and August 2013. Results: A total number of 282 patients with the mean age of 29.48 ± 21.18 years were hospitalized in this time period, of which 61% were females. The most common clinical patterns regarding the final diagnosis were Stevens-Johnson syndrome (SJS) (32%), exanthematous drug eruptions (24.5%) and toxic epidermal necrolysis (TEN) (11%). Anticonvulsants were the most frequently implicated drug group (51.8%) followed by antibiotics (33.7%) and analgesics and non-steroidal anti-inflammatory drugs (5.7%). The most common cause of drug administration was seizure (30%) and then upper respiratory tract infections (12%). The frequency distribution of clinical types of reactions was different between age groups (P < 0.001). The severe types (SJS, TEN, drug rash with eosinophilia and systemic symptoms and overlap syndrome) were more frequent in the patients aged ?50 years old (55.2%) compare to those aged ?50 years (28%) (P = 0.001). Conclusion: The main causative drugs of ACDRs were anticonvulsants and antibiotics. However, the sever types of reactions were more prevalent.

Mokhtari, Fatemeh; Nikyar, Zahra; Naeini, Bahareh Abtahi; Esfahani, Alireza Asemi; Rahmani, Siamak

2014-01-01

43

Drug distribution in man: a positron emission tomography study after oral administration of the labelled neuroprotective drug vinpocetine  

Microsoft Academic Search

Direct information on the distribution of a drug requires measurements in various tissues. Such data have until now been obtained in animals, or have indirectly been calculated from plasma measurements in humans using mathematical models. Here we suggest the use of positron emission tomography (PET) as a method to obtain direct measurements of drug distribution in the human body. The

Balázs Gulyás; Christer Halldin; Judit Sóvágó; Johan Sandell; Zsolt Cselényi; ÁdÁm Vas; Béla Kiss; Egon Kárpáti; Lars Farde

2002-01-01

44

Novel Approach of MALDI Drug Imaging, Immunohistochemistry, and Digital Image Analysis for Drug Distribution Studies in Tissues.  

PubMed

Drug efficacy strongly depends on the presence of the drug substance at the target site. As vascularization is an important factor for the distribution of drugs in tissues, we analyzed drug distribution as a function of blood vessel localization in tumor tissue. To explore distribution of the anticancer drugs afatinib, erlotinib, and sorafenib, a combined approach of matrix-assisted laser desorption/ionization (MALDI) drug imaging and immunohistochemical vessel staining was applied and examined by digital image analysis. The following two xenograft models were investigated: (1) mice carrying squamous cell carcinoma (FaDu) xenografts (ntumor = 13) were treated with afatinib or erlotinib, and (2) sarcoma (A673) xenograft bearing mice (ntumor = 8) received sorafenib treatment. MALDI drug imaging revealed a heterogeneous distribution of all anticancer drugs. The tumor regions containing high drug levels were associated with a higher degree of vascularization than the regions without drug signals (p < 0.05). When correlating the impact of blood vessel size to drug abundance in the sarcoma model, a higher amount of small vessels was detected in the tumor regions with high drug levels compared to the tumor regions with low drug levels (p < 0.05). With the analysis of coregistered MALDI imaging and CD31 immunohistochemical data by digital image analysis, we demonstrate for the first time the potential of correlating MALDI drug imaging and immunohistochemistry. Here we describe a specific and precise approach for correlating histological features and pharmacokinetic properties of drugs at microscopic level, which will provide information for the improvement of drug design, administration formula or treatment schemes. PMID:25263480

Huber, Katharina; Feuchtinger, Annette; Borgmann, Daniela M; Li, Zhoulei; Aichler, Michaela; Hauck, Stefanie M; Zitzelsberger, Horst; Schwaiger, Markus; Keller, Ulrich; Walch, Axel

2014-11-01

45

Implicit and Explicit Drug-Related Cognitions during Detoxification Treatment are Associated with Drug Relapse: An Ecological Momentary Assessment Study  

PubMed Central

Objective Relapse is a major problem in drug addiction treatment. Both drug craving and drug-related cognitions (e.g., attentional bias and implicit attitudes to drugs) may contribute to relapse. Using ecological momentary assessments (EMA), we examined whether craving and cognitions assessed during drug detoxification treatment were associated with relapse. Method Participants were 68 heroin-dependent inpatients undergoing clinical detoxification at an addiction treatment center. Participants carried around a personal digital assistant (PDA) for 1-week. Participants completed up to 4 random assessments (RAs) per day. They also completed an assessment when they experienced a temptation to use drugs (TA). At each assessment, participants reported their craving and attitudes to drugs. Implicit cognitions were assessed with a drug Stroop task (attentional bias) and an Implicit Association Test (implicit attitudes). Results Individuals who relapsed during the study week exhibited a larger attentional bias and more positive implicit attitudes to drugs than non-relapsers at TAs (but not RAs). In addition, compared to non-relapsers, relapsers reported higher levels of craving and more positive explicit attitudes to drugs at TAs compared to RAs. Additional within-subject analyses revealed that attentional bias for drugs at TAs increased before relapse. Conclusions Drug-related cognitive processes assessed using EMA were associated with relapse during drug detoxification. Real-time assessment of craving and cognitions may help to identify individuals at risk of relapse, and when they are at risk of relapse. PMID:23231572

Marhe, Reshmi; Waters, Andrew J.; van de Wetering, Ben J. M.; Franken, Ingmar H. A.

2012-01-01

46

In Vivo Methods for the Assessment of Topical Drug Bioavailability  

PubMed Central

This paper reviews some current methods for the in vivo assessment of local cutaneous bioavailability in humans after topical drug application. After an introduction discussing the importance of local drug bioavailability assessment and the limitations of model-based predictions, the focus turns to the relevance of experimental studies. The available techniques are then reviewed in detail, with particular emphasis on the tape stripping and microdialysis methodologies. Other less developed techniques, including the skin biopsy, suction blister, follicle removal and confocal Raman spectroscopy techniques are also described. PMID:17985216

Herkenne, Christophe; Alberti, Ingo; Naik, Aarti; Kalia, Yogeshvar N.; Mathy, Francois-Xavier; Preat, Veronique

2007-01-01

47

Statistical assessment of Monte Carlo distributional tallies  

SciTech Connect

Four tests are developed to assess the statistical reliability of distributional or mesh tallies. To this end, the relative variance density function is developed and its moments are studied using simplified, non-transport models. The statistical tests are performed upon the results of MCNP calculations of three different transport test problems and appear to show that the tests are appropriate indicators of global statistical quality.

Kiedrowski, Brian C [Los Alamos National Laboratory; Solomon, Clell J [Los Alamos National Laboratory

2010-12-09

48

Drug distribution in wet granulation: foam versus spray.  

PubMed

Foam granulation technology is a new wet granulation approach for pharmaceutical formulations. This study evaluates the performance of foam and spray granulation in achieving uniform drug distribution using a model formulation. To observe wetting and nuclei formation, single drop/foam penetration experiments were performed on a static powder bed comprised of varying compositions of hydrophilic/hydrophobic glass ballotini, and hydrophilic lactose/hydrophobic salicylic acid respectively. High shear granulation experiments were performed in a 5L mixer using varying compositions of hydrophilic lactose and hydrophobic salicylic acid. Four percent hydroxylpropyl methylcellulose (HPMC) solution was delivered at 90?g/min as either a foam (92% FQ) or an atomized spray whilst recording impeller power consumption. After drying, the granule size distribution was measured and the granule composition was estimated using gravimetric filtration in methanol. Foam penetration was less dependent on the powder hydrophobicity compared to drop penetration. For glass ballotini powder mixtures, foam induced nucleation created nuclei with relatively uniform structure and size regardless of the powder hydrophobicity. For salicylic acid and lactose mixtures, increasing the proportion of salicylic acid reduced the nuclei granule size for both foam and drop binder addition. The granule drug distribution was not significantly affected by the binder addition method. Processing conditions, including liquid binder amount, impeller speed, wet massing, and the wettability properties of the formulation were the dominant factors for delivering homogeneous granules. The study reveals that foam and spray granulation involve different nucleation mechanisms - spray tends to incur early liquid penetration whereas foam granulation operates well in mechanical dispersion. PMID:23057532

Tan, Melvin X L; Nguyen, Thanh H; Hapgood, Karen P

2013-09-01

49

IVAN: Intelligent Van for the Distribution of Pharmaceutical Drugs  

PubMed Central

This paper describes a telematic system based on an intelligent van which is capable of tracing pharmaceutical drugs over delivery routes from a warehouse to pharmacies, without altering carriers' daily conventional tasks. The intelligent van understands its environment, taking into account its location, the assets and the predefined delivery route; with the capability of reporting incidences to carriers in case of failure according to the established distribution plan. It is a non-intrusive solution which represents a successful experience of using smart environments and an optimized Radio Frequency Identification (RFID) embedded system in a viable way to resolve a real industrial need in the pharmaceutical industry. The combination of deterministic modeling of the indoor vehicle, the implementation of an ad-hoc radiating element and an agile software platform within an overall system architecture leads to a competitive, flexible and scalable solution. PMID:22778659

Moreno, Asier; Angulo, Ignacio; Perallos, Asier; Landaluce, Hugo; Zuazola, Ignacio Julio Garcia; Azpilicueta, Leire; Astrain, Jose Javier; Falcone, Francisco; Villadangos, Jesus

2012-01-01

50

14 CFR 1267.210 - To whom must I distribute my drug-free workplace statement?  

Code of Federal Regulations, 2011 CFR

...whom must I distribute my drug-free workplace statement? 1267.210...Section 1267.210 Aeronautics and Space NATIONAL AERONAUTICS AND SPACE ADMINISTRATION GOVERNMENTWIDE REQUIREMENTS FOR DRUG-FREE WORKPLACE (FINANCIAL...

2011-01-01

51

14 CFR 1267.210 - To whom must I distribute my drug-free workplace statement?  

Code of Federal Regulations, 2010 CFR

...whom must I distribute my drug-free workplace statement? 1267.210...Section 1267.210 Aeronautics and Space NATIONAL AERONAUTICS AND SPACE ADMINISTRATION GOVERNMENTWIDE REQUIREMENTS FOR DRUG-FREE WORKPLACE (FINANCIAL...

2010-01-01

52

14 CFR 1267.210 - To whom must I distribute my drug-free workplace statement?  

Code of Federal Regulations, 2012 CFR

...whom must I distribute my drug-free workplace statement? 1267.210...Section 1267.210 Aeronautics and Space NATIONAL AERONAUTICS AND SPACE ADMINISTRATION GOVERNMENTWIDE REQUIREMENTS FOR DRUG-FREE WORKPLACE (FINANCIAL...

2012-01-01

53

14 CFR 1267.210 - To whom must I distribute my drug-free workplace statement?  

Code of Federal Regulations, 2013 CFR

...whom must I distribute my drug-free workplace statement? 1267.210...Section 1267.210 Aeronautics and Space NATIONAL AERONAUTICS AND SPACE ADMINISTRATION GOVERNMENTWIDE REQUIREMENTS FOR DRUG-FREE WORKPLACE (FINANCIAL...

2013-01-01

54

Technology assessment and the Food and Drug Administration  

NASA Technical Reports Server (NTRS)

The statutory standards underlying the activities of the FDA, and the problems the Agency faces in decision making are discussed from a legal point of view. The premarketing clearance of new drugs and of food additives, the two most publicized and criticized areas of FDA activity, are used as illustrations. The importance of statutory standards in technology assessment in a regulatory setting is developed. The difficulties inherent in the formulation of meaningful standards are recognized. For foods, the words of the statute are inadequate, and for drugs, a statutory recognition of the various other objectives would be useful to the regulator and the regulated.

Kaplan, A. H.; Becker, R. H.

1972-01-01

55

Probabilistic modeling of percutaneous absorption for risk-based exposure assessments and transdermal drug delivery.  

SciTech Connect

Chemical transport through human skin can play a significant role in human exposure to toxic chemicals in the workplace, as well as to chemical/biological warfare agents in the battlefield. The viability of transdermal drug delivery also relies on chemical transport processes through the skin. Models of percutaneous absorption are needed for risk-based exposure assessments and drug-delivery analyses, but previous mechanistic models have been largely deterministic. A probabilistic, transient, three-phase model of percutaneous absorption of chemicals has been developed to assess the relative importance of uncertain parameters and processes that may be important to risk-based assessments. Penetration routes through the skin that were modeled include the following: (1) intercellular diffusion through the multiphase stratum corneum; (2) aqueous-phase diffusion through sweat ducts; and (3) oil-phase diffusion through hair follicles. Uncertainty distributions were developed for the model parameters, and a Monte Carlo analysis was performed to simulate probability distributions of mass fluxes through each of the routes. Sensitivity analyses using stepwise linear regression were also performed to identify model parameters that were most important to the simulated mass fluxes at different times. This probabilistic analysis of percutaneous absorption (PAPA) method has been developed to improve risk-based exposure assessments and transdermal drug-delivery analyses, where parameters and processes can be highly uncertain.

Ho, Clifford Kuofei

2004-06-01

56

Assessment Issues in Adolescent Drug Abuse Treatment Research  

Microsoft Academic Search

Experimentation with alcohol and other drugs (AOD) is commonplace among American adolescents. Despite reduction efforts, the\\u000a use of AOD by adolescents has increased over the past decade. A number of youth experience significant negative personal,\\u000a societal, economic, and health ramifications, but continue to abuse AOD and develop substance use disorders (SUD). Accurate\\u000a assessment of adolescent AOD use is essential in

Ken C. Winters; Tamara Fahnhorst

57

Risk Assessment Principle for Engineered Nanotechnology in Food and Drug  

PubMed Central

While the ability to develop nanomaterials and incorporate them into products is advancing rapidly worldwide, understanding of the potential health safety effects of nanomaterials has proceeded at a much slower pace. Since 2008, Korea Food and Drug Administration (KFDA) started an investigation to prepare “Strategic Action Plan” to evaluate safety and nano risk management associated with foods, drugs, medical devices and cosmetics using nano-scale materials. Although there are some studies related to potential risk of nanomaterials, physical-chemical characterization of nanomaterials is not clear yet and these do not offer enough information due to their limitations. Their uncertainties make it impossible to determine whether nanomaterials are actually hazardous to human. According to the above mention, we have some problems to conduct the human exposure risk assessment currently. On the other hand, uncertainty about safety may lead to polarized public debate and to businesses unwillingness for further nanotechnology investigation. Therefore, the criteria and methods to assess possible adverse effects of nanomaterials have been vigorously taken into consideration by many international organizations: the World Health Organization, the Organization for Economic and Commercial Development and the European Commission. The object of this study was to develop risk assessment principles for safety management of future nanoproducts and also to identify areas of research to strengthen risk assessment for nanomaterials. The research roadmaps which were proposed in this study will be helpful to fill up the current gaps in knowledge relevant nano risk assessment. PMID:24278592

Hwang, Myungsil; Lee, Eun Ji; Kweon, Se Young; Park, Mi Sun; Jeong, Ji Yoon; Um, Jun Ho; Kim, Sun Ah; Han, Bum Suk; Lee, Kwang Ho

2012-01-01

58

Neurotoxicity of digitoxin in adult and newborn rats: drug distribution.  

PubMed

Electrocardiographic monitoring of adult and 1 week old (newborn) rats during severe acute digitoxin toxicity demonstrated a lack of acrdiotoxicity despite marked neurotoxicity in both age groups. To examine the possibility that drug disposition is a factor in the unusual digitoxin sensitivity of newborn rats, 3H-digitoxin distribution in liver, heart, brain, kidney, adrenal, blood and fat was compared in 1 and 3 week old (weanling) rats at 2, 12 and 24 hr. H3-label was rapidly sequestered by the liver in weanlings but not in newborn rats. Newborns had significantly higher concentrations of 3H-substance in all other organs, particularly in brain (greater than 25% of the administered dose at 24 hr), indicating a cerebrotoxic basis for the newborn's sensitivity to digitoxin. Only trace amounts of 3H-substance were recovered from adult rat brain during severe neurotoxicity (72 hr) suggesting that digitoxin metabolites may be potent cerebrotoxins. Extremely high adrenal concentrations were noted in all animals. PMID:1015912

Boor, P J; Reynolds, E S; Moslen, M T

1976-11-01

59

Drug safety assessment in clinical trials: methodological challenges and opportunities.  

PubMed

Randomized controlled trials are the principal means of establishing the efficacy of drugs. However pre-marketing trials are limited in size and duration and exclude high-risk populations. They have limited statistical power to detect rare but potentially serious adverse events in real-world patients. We summarize the principal methodological challenges in the reporting, analysis and interpretation of safety data in clinical trials using recent examples from systematic reviews. These challenges include the lack of an evidentiary gold standard, the limited statistical power of randomized controlled trials and resulting type 2 error, the lack of adequate ascertainment of adverse events and limited generalizability of trials that exclude high risk patients. We discuss potential solutions to these challenges. Evaluation of drug safety requires careful examination of data from heterogeneous sources. Meta-analyses of drug safety should include appropriate statistical methods and assess the optimal information size to avoid type 2 errors. They should evaluate outcome reporting biases and missing data to ensure reliable and accurate interpretation of findings. Regulatory and academic partnerships should be fostered to provide an independent and transparent evaluation of drug safety. PMID:22906139

Singh, Sonal; Loke, Yoon K

2012-01-01

60

The assessment of impurities for genotoxic potential and subsequent control in drug substance and drug product.  

PubMed

The strategies implemented at Eli Lilly and Company to address European Medicines Agency and US Food and Drug Administration requirements governing the control of genotoxic impurities (GTIs) are presented. These strategies were developed to provide understanding with regard to the risk and potential liabilities that could be associated with developmental and marketed compounds. The strategies systematize the assessment of impurities for genotoxic potential, addressing both actual and potential impurities. Timing of activities is designed to minimize impact to development timelines while building a data package sufficient to either discharge the risk of potential GTI formation or support the implementation of a specification necessary for long-term control. This article presents the background associated with GTI control, the types of impurities that should be assessed, and the actions to be taken when an impurity is found to be genotoxic. A systematic approach to define potential degradation products derived from stress-testing studies is outlined with a proposal to perform a genotoxic risk assessment on these impurities. Finally, an Arrhenius-based strategy is proposed for a rapid assessment of the likelihood of potential degradation impurities to form in the commercial drug product formulation. Importantly, this article makes a proposal for discharging the risk of a potential GTI with supporting data. PMID:23436613

Dow, Linda K; Hansen, Marvin M; Pack, Brian W; Page, Todd J; Baertschi, Steven W

2013-05-01

61

Validation of pharmacy records in drug exposure assessment  

Microsoft Academic Search

The validity of drug exposure measurement based on pharmacy records was investigated taking into account completeness of data, drug compliance, and different methods of drug exposure measurement in pharmacy records. Data on prescription drug use were collected from home inventories and community pharmacies in a survey on drug use and compliance in 115 elderly people. To compare drug exposure in

Hong S. Lau; Anthonius de Boer; Karin S. Beuning; Arijan Porsius

1997-01-01

62

High-throughput screening of drug-binding dynamics to HERG improves early drug safety assessment.  

PubMed

The use of computational models to predict drug-induced changes in the action potential (AP) is a promising approach to reduce drug safety attrition but requires a better representation of more complex drug-target interactions to improve the quantitative prediction. The blockade of the human ether-a-go-go-related gene (HERG) channel is a major concern for QT prolongation and Torsade de Pointes risk. We aim to develop quantitative in-silico AP predictions based on a new electrophysiological protocol (suitable for high-throughput HERG screening) and mathematical modeling of ionic currents. Electrophysiological recordings using the IonWorks device were made from HERG channels stably expressed in Chinese hamster ovary cells. A new protocol that delineates inhibition over time was applied to assess dofetilide, cisapride, and almokalant effects. Dynamic effects displayed distinct profiles for these drugs compared with concentration-effects curves. Binding kinetics to specific states were identified using a new HERG Markov model. The model was then modified to represent the canine rapid delayed rectifier K(+) current at 37°C and carry out AP predictions. Predictions were compared with a simpler model based on conductance reduction and were found to be much closer to experimental data. Improved sensitivity to concentration and pacing frequency variables was obtained when including binding kinetics. Our new electrophysiological protocol is suitable for high-throughput screening and is able to distinguish drug-binding kinetics. The association of this protocol with our modeling approach indicates that quantitative predictions of AP modulation can be obtained, which is a significant improvement compared with traditional conductance reduction methods. PMID:23103500

Di Veroli, Giovanni Y; Davies, Mark R; Zhang, Henggui; Abi-Gerges, Najah; Boyett, Mark R

2013-01-01

63

21 CFR 212.90 - What actions must I take to control the distribution of PET drug products?  

Code of Federal Regulations, 2013 CFR

...must I take to control the distribution of PET drug products? 212.90 Section 212...must I take to control the distribution of PET drug products? (a) Written distribution...procedures for the control of distribution of PET drug products shipped from the PET...

2013-04-01

64

21 CFR 212.90 - What actions must I take to control the distribution of PET drug products?  

Code of Federal Regulations, 2012 CFR

...must I take to control the distribution of PET drug products? 212.90 Section 212...must I take to control the distribution of PET drug products? (a) Written distribution...procedures for the control of distribution of PET drug products shipped from the PET...

2012-04-01

65

21 CFR 212.90 - What actions must I take to control the distribution of PET drug products?  

Code of Federal Regulations, 2010 CFR

...must I take to control the distribution of PET drug products? 212.90 Section 212...must I take to control the distribution of PET drug products? (a) Written distribution...procedures for the control of distribution of PET drug products shipped from the PET...

2010-04-01

66

21 CFR 212.90 - What actions must I take to control the distribution of PET drug products?  

Code of Federal Regulations, 2011 CFR

...must I take to control the distribution of PET drug products? 212.90 Section 212...must I take to control the distribution of PET drug products? (a) Written distribution...procedures for the control of distribution of PET drug products shipped from the PET...

2011-04-01

67

Distribution and clearance of PEG-single-walled carbon nanotube cancer drug delivery vehicles in mice  

PubMed Central

Aims To study the distribution and clearance of polyethylene glycol (PEG)-ylated single-walled carbon nanotube (SWCNTs) as drug delivery vehicles for the anticancer drug cisplatin in mice. Materials & methods PEG layers were attached to SWCNTs and dispersed in aqueous media and characterized using dynamic light scattering, scanning transmission electron microscopy and Raman spectroscopy. Cytotoxicity was assessed in vitro using Annexin-V assay, and the distribution and clearance pathways in mice were studied by histological staining and Raman spectroscopy. Efficacy of PEG-SWCNT–cisplatin for tumor growth inhibition was studied in mice. Results & discussion PEG-SWCNTs were efficiently dispersed in aqueous media compared with controls, and did not induce apoptosis in vitro. Hematoxylin and eosin staining, and Raman bands for SWCNTs in tissues from several vital organs from mice injected intravenously with nanotube bioconjugates revealed that control SWCNTs were lodged in lung tissue as large aggregates compared with the PEG-SWCNTs, which showed little or no accumulation. Characteristic SWCNT Raman bands in feces revealed the presence of bilary or renal excretion routes. Attachment of cisplatin on bioconjugates was visualized with Z-contrast scanning transmission electron microscopy. PEG-SWCNT–cisplatin with the attached targeting ligand EGF successfully inhibited growth of head and neck tumor xenografts in mice. Conclusions PEG-SWCNTs, as opposed to control SWCNTs, form more highly dispersed delivery vehicles that, when loaded with both cisplatin and EGF, inhibit growth of squamous cell tumors. PMID:21143032

Bhirde, Ashwin A; Patel, Sachin; Sousa, Alioscka A; Patel, Vyomesh; Molinolo, Alfredo A; Ji, Youngmi; Leapman, Richard D; Gutkind, J Silvio; Rusling, James F

2011-01-01

68

Spatial distribution and characteristics of injecting drug users (IDU) in five Northeastern states of India  

PubMed Central

Background Injecting drugs is the major driving force of human immunodeficiency virus (HIV) epidemic in Northeastern India. We have assessed the spatial distribution of locations where injecting drug users (IDU) congregate, as well as the risk behaviour and key characteristics of IDUs to develop new strategies strengthening intervention measures for HIV prevention in this region. Methods Locations of IDUs congregation for buying and injecting drugs were identified through Key Informants (KI). Verification of the location and its characteristics were confirmed through field visits. We also conducted semi-structured and structured interviews with IDUs to learn more about their injecting behaviour and other characteristics. Results Altogether, 2462 IDU locations were identified in 5 states. The number of IDU locations was found to be greater in the states bordering Myanmar. Private houses, parks, abandoned buildings, pharmacies, graveyards, and isolated places were the most frequently chosen place for injecting drugs. Many injecting locations were visited by IDUs of varying ages, of which about 10-20% of locations were for females. In some locations, female IDUs were also involved in sex work. Sharing of needle and syringes was reported in all the states by large proportion of IDUs, mainly with close friends. However, even sharing with strangers was not uncommon. Needle and syringes were mainly procured from pharmacies, drug peddlers and friends. Lack of access to free sterile needles and syringes, and inconsistent supplies from intervention programs, were often given as the cause of sharing or re-use of needles and syringes by IDUs. Most of the IDUs described a negative attitude of the community towards them. Conclusion We highlight the injection of drugs as a problem in 5 Northeastern India states where this is the major driving force of an HIV epidemic. Also highlighted are the large numbers of females that are unrecognized as IDUs and the association between drug use and sex work. Understanding of risk behaviours and other key charecteristics of IDUs in the region will help in strengthening harm reduction efforts that can prevent HIV transmission. PMID:21281465

2011-01-01

69

A Drug Education Needs Assessment in a Rural Elementary School System: Results and Curriculum Recommendations.  

ERIC Educational Resources Information Center

This report presents the results of a needs assessment study on comprehensive drug education conducted for a small rural K-8 school. A brief review examines the literature on drug and alcohol abuse among rural youth. Parents, teachers, and students were surveyed to assess their needs, interests, and knowledge of drug and alcohol abuse. Twenty…

Sarvela, Paul D.; And Others

70

75 FR 4400 - Draft Guidance for Industry on Assessment of Abuse Potential of Drugs; Availability  

Federal Register 2010, 2011, 2012, 2013

...Guidance for Industry on Assessment of Abuse Potential of Drugs; Availability AGENCY: Food...industry entitled ``Assessment of Abuse Potential of Drugs.'' This draft guidance is...drug and other medical products with the potential for abuse that may need to be...

2010-01-27

71

Single Cell Analysis of Drug Distribution by Intravital Imaging  

PubMed Central

Recent advances in the field of intravital imaging have for the first time allowed us to conduct pharmacokinetic and pharmacodynamic studies at the single cell level in live animal models. Due to these advances, there is now a critical need for automated analysis of pharmacokinetic data. To address this, we began by surveying common thresholding methods to determine which would be most appropriate for identifying fluorescently labeled drugs in intravital imaging. We then developed a segmentation algorithm that allows semi-automated analysis of pharmacokinetic data at the single cell level. Ultimately, we were able to show that drug concentrations can indeed be extracted from serial intravital imaging in an automated fashion. We believe that the application of this algorithm will be of value to the analysis of intravital microscopy imaging particularly when imaging drug action at the single cell level. PMID:23593370

Giedt, Randy J.; Koch, Peter D.; Weissleder, Ralph

2013-01-01

72

LBNL -50132 Assessment of Grid Distributed Energy Resource Potential  

E-print Network

LBNL -50132 Assessment of µGrid Distributed Energy Resource Potential Using DER-CAM and GIS Energy, Office of Power Technologies, Clean Energy Analysis Collaborative of the U.S. Department Berkeley National Laboratory is an equal opportunity employer. #12;Assessment of µGrid Distributed Energy

Kammen, Daniel M.

73

Residues of veterinary drugs in eggs and their distribution between yolk and white  

Microsoft Academic Search

Veterinary drugs and feed additives (especially some coccidiostats) can be absorbed by the digestive tract of laying hens and transferred to the egg. Physicochemical characteristics of these compounds determine their pharmacokinetic behavior and distribution to and within the egg. Traditionally the quite lipid soluble drugs and additives are expected to yield residues only in the fat-rich yolk. However, the quite

Cornelis A. Kan; Michael Petz

2000-01-01

74

Counterfeit or Substandard? The Role of Regulation and Distribution Channel in Drug Safety  

Microsoft Academic Search

Using 1437 samples of Ciprofloxacin from 18 low-to-middle-income countries, we aim to understand the role that regulation and distribution channel have played in signaling and ensuring drug safety. According to the World Health Organization, some poor quality drugs are deliberately and fraudulently mislabeled with respect to identity or source while others can have incorrect quantities of active ingredient as a

Roger Bate; Ginger Zhe Jin; Aparna Mathur

2012-01-01

75

Medication errors in hospital: computerized unit dose drug dispensing system versus ward stock distribution system  

Microsoft Academic Search

Aim: The aim of this study was to evaluate the rates and types of drug prescription and administration errors in one pediatric nephrology ward, comparing two dispensing schemes : the first one defined as handwritten prescription plus ward stock distribution system (WSDS), and the second one as computerized prescription plus unit dose drug dispensing system (UDDDS). Method: Data were collected

Jean-Eudes Fontan; Vincent Maneglier; V. X. Nguyen; F. Brion; C. Loirat

2003-01-01

76

Film Technique for Assessing Attitudes toward Drug Users.  

ERIC Educational Resources Information Center

A color, sound film depicting five young people discussing drug use was used to test participants in three workshops and two regular drug courses. Results suggest that initial exposure to drug training increases acceptance of drug use, perhaps by dispelling fearsome myths, but extended training reinstates rejection. (Author)

Ahlgren, Andrew; Eburne, Norman

1981-01-01

77

Assessing the freshwater distribution of yellow eel . Lasne(1)  

E-print Network

Assessing the freshwater distribution of yellow eel Ã?. Lasne(1) , P. Laffaille(1,2) ABSTRACT. A review of the literature suggests that eel size data could be used to assess and analyze freshwater for assessing yellow eel stages in freshwater areas, and should have concrete applications for management

Paris-Sud XI, Université de

78

Risk assessment of technologies for detecting illicit drugs in containers  

NASA Astrophysics Data System (ADS)

This paper provides the highlights of the role risk assessment plays in the United States technology program for nonintrusive inspection of cargo containers for illicit drugs. The Counterdrug Technology Assessment Center is coordinating the national effort to develop prototype technologies for an advanced generation, nonintrusive cargo inspection system. In the future, the U.S. Customs Service could configure advanced technologies for finding not only drugs and other contraband hidden in cargo, but for a wide variety of commodities for customs duty verification purposes. The overall nonintrusive inspection system is envisioned to consist primarily of two classes of subsystems: (1) shipment document examination subsystems to prescreen exporter and importer documents; and (2) chemical and physics-based subsystems to detect and characterize illicit substances. The document examination subsystems would use software algorithms, artificial intelligence, and neural net technology to perform an initial prescreening of the information on the shipping manifest for suspicious patterns. This would be accomplished by creating a `profile' from the shipping information and matching it to trends known to be used by traffickers. The chemical and physics-based subsystems would apply nuclear physics, x-ray, gas chromatography and spectrometry technologies to locate and identify contraband in containers and other conveyances without the need for manual searches. The approach taken includes using technology testbeds to assist in evaluating technology prototypes and testing system concepts in a fully instrumented but realistic operational environment. This approach coupled with a substance signature phenomenology program to characterize those detectable elements of benign, as well as target substances lends itself particularly well to the topics of risk assessment and elemental characterization of substances. A technology testbed established in Tacoma, Washington provides a national facility for testing and evaluating existing and emerging prototype systems in an operational environment. The results of initial tests using the advanced x-ray subsystem installed at the testbed are given in this paper. A description of typical cargo contents and those characteristics applicable to nuclear interrogation techniques are provided in the appendix.

Brandenstein, Albert E.

1995-03-01

79

Pharmacokinetic characterization and tissue distribution of the new glucocorticoid soft drug loteprednol etabonate in rats and dogs.  

PubMed

Loteprednol etabonate, a new glucocorticoid soft drug with a characteristic chloromethyl ester function in the 17 beta-position, is currently in the early phases of clinical development. As the basis for human trials, this study describes a new reversed-phase high-performance liquid chromatographic method for the determination of levels of drug in plasma and urine samples and assesses the pharmacokinetic properties of loteprednol etabonate in dogs and rats. Intravenous administration of loteprednol etabonate (5 mg/kg) to dogs revealed a terminal half-life of 2.8 h, a volume of distribution of 3.7 L/kg, and a total body clearance of 0.9 L/h/kg. Intact loteprednol etabonate was not detectable in the urine. After oral administration of the drug (5 mg/kg) to dogs, only metabolites, but no intact drug, were found in the plasma, an indication for a high first-pass effect. A pronounced binding of the drug to plasma protein (> 90%) and a high erythrocyte-buffer partition coefficient of 7.8 were determined in vitro. Preliminary information about tissue distribution and possible metabolic pathways were obtained in rats after oral administration of a 14C-labeled loteprednol etabonate suspension (5 mg/kg). pH-selective extraction into ethyl acetate revealed three distinguishable fractions: (1) a neutral lipophilic fraction, presumably intact drug, (2) an acidic, lipophilic fraction, and (3) a hydrophilic nonextractable fraction. Levels of intact drug and metabolites were highest in liver and kidney, whereas significantly lower levels were found in other investigated organs (lung, brain, heart).(ABSTRACT TRUNCATED AT 250 WORDS) PMID:1491342

Hochhaus, G; Chen, L S; Ratka, A; Druzgala, P; Howes, J; Bodor, N; Derendorf, H

1992-12-01

80

Combined neuropsychological and neurophysiological assessment of drug effects on groups and individuals  

Microsoft Academic Search

An initial standardized approach for combining neuropsychological and neurophysiological measures in order to assess the neurocognitive effects of drugs in groups and individuals is introduced. Its application is illustrated with sedatives, antiepileptic drugs, psychostimulants, antihistamines, and intoxicants. Task performance, electroencephalography, and evoked potential measures during computerized attention and memory testing that are most sensitive to drug effects are identified in

Alan Gevins; Aaron B Ilan; An Jiang; Lita Sam-Vargas; Cliff Baum; Cynthia S Chan

2011-01-01

81

Anticancer efficacy and absorption, distribution, metabolism, and toxicity studies of Aspergiolide A in early drug development  

PubMed Central

Since the first anthracycline was discovered, many other related compounds have been studied in order to overcome its defects and improve efficacy. In the present paper, we investigated the anticancer effects of a new anthracycline, aspergiolide A (ASP-A), from a marine-derived fungus in vitro and in vivo, and we evaluated the absorption, distribution, metabolism, and toxicity drug properties in early drug development. We found that ASP-A had activity against topoisomerase II that was comparable to adriamycin. ASP-A decreased the growth of various human cancer cells in vitro and induced apoptosis in BEL-7402 cells via a caspase-dependent pathway. The anticancer efficacy of ASP-A on the growth of hepatocellular carcinoma xenografts was further assessed in vivo. Results showed that, compared with the vehicle group, ASP-A exhibited significant anticancer activity with less loss of body weight. A pharmacokinetics and tissue distribution study revealed that ASP-A was rapidly cleared in a first order reaction kinetics manner, and was enriched in cancer tissue. The maximal tolerable dose (MTD) of ASP-A was more than 400 mg/kg, and ASP-A was not considered to be potentially genotoxic or cardiotoxic, as no significant increase of micronucleus rates or inhibition of the hERG channel was seen. Finally, an uptake and transport assay of ASP-A was performed in monolayers of Caco-2 cells, and ASP-A was shown to be absorbed through the active transport pathway. Altogether, these results indicate that ASP-A has anticancer activity targeting topoisomerase II, with a similar structure and mechanism to adriamycin, but with much lower toxicity. Nonetheless, further molecular structure optimization is necessary. PMID:25378909

Wang, Yuanyuan; Qi, Xin; Li, Dehai; Zhu, Tianjiao; Mo, Xiaomei; Li, Jing

2014-01-01

82

Assessment of distributed photovoltair electric-power systems  

NASA Astrophysics Data System (ADS)

The development of a methodology to assess the potential impacts of distributed photovoltaic (PV) systems on electric utility systems, including subtransmission and distribution networks, and to apply that methodology to several illustrative examples was developed. The investigations focused upon five specific utilities. Impacts upon utility system operations and generation mix were assessed using accepted utility planning methods in combination with models that simulate PV system performance and life cycle economics. Impacts on the utility subtransmission and distribution systems were also investigated. The economic potential of distributed PV systems was investigated for ownership by the utility as well as by the individual utility customer.

Neal, R. W.; Deduck, P. F.; Marshall, R. N.

1982-10-01

83

Distribution of genetic polymorphisms of genes encoding drug metabolizing enzymes & drug transporters - a review with Indian perspective  

PubMed Central

Phase I and II drug metabolizing enzymes (DME) and drug transporters are involved in the absorption, distribution, metabolism as well as elimination of many therapeutic agents, toxins and various pollutants. Presence of genetic polymorphisms in genes encoding these proteins has been associated with marked inter-individual variability in their activity that could result in variation in drug response, toxicity as well as in disease predisposition. The emergent field pharmacogenetics and pharmacogenomics (PGx) is a promising discipline, as it predicts disease risk, selection of proper medication with regard to response and toxicity, and appropriate drug dosage guidance based on an individual's genetic make-up. Consequently, genetic variations are essential to understand the ethnic differences in disease occurrence, development, prognosis, therapeutic response and toxicity. For that reason, it is necessary to establish the normative frequency of these genes in a particular population before unraveling the genotype-phenotype associations. Although a fair amount of allele frequency data are available in Indian populations, the existing pharmacogenetic data have not been compiled into a database. This review was intended to compile the normative frequency distribution of the variants of genes encoding DMEs (CYP450s, TPMT, GSTs, COMT, SULT1A1, NAT2 and UGTs) and transporter proteins (MDR1, OCT1 and SLCO1B1) with Indian perspective. PMID:24604039

Umamaheswaran, Gurusamy; Kumar, Dhakchinamoorthi Krishna; Adithan, Chandrasekaran

2014-01-01

84

Rapid Assessment of Drug Susceptibilities of Mycobacterium tuberculosis by Means of Luciferase Reporter Phages  

Microsoft Academic Search

Effective chemotherapy of tuberculosis requires rapid assessment of drug sensitivity because of the emergence of multidrug-resistant Mycobacterium tuberculosis. Drug susceptibility was assessed by a simple method based on the efficient production of photons by viable mycobacteria infected with specific reporter phages expressing the firefly luciferase gene. Light production was dependent on phage infection, expression of the luciferase gene, and the

William R. Jacobs Jr.; Raul G. Barletta; Rupa Udani; John Chan; Gary Kalkut; Gabriel Sosne; Tobias Kieser; Gary J. Sarkis; Graham F. Hatfull; Barry R. Bloom

1993-01-01

85

21 CFR 212.90 - What actions must I take to control the distribution of PET drug products?  

21 Food and Drugs 4 2014-04-01 2014-04-01 false What actions must I take to control the distribution of PET drug products? 212.90 Section 212.90 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF...

2014-04-01

86

Assessing Foodshelves' Ability to Distribute Healthy Foods to Foodshelf Clients  

Microsoft Academic Search

Foodshelves provide a vital service of distributing food to food insecure families, but the resources foodshelves have to source and distribute healthy food and the extent to which this emergency food is healthy have not been evaluated. All member foodshelves of the Emergency Foodshelf Network (n = 58), a food bank in Minnesota, were sent a survey that assessed resources

Jessica S. Rochester; Marilyn S. Nanney; Mary Story

2011-01-01

87

Sex, drugs, and HIV: Rapid assessment of HIV risk behaviors among street-based drug using sex workers in Durban, South Africa  

Microsoft Academic Search

South Africa is experiencing significant changes in patterns of illicit drug use, including increasing injection and non-injection drug use, and the use of drugs by persons engaged in sex work, both of which could further expand the HIV\\/AIDS epidemic. In 2005, a rapid ethnographic assessment was conducted in Durban, South Africa, to learn more about patterns of drug use and

Richard Needle; Karen Kroeger; Hrishikesh Belani; Angeli Achrekar; Charles D. Parry; Sarah Dewing

2008-01-01

88

Income distribution and risk of fatal drug overdose in New York City neighborhoods  

Microsoft Academic Search

Accidental drug overdose is a substantial cause of mortality for drug users. Neighborhood-level factors, such as income distribution, may be important determinants of overdose death independent of individual-level factors. We used data from the Office of the Chief Medical Examiner to identify all cases of accidental deaths in New York City (NYC) in 1996 and individual-level covariates. We used 1990

Sandro Galea; Jennifer Ahern; David Vlahov; Phillip O Coffin; Crystal Fuller; Andrew C Leon; Kenneth Tardiff

2003-01-01

89

Absorption, distribution, metabolism, and excretion considerations for the development of antibody-drug conjugates.  

PubMed

Antibody-drug conjugates (ADCs) are a class of therapeutics that are designed to deliver potent small-molecule drugs selectively to cells that express a specific target antigen while limiting systemic exposure to the drug. This is accomplished by conjugating a potent drug onto an antibody-based therapeutic with a linker that is exquisitely stable in plasma. The development of an effective ADC requires optimizing a number of design elements and an extensive understanding of absorption, distribution, metabolism/catabolism, and elimination (ADME) processes for the ADC construct. Furthermore, as ADCs are a combination of an antibody and small-molecule drug, understanding key aspects of the ADME of each individual component is needed. This review aims to provide considerations for the development of ADCs from an ADME point of view. PMID:25048520

Han, Tae H; Zhao, Baiteng

2014-11-01

90

Convection-enhanced distribution of large molecules in gray matter during interstitial drug infusion.  

PubMed

Many novel experimental therapeutic agents, such as neurotrophic factors, enzymes, biological modifiers, and genetic vectors, do not readily cross the blood-brain barrier. An effective strategy to deliver these compounds to the central nervous system is required for their application in vivo. Under normal physiological conditions, brain interstitial fluid moves by both bulk flow (convection) and diffusion. It has recently been shown that interstitial infusion into the white matter can be used to increase bulk flow, produce interstitial convection, and efficiently and homogeneously deliver drugs to large regions of brain without significant functional or structural damage. In theory, even more uniform distribution is likely in gray matter. In the current study, four experiments were performed to examine if convection-enhanced delivery could be used to achieve regional distribution of large molecules in gray matter. First, the volume and consistency of anatomical distribution of 20 microliters of phaseolus vulgaris-leukoagglutinin (PHA-L; molecular weight (MW) 126 kD) after continuous high-flow microinfusion into the striatum of five rats over 200 minutes were determined using immunocytochemistry and quantified with image analysis. Second, the concentration profile of 14C-albumin (MW 69 kD) infused under identical conditions was determined in four hemispheres using quantitative autoradiography. Third, the volume of distribution after convection-enhanced infusion of 250 or 500 microliters biotinylated dextran (b-dextran, MW 10 kD), delivered over 310 minutes into the caudate and putamen of a rhesus monkey from one (250 microliters) or two (500 microliters) cannulas, was determined using immunocytochemistry and quantified with image analysis. Finally, the ability to target all dopaminergic neurons of the nigrostriatal tract via perfusion of the striatum with subsequent retrograde transport was assessed in three experiments by immunohistochemical analysis of the mesencephalon following a 300-minute infusion of 27 microliters horseradish peroxidase-labeled wheat germ agglutinin (WGA-HRP) into the striatum. Convection-enhanced delivery reproducibly distributed the large-compound PHA-L throughout the rat striatum (the percent volume of the striatum perfused, Vs, was 86% +/- 5%; mean +/- standard deviation) and produced a homogeneous tissue concentration in the perfused region (concentration of 14C-albumin relative to infusate concentration 30% +/- 5%). In the monkey, the infusion widely distributed b-dextran within the striatum using one cannula (caudate and putamen Vs = 76% and 76%) or two cannulas (Vs = 90% and 71%).(ABSTRACT TRUNCATED AT 400 WORDS) PMID:7539062

Lieberman, D M; Laske, D W; Morrison, P F; Bankiewicz, K S; Oldfield, E H

1995-06-01

91

Quantitative Assessment of Distributed Energy Resource Benefits  

SciTech Connect

Distributed energy resources (DER) offer many benefits, some of which are readily quantified. Other benefits, however, are less easily quantifiable because they may require site-specific information about the DER project or analysis of the electrical system to which the DER is connected. The purpose of this study is to provide analytical insight into several of the more difficult calculations, using the PJM power pool as an example. This power pool contains most of Pennsylvania, New Jersey, Maryland, and Delaware. The techniques used here could be applied elsewhere, and the insights from this work may encourage various stakeholders to more actively pursue DER markets or to reduce obstacles that prevent the full realization of its benefits. This report describes methodologies used to quantify each of the benefits listed in Table ES-1. These methodologies include bulk power pool analyses, regional and national marginal cost evaluations, as well as a more traditional cost-benefit approach for DER owners. The methodologies cannot however determine which stakeholder will receive the benefits; that must be determined by regulators and legislators, and can vary from one location to another.

Hadley, S.W.

2003-05-22

92

Principles of initial experimental drug abuse liability assessment in humans  

Microsoft Academic Search

This paper describes the rationale and procedures for conducting what is considered by many to be the current “gold standard” for initial abuse liability testing of a novel compound: the classic acute dose–effect comparison study in volunteers with histories of drug abuse. Such a trial is most appropriate for predicting the likelihood of abuse by drug abusers and, in turn,

Roland R. Griffiths; George E. Bigelow; Nancy A. Ator

2003-01-01

93

A practical assessment of transdermal drug delivery by skin electroporation  

Microsoft Academic Search

Transdermal drug delivery has many potential advantages, but the skin's poorly-permeable stratum corneum blocks delivery of most drugs at therapeutic levels. Short high-voltage pulses have been used to electroporate the skin's lipid bilayer barriers and thereby deliver compounds at rates increased by as much as four orders of magnitude. Evidence that the observed flux enhancement is due to physical alteration

Mark R Prausnitz

1999-01-01

94

Assessing Nigeria’s drug control policy, 1994–2000  

Microsoft Academic Search

Drugs became a public issue in Nigeria by the 1960s with discoveries of cannabis farms in the country, arrests of Nigerian cannabis traffickers abroad, and reports of psychological disorders suspected to be associated with cannabis use. However, it was not until the early 1980s that the problem of drug trafficking had become a major social issue with the potential of

Isidore S Obot

2004-01-01

95

Look Alike\\/ Sound Alike Algorithms for Assessing Drug Name Similarities  

Microsoft Academic Search

1.0 Background Approximately 12.5 percent of the medication errors reported to the FDA are a result of confusion between drug names, which can have a direct and serious health consequence to a patient. Factors contributing to the confusion include illegible handwriting, similar packaging and labeling, incorrect selection from a computerized list, incomplete knowledge of drug names, newly available products, or

Erica Kolatch; Jessica Toye; Bonnie Dorr

2004-01-01

96

An Assessment of Drug Testing within the Construction Industry.  

ERIC Educational Resources Information Center

Investigates the efficacy of workplace drug-testing programs in reducing injury incident rates and workers' compensation experience-rating modification factors within the construction industry. Analyses indicate that companies with drug-testing programs experienced a 51 percent reduction in incident rates within two years of implementation.…

Gerber, Jonathan K.; Yacoubian, George S., Jr.

2002-01-01

97

Plasmodium falciparum Drug Resistance Phenotype as Assessed by Patient Antimalarial Drug Levels and Its Association With pfmdr1 Polymorphisms  

PubMed Central

Background.?Multidrug-resistant Plasmodium falciparum is a major threat to global malaria control. Parasites develop resistance by gradually acquiring genetic polymorphisms that decrease drug susceptibility. The aim of this study was to investigate the extent to which parasites with different genetic characteristics are able to withstand individual drug blood concentrations. Methods.?We analyzed 2 clinical trials that assessed the efficacy and effectiveness of artemether-lumefantrine. As a proof of concept, we used measured day 7 lumefantrine concentrations to estimate the concentrations at which reinfections multiplied. P. falciparum multidrug resistance gene 1 (pfmdr1) genotypes of these parasites were then correlated to drug susceptibility. Results.?Reinfecting parasites with the pfmdr1 N86/184F/D1246 haplotype were able to withstand lumefantrine blood concentrations 15-fold higher than those with the 86Y/Y184/1246Y haplotype. Conclusions.?By estimating drug concentrations, we were able to quantify the contribution of pfmdr1 single-nucleotide polymorphisms to reduced lumefantrine susceptibility. The method can be applied to all long–half-life antimalarial drugs, enables early detection of P. falciparum with reduced drug susceptibility in vivo, and represents a novel way for unveiling molecular markers of antimalarial drug resistance. PMID:23225895

Malmberg, Maja; Ferreira, Pedro E.; Tarning, Joel; Ursing, Johan; Ngasala, Billy; Bjorkman, Anders; Martensson, Andreas; Gil, Jose P.

2013-01-01

98

Assessment of Club Patrons' Alcohol and Drug Use  

PubMed Central

Background Young adulthood (ages 18–25 years) represents a time when high-risk behaviors, including alcohol and drug use, peak. Electronic music dance events (EMDEs) featured at clubs provide an ecologic niche for these high-risk behaviors. Purpose This paper examines the prevalence of alcohol and drug use among EMDE patrons. Examination of personal characteristics associated with exit levels of alcohol and drug use identifies important indicators of risk taking for prevention strategies. Methods Data were collected anonymously during 2010–2012 from 2028 patrons as they entered and exited clubs in the San Francisco Bay area featuring EMDEs. Nearly half were aged ?25 years. Biological measures of drug and alcohol and self-reported personal characteristics were attained. Analyses were completed in 2012. Results At entrance, more than one fifth of patrons were positive for drug use and one fourth arrived either impaired (blood alcohol concentration [BAC]: 0.05%–0.079%) or intoxicated (BAC: >0.08%) by alcohol. At exit, one fourth tested positive for drugs, and nearly half were impaired or intoxicated by alcohol. Individual characteristics that were important for levels of risk included prior alcohol use behaviors, sexual identity, ethnic/racial identity, and transportation to the event. Gender did not differentiate for alcohol use but fewer women used drugs. Conclusions Findings confirm the importance of targeting EMDEs for prevention efforts. EMDEs attract young working adults who are engaged in heavy alcohol and/or drug use. Targeting these social settings for delivering public health prevention strategies regarding alcohol and drug use and related harms is indicated by the findings. PMID:24139778

Miller, Brenda A.; Byrnes, Hilary F.; Branner, Amy C.; Voas, Robert; B. Johnson, Mark

2014-01-01

99

Influence of drug distribution and solubility on release from geopolymer pellets--a finite element method study.  

PubMed

This study investigates the influence of drug solubility and distribution on its release from inert geopolymer pellets of three different sizes (1.5 × 1.5, 3 × 6, and 6 × 6 mm), having the same geopolymer composition and containing highly potent opioid fentanyl, sumatriptan, theophylline, or saccharin. Scanning electron microscopy, nitrogen sorption, drug solubility, permeation, and release experiments were performed, and estimates of the drug diffusion coefficients and solubilities in the geopolymer matrix were derived with the aid of finite element method (FEM). FEM was further employed to investigate the effect of a nonuniform drug distribution on the drug release profile. When inspecting the release profiles for each drug, it was observed that their solubilities in the geopolymer matrix imposed a much greater influence on the drug release rate than their diffusion coefficients. Concentrating the initial drug load in FEM into nonuniformly distributed drug regions inside the matrix created drug release profiles that more closely resembled experimental data than an FEM-simulated uniform drug distribution did. The presented FEM simulations and visualization of drug release from geopolymers under varying initial and dynamic conditions should open up for more systematic studies of additional factors that influence the drug release profile from porous delivery vehicles. PMID:22308066

Jämstorp, Erik; Strømme, Maria; Bredenberg, Susanne

2012-05-01

100

Label-free imaging of drug distribution and metabolism in colon cancer cells by Raman  

E-print Network

K¨ottinga and Klaus Gerwert*a Targeted cancer therapies block cancer growth and spread using small targeting mechanism at the atomic level in cells. It demonstrates that Raman microscopy will open avenues of drugs, such as accumulation at the level of the targeted cell/tissue, is also desired. The distribution

Gerwert, Klaus

101

Hospital drug distribution systems in the UK and Germany ? a study of medication errors  

Microsoft Academic Search

The aim of this study was to compare the incidence of medication errors and the stages of the drug distribution system at which they occur in a United Kingdom (UK) hospital using the ward pharmacy system, a German hospital using the unit dose system and a German hospital using their traditional system. Medication errors were identified by observing the preparation

Katja Taxis; Bryony Dean; Nick Barber

1999-01-01

102

A Choice Procedure to Assess the Aversive Effects of Drugs in Rodents  

ERIC Educational Resources Information Center

The goal of this series of experiments was to develop an operant choice procedure to examine rapidly the punishing effects of intravenous drugs in rats. First, the cardiovascular effects of experimenter-administered intravenous histamine, a known aversive drug, were assessed to determine a biologically active dose range. Next, rats responded on…

Podlesnik, Christopher A.; Jimenez-Gomez, Corina; Woods, James H.

2010-01-01

103

Assessment of Alcohol and Other Drug Use Behaviors in Health Professions Students  

ERIC Educational Resources Information Center

Alcohol and other drug (AOD) use behaviors of health professions students (HPS) were assessed by surveying both university-based HPS and other nursing programs in a Midwestern state in 1999. Response was 2,646 (56.4%) of surveyed students. Family history of alcohol-related and drug-related problems were reported by 39.8% and 13.9%, respectively,…

Baldwin, Jeffrey N.; Scott, David M.; Agrawal, Sangeeta; Bartek, Jean K.; Davis-Hall, R. Ellen; Reardon, Thomas P.; DeSimone, Edward M., II

2006-01-01

104

Surveying Teens in School to Assess the Prevalence of Problematic Drug Use  

ERIC Educational Resources Information Center

Background: Illicit drug use by school-aged teens can adversely affect their health and academic achievement. This study used a survey administered in schools to assess the prevalence of problematic drug use among teenagers in a Midwestern community. Methods: Self-report data were collected from 11th- and 12th-grade students (N = 3974) in 16…

Falck, Russel S.; Nahhas, Ramzi W.; Li, Linna; Carlson, Robert G.

2012-01-01

105

Impact of biomarker development on drug safety assessment  

SciTech Connect

Drug safety has always been a key aspect of drug development. Recently, the Vioxx case and several cases of serious adverse events being linked to high-profile products have increased the importance of drug safety, especially in the eyes of drug development companies and global regulatory agencies. Safety biomarkers are increasingly being seen as helping to provide the clarity, predictability, and certainty needed to gain confidence in decision making: early-stage projects can be stopped quicker, late-stage projects become less risky. Public and private organizations are investing heavily in terms of time, money and manpower on safety biomarker development. An illustrative and 'door opening' safety biomarker success story is the recent recognition of kidney safety biomarkers for pre-clinical and limited translational contexts by FDA and EMEA. This milestone achieved for kidney biomarkers and the 'know how' acquired is being transferred to other organ toxicities, namely liver, heart, vascular system. New technologies and molecular-based approaches, i.e., molecular pathology as a complement to the classical toolbox, allow promising discoveries in the safety biomarker field. This review will focus on the utility and use of safety biomarkers all along drug development, highlighting the present gaps and opportunities identified in organ toxicity monitoring. A last part will be dedicated to safety biomarker development in general, from identification to diagnostic tests, using the kidney safety biomarkers success as an illustrative example.

Marrer, Estelle, E-mail: estelle.marrer@novartis.co [Translational Sciences, Novartis Institutes for Biomedical Research, CH-4002 Basel (Switzerland); Dieterle, Frank [Molecular Diagnostics, Novartis Pharma, CH-4002 Basel (Switzerland)

2010-03-01

106

Assessment of Drug Transporter Function Using Fluorescent Cell Imaging  

PubMed Central

ATP-binding cassette (ABC) proteins, including the breast cancer resistance protein (BCRP) and the multidrug resistance proteins (MDRs), actively transport structurally diverse chemicals from a number of tissues. Moreover, transporters are being increasingly cited as mediators of clinically relevant drug-drug interactions. The potential outcomes of concomitantly administering two drugs that interact at the same transporter include altered disposition and toxicity and/or efficacy of one or both of the drugs. Research demonstrating the role of transporters in clinical pharmacokinetics has shed light on the need for in vitro screening methods that detect drug-transporter interactions during preclinical development. This paper describes a cell-based model for the detection of functional inhibitors of BCRP and MDR1 by measuring fluorescent substrate accumulation in suspended cells that overexpress or endogenously express these proteins using an automated cell counter. An alternate protocol is provided describing the use of a spectrophotometer with fluorescence detection capabilities to identify functional inhibitors of BCRP and MDR1 in transporter overexpressing cells. While a spectrophotometer is available in most laboratories, an automatic cell counter offers convenience, sensitivity, and speed in measuring the cellular accumulation of fluorescent substrates and identification of novel inhibitors. PMID:24510579

Bircsak, Kristin M.; Gibson, Christopher J.; Robey, Robert W.

2013-01-01

107

Assessment of potential drug interactions by characterization of human drug metabolism pathways using non-invasive bile sampling  

PubMed Central

Aim Characterization of the biliary disposition of GSK1325756, using a non-invasive bile sampling technique and spectrometric analyses, to inform the major routes of metabolic elimination and to enable an assessment of victim drug interaction risk. Method Sixteen healthy, elderly subjects underwent non-invasive bile capture using a peroral string device (Entero-Test®) prior to and following a single oral dose of GSK1325756 (100 mg). The device was swallowed by each subject and once the weighted string was judged to have reached the duodenum, gallbladder contraction was stimulated in order to release bile. The string was then retrieved via the mouth and bile samples were analyzed for drug-related material using spectrometric and spectroscopic techniques following solvent extraction. Results Nuclear magnetic resonance spectroscopy (NMR) indicated that the O-glucuronide metabolite was the major metabolite of GSK1325756, representing approximately 80% of drug-related material in bile. As bile is the major clearance route for GSK1325756 (only 4% of the administered dose was excreted in human urine), this result indicates that uridine 5'-diphospho-glucuronosyltransferases (UGTs) are the major drug metabolizing enzymes responsible for drug clearance. The relatively minor contribution made by oxidative routes reduces the concern of CYP-mediated victim drug interactions. Conclusion The results from this study demonstrate the utility of deploying the Entero-Test® in early human studies to provide information on the biliary disposition of drugs and their metabolites. This technique can be readily applied in early clinical development studies to provide information on the risk of interactions for drugs that are metabolized and eliminated in bile. PMID:22670830

Bloomer, Jackie C; Nash, Mike; Webb, Alison; Miller, Bruce E; Lazaar, Aili L; Beaumont, Claire; Guiney, William J

2013-01-01

108

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...

109

Reliability of fuzzy risk assessment by information distribution  

Microsoft Academic Search

By reviewing approaches based on the method of information distribution to calculate fuzzy risk, we suggest two models for studying the reliability of fuzzy risk assessment. In particular, we confirm that a soft histogram estimate can improve a classical histogram estimate in raising 23% work efficiency, and the optimal scheme in reducing disaster based on a possibility-probability risk is more

Huang Chongfu

2000-01-01

110

Condition Assessment of Drinking Water Transmission and Distribution Systems  

EPA Science Inventory

Condition assessment of water transmission and distribution mains is the collection of data and information through direct and/or indirect methods, followed by analysis of the data and information, to make a determination of the current and/or future structural, water quality, an...

111

Observable Weight Distributions and Children's Individual Weight Assessment  

Microsoft Academic Search

Social networks theory suggests obesity is “contagious” within peer groups in that known friends highly influence weight. On the other hand, an alternative model suggests that observable weight distributions affect perception of one's own obesity level. We examine whether the BMI levels of the most obese classmates in the individual student's grade by gender is positively associated with “under-assessment” of

H. Shelton Brown; Alexandra E. Evans; Gita G. Mirchandani; Steven H. Kelder; Deanna M. Hoelscher

2010-01-01

112

Causality Assessment for Suspected DILI During Clinical Phases of Drug Development.  

PubMed

Causality assessment is a critical step in establishing the diagnosis of drug induced liver injury (DILI) during drug development. DILI may resemble almost any type of liver disease, and often presents a serious challenge to clinical investigators and drug makers. The diagnosis of DILI is largely based upon a combination of a compatible clinical course, exclusion of all other reasonable causes, resemblance of clinical and pathological features to known features of liver injury due to the drug (i.e., "drug's signature"), and incidence of liver injury among patients treated with the drug compared to placebo or comparator. Causality assessment for suspected DILI is currently performed using either evaluation by physicians with expertise in liver disorders (i.e., expert opinion) or standardized scoring instruments such as the Roussel Uclaf Causality Assessment Method (RUCAM). Both approaches are widely used in the post marketing setting. Causality assessment based on expert opinion is considered superior to standardized instruments such as RUCAM, in the setting of drug development, and is currently the preferred approach during clinical trials. There is a need for a systematic revision of RUCAM that will render it more suitable for the setting of clinical trials and drug development. Careful monitoring and meticulous data collection during clinical trials are essential in all cases with established liver injury to allow for a proper causality assessment. A workshop was convened to discuss best practices for the assessment of drug-induced liver injury (DILI) in clinical trials. This publication is based on the conclusions of this workshop. PMID:25352327

Regev, Arie; Seeff, Leonard B; Merz, Michael; Ormarsdottir, Sif; Aithal, Guruprasad P; Gallivan, Jim; Watkins, Paul B

2014-11-01

113

Similarity Between Obesity and Drug Addiction as Assessed  

E-print Network

for a decreased sensitivity of DA D2 regulated reward circuits. Understanding the mechanism in food intake, Overeating, and Pathological Attachment to Food: Independ- ent or Addictive Disorders? (ed: Mark S. Gold-addicted subjects for the drug and in the case of the obese subjects for food as a means to temporarily com- pensate

Homes, Christopher C.

114

Phototoxicity assessment of drugs and cosmetic products using E. coli  

Microsoft Academic Search

A gram negative bacteria Escherichia coli (Dh5? strain) was developed as an alternate test system of phototoxicity. Eight drugs (antibiotics) and cosmetic products (eight face creams) were examined for their phototoxicity using this test system. Five known phototoxic compounds were used to validate the test system. UVA-radiation induced phototoxicity of these compounds was tested by agar gel diffusion assay. Decrease

K. Verma; N. Agrawal; R. B. Misra; M. Farooq; R. K. Hans

2008-01-01

115

Evolution of the food and drug administration approach to liver safety assessment for new drugs: current status and challenges.  

PubMed

Prompted by approval in 1997 of troglitazone and bromfenac, two drugs that promptly began to show serious and sometimes fatal liver toxicity, we began at the Food and Drug Administration (FDA) a series of annual conferences in 1999 to consider issues of drug-induced liver injury (DILI). First inviting reviewers of new drug applications we opened the audiences in 2001 to pharmaceutical industry and academic consultants to industry and FDA, and slides shown at the meetings were posted on the internet to be available at the website of the American Association for the Study of Liver Diseases (AASLD)-go to ( http://www.aasld.org/dili/Pages/default.aspx ). Observations by Dr. Hyman J. Zimmerman that "drug-induced hepatocellular jaundice is a serious lesion" with possible mortality formed a basis for developing a computer program to plot peak serum values for alanine aminotransferase (ALT) and total bilirubin (TBL) in an x-y log-log graph for all subjects enrolled in clinical trials. This program had the capability to show the time course of all liver tests for individuals who had both hepatocellular injury and reduced whole liver function, plus clinical narratives to diagnose the severity and most likely cause of the abnormalities. We called the program eDISH (for evaluation of Drug-Induced Serious Hepatotoxicity), and began in 2004 to use it to assess DILI in clinical trial subjects. From 2008, comments made by the presenters at the conferences about their slides and ensuing discussions have been added to the website. All this has raised awareness of the problem, and since 1997, the FDA has not had to withdraw a single drug because of post-marketing hepatotoxicity. Many issues still remain to be resolved; among the most controversial is the best method to estimate likelihood that a given liver injury was actually caused by the drug in question. On November 9, 2012, a workshop was convened to discuss the best practices for the assessment of drug-induced liver injury (DILI) in clinical trials. PMID:25352324

Senior, John R

2014-11-01

116

An Ecological Assessment of Drug-Related Problem Situations for American Indian Adolescents of the Southwest  

PubMed Central

This study examined difficult situations related to drug and alcohol use as identified by American Indian youth in the South-west. Sixty-two contextually based items were developed from focus group data, and were administered to 71 American Indian youth. The items measured the frequency in which youth experienced specific drug-related situations, as well as the perceived difficulty in resisting drug use offers in those situations: The results indicated that the most frequent and difficult drug and alcohol situations occurred primarily with friends or cousins at their homes or after school. Implications for culturally specific assessment, prevention, and treatment are discussed. PMID:21359121

Okamoto, Scott K.; LeCroy, Craig Winston; Dustman, Patricia; Hohmann-Marriott, Bryndl; Kulis, Stephen

2011-01-01

117

Pharmacokinetic and pharmacodynamic drug-drug interaction assessment between pradigastat and digoxin or warfarin.  

PubMed

Pradigastat, a novel diacylglycerol acyltransferase-1 inhibitor, was evaluated for both pharmacokinetic (PK) and pharmacodynamic (PD) drug-drug interactions when co-administered with digoxin or warfarin in healthy subjects. This open-label study included two parallel subject cohorts each with three sequential treatment periods. Forty subjects were enrolled in the study with 20 subjects allocated to each cohort. PK and PD (PT/INR for warfarin only) samples were collected in each period. The statistical analysis results showed that the 90% CIs of the geometric mean ratios of digoxin, R-warfarin, and S-warfarin PK parameters (AUC and Cmax ) were all within 0.80-1.25 interval. The 90% CIs of the geometric mean ratios of pradigastat PK parameters (AUC and Cmax ) were within 0.80-1.25 interval when co-administered with warfarin; while co-administration with digoxin slightly reduced pradigastat exposure (?15%). The results also showed that 90% CIs of the geometric mean ratios of warfarin PD parameters (AUCPT , PTmax , AUCINR , and INRmax ) were within 0.80-1.25 interval. Pradigastat and digoxin or warfarin had no relevant clinical PK or PD drug-drug interactions. Administration of pradigastat and warfarin or pradigastat and digoxin as a mono or combined treatment appears to be safe and tolerated. PMID:24619917

Yan, Jing-He; Meyers, Dan; Lee, Zachary; Danis, Kate; Neelakantham, Srikanth; Majumdar, Tapan; Rebello, Sam; Sunkara, Gangadhar; Chen, Jin

2014-07-01

118

Assessment of Pharmacists Knowledge, Attitude and Practices Regarding Herbal Drug Information Services  

PubMed Central

Rational: Research suggests that increased consumption of herbal drugs is raising important public health concerns such as safety issues that may involve adverse effects and herb-drug interactions. The main objective of this study is to investigate the role of Pharmacists in herbal drug information dissemination. Method: We investigated the demographics, knowledge, attitude and practices regarding herbal drug information and regulatory laws among Pharmacists living in the six (6) States that constitute the Niger-Delta region of Nigeria. A total of 300 self-administered questionnaires were distributed to Pharmacists aged 21 years and above. Findings: About half of the respondents (48.72 %) were Hospital based Pharmacists. Knowledge of herbal drugs was 46.33 % while 64 .0 % showed positive attitude towards its use. Most of the information on herbal drugs were sourced from the internet (23.08 %) while 53.48 % were aware of the laws and regulations controlling herbal drugs in Nigeria. 88.64 % were in favour of the establishment of a National Herbal Drug Research and Development Agency and 55.68 % strongly agreeing to the setting up of a Herbal Drug Information Centre. Conclusion: The availability of herbal drug information services will not only enhance the performance of the Pharmacists, but will also add value to the life of the patients. PMID:24826042

Atavwoda, Abere Tavs; Gabriel, Aina Ayodele

2012-01-01

119

Human carcinogenic risk evaluation, Part III: Assessing cancer hazard and risk in human drug development.  

PubMed

Assessing cancer risk for human pharmaceuticals is important because drugs are taken at pharmacologically active doses and often on a chronic basis. Epidemiologic studies on patient populations have limited value because of the long latency period for most cancers and because these studies lack sensitivity. The Center for Drug Evaluation and Research (CDER) of the U.S. Food and Drug Administration relies on short-term surrogate assays (genetic toxicology studies) to assess risk to patients involved in clinical trials and on rodent carcinogenicity studies to assess cancer risk for drug approval. Unlike some other agencies that typically perform quantitative risk assessments on chemical pollutants or pesticide products, CDER does not perform such quantitative extrapolations. Rather, the evaluation of risk is the result of an integrated assessment of what is known about the drug, and risk is considered in the context of the clinical benefit. Mode of action of carcinogenesis and thresholds for effects are important considerations. The results of carcinogenicity studies of approved products are published in the drug labeling and individual clinicians balance risk and benefit in making prescribing decisions. PMID:15141097

Jacobs, Abigail; Jacobson-Kram, David

2004-10-01

120

Distribution of Drug Molecules in Lipid Membranes: Neutron Diffraction and MD Simulations.  

NASA Astrophysics Data System (ADS)

Non-steroidal anti-inflammatory drugs (NSAIDs) e.g. Aspirin and Ibuprofen, with chronic usage cause gastro intestinal (GI) toxicity. It has been shown experimentally that NSAIDs pre-associated with phospholipids reduce the GI toxicity and also increase the therapeutic activity of these drugs compared to the unmodified ones. In this study, using neutron diffraction, the DOPC lipid bilayer structure (with and without drug) as well as the distribution of a model NSAID (Ibuprofen) as a function of its position along the membrane normal was obtained at sub-nanometer resolution. It was found that the bilayer thickness reduces as the drug is added. Further, the results are successfully compared with atomistic Molecular Dynamics simulations. Based on this successful comparison and motivated by atomic details from MD, quasi-molecular modeling of the lipid membrane is being carried out and will be presented. The above study is expected to provide an effective methodology to design drug delivery nanoparticles based on a variety of soft condensed matter such as lipids or polymers.

Boggara, Mohan; Mihailescu, Ella; Krishnamoorti, Ramanan

2009-03-01

121

Development of extended release dosage forms using non-uniform drug distribution techniques.  

PubMed

Development of an extended release oral dosage form for nifedipine using the non-uniform drug distribution matrix method was conducted. The process conducted in a fluid bed processing unit was optimized by controlling the concentration gradient of nifedipine in the coating solution and the spray rate applied to the non-pareil beads. The concentration of nifedipine in the coating was controlled by instantaneous dilutions of coating solution with polymer dispersion transported from another reservoir into the coating solution at a controlled rate. The USP dissolution method equipped with paddles at 100 rpm in 0.1 N hydrochloric acid solution maintained at 37 degrees C was used for the evaluation of release rate characteristics. Results indicated that (1) an increase in the ethyl cellulose content in the coated beads decreased the nifedipine release rate, (2) incorporation of water-soluble sucrose into the formulation increased the release rate of nifedipine, and (3) adjustment of the spray coating solution and the transport rate of polymer dispersion could achieve a dosage form with a zero-order release rate. Since zero-order release rate and constant plasma concentration were achieved in this study using the non-uniform drug distribution technique, further studies to determine in vivo/in vitro correlation with various non-uniform drug distribution dosage forms will be conducted. PMID:12098848

Huang, Kuo-Kuang; Wang, Da-Peng; Meng, Chung-Ling

2002-05-01

122

Phototoxicity assessment of drugs and cosmetic products using E. coli.  

PubMed

A gram negative bacteria Escherichia coli (Dh5alpha strain) was developed as an alternate test system of phototoxicity. Eight drugs (antibiotics) and cosmetic products (eight face creams) were examined for their phototoxicity using this test system. Five known phototoxic compounds were used to validate the test system. UVA-radiation induced phototoxicity of these compounds was tested by agar gel diffusion assay. Decrease in colony forming units (CFU) was taken as an end point of phototoxicity. The phototoxic compounds and antibiotics produced significant reduction in CFU (p<0.001) at 80 microg/ml concentrations under exposure to UVA-radiation (5.4-10.8 J/cm(2)). One face cream was found phototoxic and produced significant decrease in CFU of E. coli at 1.0mg/ml concentration under UVA exposure (10.8 J/cm(2)). The minimum effective concentration of tetracycline and dose of UVA-radiation were also determined by observing growth inhibition of E. coli through disc diffusion assay. The observations suggested that E. coli can be used as an alternative test system for phototoxicity evaluation of chemicals. A battery of test systems is required to conclude the toxic/phototoxic potential of a chemical agent. In view of the speed, easiness, sensitivity and low cost, E. coli is introduced as one of the alternate test system for phototoxicity studies in safety evaluation of various chemical ingredients or formulations used in cosmetics and drugs. PMID:17919881

Verma, K; Agrawal, N; Misra, R B; Farooq, M; Hans, R K

2008-02-01

123

Assessment of Transmural Distribution of Myocardial Perfusion With Contrast Echocardiography  

Microsoft Academic Search

Background—We hypothesized that by using our newly defined method of destroying microbubbles and measuring their rate of tissue replenishment, we could assess the transmural distribution of myocardial perfusion. Methods and Results—We studied 12 dogs before and after creation of left anterior descending coronary artery stenoses both at rest and during hyperemia (n562 stages). Microbubbles were administered as a constant infusion,

Andre Z. Linka; Jiri Sklenar; Kevin Wei; Ananda R. Jayaweera; Danny M. Skyba; Sanjiv Kaul

124

Emergence of orphan drugs in the United States: a quantitative assessment of the first 25 years  

Microsoft Academic Search

The 1983 US Orphan Drug Act has stimulated the development of new therapies for rare diseases. To provide the first comprehensive overview of orphan-designated products and their indications, this article quantitatively analyses the characteristics and distribution of orphan designations and approvals by the US Food and Drug Administration from 1983 to August 2008. Of the 1,892 orphan-designated products, 326 received

M. Miles Braun; Sheiren Farag-El-Massah; Kui Xu; Timothy R. Coté

2010-01-01

125

High-Throughput Phase-Distribution Method to Determine Drug-Cyclodextrin Binding Constants  

PubMed Central

A high-throughput method has been developed to measure drug-cyclodextrin binding constants. It measures the distribution ratio of a drug between a polymer film [polyvinyl chloride (PVC) with 67% (w/w) dioctyl sebacate (DOS)] and a cyclodextrin-containing buffer in a 96-well format. Measurements of distribution ratios at several cyclodextrin concentrations lead to binding constants. Binding constants for econazole with six CDs have been determined in one 96-well microplate with four replications of each condition in 10 h. The K1:1/103 M?1 values are 3.98±0.13, 3.90±0.22, 29.3±2.2, 0.66±0.04 1.78±0.30, 4.08±0.50, with (2-hydroxyethyl)-?-cyclodextrin, (2-hydroxypropyl)-?-cyclodextrin, 2,6-di-O-methyl-?-cyclodextrin, hepta-kis(2,3,6-tri-O-methyl)-?-cyclodextrin, ?-cyclodextrin, ?-cyclodextrin, respectively. It is likely that 1:2 complexes are also formed in some cases. This method has also been applied to study the binding behavior as a function of the drug concentration and pH. Binding weakens at higher drug concentration which may be due to the self-association of the drug. An acidic environment decreases the binding constant of CD with the basic econazole. The formation of the 1:2 complexes is completely suppressed in acid as well. This protocol is faster than the phase-solubility method. Moreover, the material requirement is up to four orders of magnitude lower. PMID:18428984

CHEN, ZHI; LU, DUJUAN; WEBER, STEPHEN G.

2009-01-01

126

Observable weight distributions and children's individual weight assessment.  

PubMed

Social networks theory suggests obesity is "contagious" within peer groups in that known friends highly influence weight. On the other hand, an alternative model suggests that observable weight distributions affect perception of one's own obesity level. We examine whether the BMI levels of the most obese classmates in the individual student's grade by gender is positively associated with "under-assessment" of obesity and overweight (i.e., independently measured obesity or overweight, but subjective self-assessment of normal weight). The data are the 2004-2005 School Physical Activity and Nutrition III (SPAN), a stratified, multistage probability sample of 4th, 8th, and 11th grade public school children in Texas. We used logistic regression to test whether the gender-specific 85th percentile BMI level within the individual student's grade at their school is positively associated with "under-assessment" of obesity and overweight. The results show that students are much more likely to under-assess their own weight if the gender-specific 85th percentile BMI level is higher in their grade at their school. These data suggest that observable weight distributions play a key role in the obesity epidemic. PMID:19543215

Brown, H Shelton; Evans, Alexandra E; Mirchandani, Gita G; Kelder, Steven H; Hoelscher, Deanna M

2010-01-01

127

Probabilistic modeling of percutaneous absorption for risk-based exposure assessments and transdermal drug delivery  

Microsoft Academic Search

Chemical transport through human skin can play a significant role in human exposure to toxic chemicals in the workplace, as well as to chemical\\/biological warfare agents in the battlefield. The viability of transdermal drug delivery also relies on chemical transport processes through the skin. Models of percutaneous absorption are needed for risk-based exposure assessments and drug-delivery analyses, but previous mechanistic

Clifford K. Ho

2004-01-01

128

Diagnostic Accuracy of Kato-Katz and FLOTAC for Assessing Anthelmintic Drug Efficacy  

Microsoft Academic Search

BackgroundSensitive diagnostic tools are required for an accurate assessment of prevalence and intensity of helminth infections in areas undergoing regular deworming, and for monitoring anthelmintic drug efficacy. We compared the diagnostic accuracy of the Kato-Katz and FLOTAC techniques in the frame of a drug efficacy trial.Methodology\\/Principal FindingsStool samples from 343 Zanzibari children were subjected to duplicate Kato-Katz thick smears and

Stefanie Knopp; Benjamin Speich; Jan Hattendorf; Laura Rinaldi; Khalfan A. Mohammed; I. Simba Khamis; Alisa S. Mohammed; Marco Albonico; David Rollinson; Hanspeter Marti; Giuseppe Cringoli; Jürg Utzinger

2011-01-01

129

Assessment of Alcohol and Other Drug Use Behaviors in Health Professions Students  

Microsoft Academic Search

Alcohol and other drug (AOD) use behaviors of health professions students (HPS) were assessed by surveying both university-based HPS and other nursing programs in a Midwestern state in 1999. Response was 2,646 (56.4%) of surveyed students. Family history of alcohol-related and drug-related problems were reported by 39.8% and 13.9%, respectively, with 42.6% of respondents reporting one or both. Among nursing

Jeffrey N. Baldwin; David M. Scott; Sangeeta Agrawal; Jean K. Bartek; R. Ellen Davis-Hall; Thomas P. Reardon; Edward M. DeSimone II

2006-01-01

130

Principles of drug abuse liability assessment in laboratory animals  

Microsoft Academic Search

This paper describes the rationale for use of preclinical assessments of abuse liability in laboratory animals, and then discusses ‘cross-cutting’ methodological issues that apply to behavioral evaluations intended to contribute to an abuse liability evaluation package. Issues include use of: (1) positive and negative control conditions; (2) full dose–effect evaluations, (3) multiple dependent measures, (4) pharmacokinetic evaluations to guide choice

Nancy A. Ator; Roland R. Griffiths

2003-01-01

131

Perpetrators of pharmacokinetic drug-drug interactions arising from altered cytochrome P450 activity: a criteria-based assessment  

PubMed Central

AIMS To catalogue the perpetrators of CYP-mediated pharmacokinetic drug–drug interactions (PK-DDIs) using clinically relevant criteria, and to compare this with an analogous catalogue. METHODS Candidate inhibitors and inducers of CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A (‘perpetrators’) were evaluated using published clinical pharmacokinetic interaction studies. Studies were selected on the basis of ?six human subjects, use of a validated in vivo probe substrate for the CYP enzyme, and clinically relevant dosing. Inhibitors were described according to the FDA classifications of strong, moderate or weak, whereas inducers were classified as major (?twofold decrease in AUC) or weak (Drug Interaction Table (CDIT) were compared with the ‘accepted’ major perpetrators. RESULTS From a list of 216 candidate drugs (349 CYP-perpetrator pairs, CYP-PPs), 36 inhibitors and eight inducers were accepted as major perpetrators of PK-DDIs, resulting in 58 CYP-PPs. In comparison, the clinical version of the CDIT had a sensitivity of 33% and a positive predictive value of 68%. One hundred and ninety-nine CYP-PPs were rejected as major perpetrators, and 92 CYP-PPs had insufficient published human pharmacokinetic data for robust classification. CONCLUSIONS Using a criteria-based assessment, the number of drugs that are proven or likely major perpetrators of CYP-mediated PK-DDIs is relatively small. Current clinical decision support on PK-DDIs is inconsistent with the published evidence and can be improved using simple criteria. PMID:21223357

Polasek, Thomas M; Lin, Frank P Y; Miners, John O; Doogue, Matthew P

2011-01-01

132

Solving ODEs: Cardiac drug risk assessment The heat equation and finite elements: electrical propagation in the heart Object-oriented scientific computing: Applications  

E-print Network

Solving ODEs: Cardiac drug risk assessment The heat equation and finite elements: electrical;Solving ODEs: Cardiac drug risk assessment The heat equation and finite elements: electrical propagation in the heart Solving ODEs: Cardiac drug risk assessment #12;Solving ODEs: Cardiac drug risk assessment The heat

Martin, Ralph R.

133

The biopharmaceutics risk assessment roadmap for optimizing clinical drug product performance.  

PubMed

The biopharmaceutics risk assessment roadmap (BioRAM) optimizes drug product development and performance by using therapy-driven target drug delivery profiles as a framework to achieve the desired therapeutic outcome. Hence, clinical relevance is directly built into early formulation development. Biopharmaceutics tools are used to identify and address potential challenges to optimize the drug product for patient benefit. For illustration, BioRAM is applied to four relatively common therapy-driven drug delivery scenarios: rapid therapeutic onset, multiphasic delivery, delayed therapeutic onset, and maintenance of target exposure. BioRAM considers the therapeutic target with the drug substance characteristics and enables collection of critical knowledge for development of a dosage form that can perform consistently for meeting the patient's needs. Accordingly, the key factors are identified and in vitro, in vivo, and in silico modeling and simulation techniques are used to elucidate the optimal drug delivery rate and pattern. BioRAM enables (1) feasibility assessment for the dosage form, (2) development and conduct of appropriate "learning and confirming" studies, (3) transparency in decision-making, (4) assurance of drug product quality during lifecycle management, and (5) development of robust linkages between the desired clinical outcome and the necessary product quality attributes for inclusion in the quality target product profile. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 103:3377-3397, 2014. PMID:25256402

Selen, Arzu; Dickinson, Paul A; Müllertz, Anette; Crison, John R; Mistry, Hitesh B; Cruañes, Maria T; Martinez, Marilyn N; Lennernäs, Hans; Wigal, Tim L; Swinney, David C; Polli, James E; Serajuddin, Abu T M; Cook, Jack A; Dressman, Jennifer B

2014-11-01

134

Developing and evaluating distributions for probabilistic human exposure assessments  

SciTech Connect

This report describes research carried out at the Lawrence Berkeley National Laboratory (LBNL) to assist the U. S. Environmental Protection Agency (EPA) in developing a consistent yet flexible approach for evaluating the inputs to probabilistic risk assessments. The U.S. EPA Office of Emergency and Remedial Response (OERR) recently released Volume 3 Part A of Risk Assessment Guidance for Superfund (RAGS), as an update to the existing two-volume set of RAGS. The update provides policy and technical guidance on performing probabilistic risk assessment (PRA). Consequently, EPA risk managers and decision-makers need to review and evaluate the adequacy of PRAs for supporting regulatory decisions. A critical part of evaluating a PRA is the problem of evaluating or judging the adequacy of input distributions PRA. Although the overarching theme of this report is the need to improve the ease and consistency of the regulatory review process, the specific objectives are presented in two parts. The objective of Part 1 is to develop a consistent yet flexible process for evaluating distributions in a PRA by identifying the critical attributes of an exposure factor distribution and discussing how these attributes relate to the task-specific adequacy of the input. This objective is carried out with emphasis on the perspective of a risk manager or decision-maker. The proposed evaluation procedure provides consistency to the review process without a loss of flexibility. As a result, the approach described in Part 1 provides an opportunity to apply a single review framework for all EPA regions and yet provide the regional risk manager with the flexibility to deal with site- and case-specific issues in the PRA process. However, as the number of inputs to a PRA increases, so does the complexity of the process for calculating, communicating and managing risk. As a result, there is increasing effort required of both the risk professionals performing the analysis and the risk manager reviewing it. For deterministic risk assessments, the use of default inputs has improved the ease and the consistency of both performing and reviewing assessments. By analogy, it is expected that similar advantage will be seen in the field of probabilistic risk assessment through the introduction of default distributions. In Part 2 of this report, we consider when a default distribution might be appropriate for use in PRA and work towards development of recommended task-specific distributions for several frequently used exposure factors. An approach that we develop using body weight and exposure duration as case studies offers a transparent way for developing task-specific exposure factor distributions. A third case study using water intake highlights the need for further study aimed at improving the relevance of ''short-term'' data before recommendations on task-specific distributions of water intake can be made.

Maddalena, Randy L.; McKone, Thomas E.

2002-08-01

135

New drug adoption models: a review and assessment of future needs.  

PubMed

New drug products today are the key to survival in the pharmaceutical industry. However, the new product development process in the pharmaceutical industry also happens to be one of the riskiest and most expensive undertakings because of the huge research and development costs involved. Consequently market forecasting of new pharmaceutical products takes on added importance if the formidable investments are to be recovered. New drug adoption models provide the marketer with a means to assess new product potential. Although several adoption models are available in the marketing literature for assessing potential of common consumer goods, the unique characteristics of the prescription drug market makes it necessary to examine the current state of pharmaceutical innovations. The purpose of this study, therefore, is to: (1) review new drug adoption models in the pharmaceutical literature, (2) evaluate the existing models of new drug adoption using the ten criteria for a good model as prescribed by Zaltman and Wallendorf (1983), and (3) provide an overall assessment and a ¿prescription¿ for better forecasting of new drug products. PMID:10143893

Agrawal, M; Calantone, R J

1995-01-01

136

Advances in the Science of Adolescent Drug Involvement: Implications for Assessment and Diagnosis  

PubMed Central

Purpose of review Adolescence is a developmental period characterized by relatively high rates of substance use and substance use disorders. Precise assessment and classification of adolescent drug use behaviors is essential in gaining an accurate understanding of the nature and extent of adolescent drug use, and possible intervention or treatment needs. There have been a select group of recently published research reports and manuscripts that address critical and emerging issues pertaining to the classification and assessment of alcohol and other drug use behaviors among adolescents. An overview of these publications is provided and their clinical relevance is discussed. Recent findings The paper will focus on recent research, most from the U.S., that addresses four main issues. One is the application of the new DSM-5 criteria to adolescents, including the advantages and disadvantages of the new criteria for substance use disorders. The second issue pertains to advances in instrumentation that provide new tools for researchers and clinicians in assessing substance use in adolescents. A significant public health issue is addressed as the third theme in the paper – screening for alcohol abuse in college settings. Finally, the paper reviews how the emerging science of brain development can inform the assessment process. Summary Recent advances in the adolescent drug abuse assessment field continue to inform clinical service and research. As a whole these advances have strengthened the field, but continued research is needed to further refine assessment practices and standards and to better understand how to define a substance use disorder In youth. PMID:23695531

Winters, Ken

2013-01-01

137

Assessment of Methodological Quality of Economic Evaluations in Belgian Drug Reimbursement Applications  

PubMed Central

Objectives This paper aims to assess the methodological quality of economic evaluations included in Belgian reimbursement applications for Class 1 drugs. Materials and Methods For 19 reimbursement applications submitted during 2011 and Spring 2012, a descriptive analysis assessed the methodological quality of the economic evaluation, evaluated the assessment of that economic evaluation by the Drug Reimbursement Committee and the response to that assessment by the company. Compliance with methodological guidelines issued by the Belgian Healthcare Knowledge Centre was assessed using a detailed checklist of 23 methodological items. The rate of compliance was calculated based on the number of economic evaluations for which the item was applicable. Results Economic evaluations tended to comply with guidelines regarding perspective, target population, subgroup analyses, comparator, use of comparative clinical data and final outcome measures, calculation of costs, incremental analysis, discounting and time horizon. However, more attention needs to be paid to the description of limitations of indirect comparisons, the choice of an appropriate analytic technique, the expression of unit costs in values for the current year, the estimation and valuation of outcomes, the presentation of results of sensitivity analyses, and testing the face validity of model inputs and outputs. Also, a large variation was observed in the scope and depth of the quality assessment by the Drug Reimbursement Committee. Conclusions Although general guidelines exist, pharmaceutical companies and the Drug Reimbursement Committee would benefit from the existence of a more detailed checklist of methodological items that need to be reported in an economic evaluation. PMID:24386474

Simoens, Steven

2013-01-01

138

Cold air distribution in office buildings: Technology assessment for California  

SciTech Connect

This paper presents the results of a study to assess the current state of practice, and energy and operating cost implications of cold air distribution in California, and to identify the key research needs for the continued development of this technology in new commercial buildings in the state. Whole-building energy simulations were made to compare the energy performance of a prototypical office building in three California climates using conventional and cold air distribution, with and without ice storage, to show the impacts of load shifting, energy use, and utility costs for three typical utility rate structures. The merits of economizers and fan-powered mixing boxes were also studied when used in conjunction with cold air delivery. A survey was conducted to assess the perceived strengths and limitations of this technology, perceived barriers to its widespread use, and user experience. The survey was based on interviews with consulting engineers, equipment manufacturers, researchers, utility representatives, and other users of cold air distribution technology. Selected findings from the industry survey are also discussed. Cold air distribution (CoAD) is found to always reduce fan energy use in comparison to conventional 55[degrees]F (13[degrees]C) air distribution systems, when conditioned air is delivered directly to the space (no fan-powered mixing boxes). Total building energy use for ice storage/CoAD systems was always higher than a well-designed conventional system, but significantly lower than a commonly-installed packaged system. When a favorable utility rate structure was applied, the load-shifting benefits of ice storage/CoAD systems produced the lowest annual operating costs of all system-plant configurations studied.

Bauman, F.S.; LaBege, P. (California Univ., Berkeley, CA (United States). Center for Environmental Design Research); Borgers, T. (Humboldt State Univ., Arcata, CA (United States). Dept. of Chemistry); Gadgil, A.J. (Lawrence Berkeley Lab., CA (United States))

1992-06-01

139

Cold Air Distribution in Office Buildings: Technology Assessment for California  

SciTech Connect

This paper presents the results of a study to assess the current state of practice, and energy and operating cost implications of cold air distribution in California, and to identify the key research needs for the continued development of this technology in new commercial buildings in the state. Whole-building energy simulations were made to compare the energy performance of a prototypical office building in three California climates using conventional and cold air distribution, with and without ice storage, to show the impacts of load shifting, energy use, and utility costs for three typical utility rate structures. The merits of economizers and fan-powered mixing boxes were also studied when used in conjunction with cold air delivery. A survey was conducted to assess the perceived strengths and limitations of this technology, perceived barriers to its widespread use, and user experience. The survey was based on interviews with consulting engineers, equipment manufacturers, researchers, utility representatives, and other users of cold air distribution technology. Selected findings from the industry survey are also discussed. Cold air distribution (CoAD) is found to always reduce fan energy use in comparison to conventional 55 F (13 C) air distribution systems, when conditioned air is delivered directly to the space (no fan-powered mixing boxes). Total building energy use for ice storage/CoAD systems was always higher than a well-designed conventional system, but significantly lower than a commonly-installed packaged system. When a favorable utility rate structure was applied, the load-shifting benefits of ice storage/CoAD systems produced the lowest annual operating costs of all system-plant configurations studied.

Bauman, F.S.; Borgers, T.; LaBerge, P.; Gadgil, A.J.

1992-06-01

140

Drugs.  

ERIC Educational Resources Information Center

This document contains the third volume of "Today's Delinquent," an annual publication of the National Center for Juvenile Justice. This volume deals with the issue of drugs and includes articles by leading authorities in delinquency and substance abuse who share their views on causes and cures for the drug problem among youth in this country.…

Hurst, Hunter, Ed.; And Others

1984-01-01

141

Drug susceptibility distributions in slowly growing non-tuberculous mycobacteria using MGIT 960 TB eXiST.  

PubMed

In general, uniform clinical antibiotic susceptibility breakpoints (CBPs) for slowly growing nontuberculous mycobacteria (NTM) have not been established. The aim of this study was to determine wild-type drug susceptibility distributions for relevant antibiotics using Bactec MGIT 960 equipped with EpiCenter TB eXiST and to derive epidemiological cut-offs (ECOFFs) from semi quantitative drug susceptibility measurements. One hundred and twenty-six NTM clinical isolates (Mycobacterium avium n=58, Mycobacterium intracellulare n=18, Mycobacterium kansasii n=50) were investigated in this study. Drug susceptibility distributions and MIC90 values were determined for clarithromycin, ethambutol, rifampicin, rifabutin, ofloxacin, moxifloxacin, and amikacin using Bactec MGIT 960/EpiCenter TB eXiST. For most species/drug combinations ECOFFs were determined. For some species/drug combinations ECOFFs were not defined as either the isolates were susceptible to the lowest drug concentration tested or because isolates, in part, had MIC levels exceeding the highest drug concentration tested. This study describes drug susceptibility distributions and MIC90 values of M. avium, M. intracellulare, and M. kansasii that may aid the definition of CBPs when correlating in vitro drug susceptibility with clinical outcomes in future studies. PMID:23689069

Hombach, Michael; Somoskövi, Akos; Hömke, Rico; Ritter, Claudia; Böttger, Erik C

2013-07-01

142

Industrial Power Distribution System Reliability Assessment utilizing Markov Approach  

NASA Astrophysics Data System (ADS)

A method to perform power system reliability analysis using Markov Approach, Reliability Block Diagrams and Fault Tree analysis has been presented. The Markov method we use is a state space model and is based on state diagrams generated for a one line industrial power distribution system. The Reliability block diagram (RBD) method is a graphical and calculation tool used to model the distribution power system of an industrial facility. Quantitative reliability estimations on this work are based on CARMS and Block Sim simulations as well as state space, RBD's and Failure Mode analyses. The power system reliability was assessed and the main contributors to power system reliability have been identified, both qualitatively and quantitatively. Methods to improve reliability have also been provided including redundancies and protection systems that might be added to the system in order to improve reliability.

Guzman-Rivera, Oscar R.

143

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

PubMed Central

Background Within a ten year period South Africa has developed a substantial illicit drug market. Data on HIV risk among drug using populations clearly indicate high levels of HIV risk behaviour due to the sharing of injecting equipment and/or drug-related unprotected sex. While there is international evidence on and experience with adequate responses, limited responses addressing drug use and drug-use-related HIV and other health risks are witnessed in South Africa. This study aimed to explore the emerging problem of drug-related HIV transmission and to stimulate the development of adequate health services for the drug users, by linking international expertise and local research. Methods A Rapid Assessment and Response (RAR) methodology was adopted for the study. For individual and focus group interviews a semi-structured questionnaire was utilised that addressed key issues. Interviews were conducted with a total of 84 key informant (KI) participants, 63 drug user KI participants (49 males, 14 females) and 21 KI service providers (8 male, 13 female). Results and Discussion Adverse living conditions and poor education levels were cited as making access to treatment harder, especially for those living in disadvantaged areas. Heroin was found to be the substance most available and used in a problematic way within the Pretoria area. Participants were not fully aware of the concrete health risks involved in drug use, and the vague ideas held appear not to allow for concrete measures to protect themselves. Knowledge with regards to substance related HIV/AIDS transmission is not yet widespread, with some information sources disseminating incorrect or unspecific information. Conclusions The implementation of pragmatic harm-reduction and other evidence-based public health care policies that are designed to reduce the harmful consequences associated with substance use and HIV/AIDS should be considered. HIV testing and treatment services also need to be made available in places accessed by drug users. PMID:21631928

2011-01-01

144

Assessment of algorithms for predicting drug-drug interactions via inhibition mechanisms: comparison of dynamic and static models  

PubMed Central

AIMS Static and dynamic models (incorporating the time course of the inhibitor) were assessed for their ability to predict drug–drug interactions (DDIs) using a population-based ADME simulator (Simcyp®V8). The impact of active metabolites, dosing time and the ability to predict inter-individual variability in DDI magnitude were investigated using the dynamic model. METHODS Thirty-five in vivo DDIs involving azole inhibitors and benzodiazepines were predicted using the static and dynamic model; both models were employed within Simcyp for consistency in parameters. Simulations comprised of 10 trials with matching population demographics and dosage regimen to the in vivo studies. Predictive utility of the static and dynamic model was assessed relative to the inhibitor or victim drug investigated. RESULTS Use of the dynamic and static models resulted in comparable prediction success, with 71 and 77% of DDIs predicted within two-fold, respectively. Over 40% of strong DDIs (>five-fold AUC increase) were under-predicted by both models. Incorporation of the itraconazole metabolite into the dynamic model resulted in increased prediction accuracy of strong DDIs (80% within two-fold). Bias and imprecision in prediction of triazolam DDIs were higher in comparison with midazolam and alprazolam; >50% of triazolam DDIs were under-predicted regardless of the model used. Predicted inter-individual variability in the AUC ratio (coefficient of variation of 45%) was consistent with the observed variability (50%). CONCLUSIONS High prediction accuracy was observed using both the Simcyp dynamic and static models. The differences observed with the dose staggering and the incorporation of active metabolite highlight the importance of these variables in DDI prediction. PMID:21143503

Guest, Eleanor J; Rowland-Yeo, Karen; Rostami-Hodjegan, Amin; Tucker, Geoffrey T; Houston, J Brian; Galetin, Aleksandra

2011-01-01

145

Investigation of drug distribution in tablets using surface enhanced Raman chemical imaging.  

PubMed

This paper reports the first application of surface enhanced Raman chemical imaging on pharmaceutical tablets containing the active ingredient (API) in very low concentrations. Taking advantage of the extremely intensive Raman signals in the presence of silver colloids, image aquisition time was radically decreased. Moreover, the investigation of drug distribution below the detection limit of regular micro-Raman spectrometry was made feasible. The characteristics of different manufacturing technologies could be revealed at very low API concentrations by using chemometric methods for processing and evaluating the large number of varying spectra provided with this imaging method. PMID:23313776

Firkala, Tamás; Farkas, Attila; Vajna, Balázs; Farkas, István; Marosi, György

2013-03-25

146

Chemotherapy of cervical carcinoma: use of Tc-99m-MAA infusion to predict drug distribution  

SciTech Connect

Nineteen patients with cervical cancer had infusion of Tc-99m-macroaggregated albumin particles (MAA) via bilateral internal iliac artery catheters to aid in dividing chemotherapeutic dose appropriately between the two catheters. Unequal drug distribution was used to minimize extrapelvic complications (local gluteal burns) by reducing the dose to the side with the greatest gluteal perfusion or to increase the dose to the tumor regions that showed heightened perfusion. Pulmonary uptake, due primarily to arteriovenous shunting in the tumor bed, was seen in all patients. The authors suggest that bulk reduction of locally advanced cervical carcinoma in patients without prior irradiation may be achieved by intra-arterial chemotherapy with tolerable toxicity.

Kim, E.E.; Bledin, A.G.; Kavanagh, J.; Haynie, T.P.; Chuang, V.P.

1984-03-01

147

Validation of radiolabeling of drug formulations for aerosol deposition assessment of orally inhaled products.  

PubMed

Radiolabeling of inhaler formulations for imaging studies is an indirect method of determining lung deposition and regional distribution of drug in human subjects. Hence, ensuring that the radiotracer and drug exhibit similar aerodynamic characteristics when aerosolized, and that addition of the radiotracer has not significantly altered the characteristics of the formulation, are critical steps in the development of a radiolabeling method. The validation phase should occur during development of the radiolabeling method, prior to commencement of in vivo studies. The validation process involves characterization of the aerodynamic particle size distribution (APSD) of drug in the reference formulation, and of both drug and radiotracer in the radiolabeled formulation, using multistage cascade impaction. We propose the adoption of acceptance criteria similar to those recommended by the EMA and ISAM/IPAC-RS for determination of therapeutic equivalence of orally inhaled products: (a) if only total lung deposition is being quantified, the fine particle fraction ratio of both radiolabeled drug and radiotracer to that of the reference drug should fall between 0.85 and 1.18, and (b) if regional lung deposition (e.g., outer and inner lung regions) is to be quantified, the ratio of both radiolabeled drug and radiotracer to reference drug on each impactor stage or group of stages should fall between 0.85 and 1.18. If impactor stages are grouped together, at least four separate groups should be provided. In addition, while conducting in vivo studies, measurement of the APSD of the inhaler used on each study day is recommended to check its suitability for use in man. PMID:23215848

Devadason, Sunalene G; Chan, Hak-Kim; Haeussermann, Sabine; Kietzig, Claudius; Kuehl, Philip J; Newman, Stephen; Sommerer, Knut; Taylor, Glyn

2012-12-01

148

Applications of Genetically Modified Tools to Safety Assessment in Drug Development  

PubMed Central

The process of new drug development consists of several stages; after identifying potential candidate compounds, preclinical studies using animal models link the laboratory and human clinical trials. Among many steps in preclinical studies, toxicology and safety assessments contribute to identify potential adverse events and provide rationale for setting the initial doses in clinical trials. Gene modulation is one of the important tools of modern biology, and is commonly employed to examine the function of genes of interest. Advances in new drug development have been achieved by exploding information on target selection and validation using genetically modified animal models as well as those of cells. In this review, a recent trend of genetically modified methods is discussed with reference to safety assessments, and the exemplary applications of gene-modulating tools to the tests in new drug development were summarized. PMID:24278499

Kay, Hee Yeon; Wu, Hongmin; Lee, Seo In

2010-01-01

149

Simulated drug discovery process to conduct a synoptic assessment of pharmacy students.  

PubMed

OBJECTIVE. To implement and assess a task-based learning exercise that prompts pharmacy students to integrate their understanding of different disciplines. DESIGN. Master of pharmacy (MPharm degree) students were provided with simulated information from several preclinical science and from clinical trials and asked to synthesize this into a marketing authorization application for a new drug. Students made a link to pharmacy practice by creating an advice leaflet for pharmacists. ASSESSMENT. Students' ability to integrate information from different disciplines was evaluated by oral examination. In 2 successive academic years, 96% and 82% of students demonstrated an integrated understanding of their proposed new drug. Students indicated in a survey that their understanding of the links between different subjects improved. CONCLUSION. Simulated drug discovery provides a learning environment that emphasizes the connectivity of the preclinical sciences with each other and the practice of pharmacy. PMID:24672074

Richardson, Alan; Curtis, Anthony D M; Moss, Gary P; Pearson, Russell J; White, Simon; Rutten, Frank J M; Perumal, Dhaya; Maddock, Katie

2014-03-12

150

An Assessment of Prison-Based Drug Treatment; Texas' In-Prison Therapeutic Community Program.  

ERIC Educational Resources Information Center

Provides an overview of a comprehensive, prison-based treatment assessment, including a six-month follow-up study. Results show that 80% of the inmates referred to the program graduated. Graduates demonstrated marked reductions in criminal and drug-use activity and had lower relapse and recidivism rates when compared to other parolees. (RJM)

Knight, Kevin; Simpson, D. Dwayne; Chatham, Lois R.; Camacho, L. Mabel

1997-01-01

151

Children Exposed to Drugs in Utero: Their Scores on the Miller Assessment for Preschoolers.  

ERIC Educational Resources Information Center

The Miller Assessment for Preschoolers was administered to 54 children who had been prenatally exposed to drugs. Results indicated a tendency toward the lower end of the spectrum with poorer performance identified on test items measuring tactile, proprioceptive, and vestibular processing and language. (JOW)

Fulks, Mary-Ann L.; Harris, Susan R.

1995-01-01

152

Statistical assessment of dissolution and drug release profile similarity using a model-dependent approach  

Microsoft Academic Search

A general multivariate procedure for assessing the similarity of dissolution and drug release profiles was developed. A mathematical model is fit to the data, and Hotelling's T2 test is used to calculate the joint confidence region around the vector of differences between least-squares estimates of the parameters in the model. The method of Lagrange multipliers is used to determine if

Mark R. Berry; Michael D. Likar

2007-01-01

153

Maine Student Athlete Alcohol and Other Drug Use Assessment, 1991. Summary Report.  

ERIC Educational Resources Information Center

This report presents findings from the Maine Student Athlete Alcohol and Other Drug Use Assessment conducted in 1991. It is noted that the survey instrument was comprised of 155 questions and was completed by 2,891 junior and senior high school student athletes in grades 7 through 12. Results are presented in these areas: (1) percent of athletes…

Primmerman, William

154

Assessing malaria drug resistance in US military areas of operation using microarrays.  

E-print Network

Assessing malaria drug resistance in US military areas of operation using microarrays. A. Taylor Bright University of California, San Diego Background: Malaria inflicts an incredible burden of the developed world, roughly 40% of the world's population live in areas where malaria is endemic(1

Gleeson, Joseph G.

155

USE OF CASE REPORTS IN ASSESSING ADVERSE OUTCOMES OF HUMAN PRENATAL DRUG EXPOSURES: AN APPROACH  

EPA Science Inventory

The use of case reports for assessing the developmental consequences of prenatal drug exposure is limited by the inability to determine the incidence of adverse outcomes and by the high likelihood for bias. Yet, because it is impossible to conduct clinical trials for the assessme...

156

This Report is distributed annually to Lehigh faculty, staff and students in compliance with the Drug-Free Workplace Act of 1988 and the Drug-Free Schools and Communities Act of 1989.  

E-print Network

of illicit drugs and the abuse of alcohol. D. A description of any drug or alcohol counseling, treatment of illicit drugs and alcohol by students and employees on its property or as part of its activities. B or distribution of illicit drugs and alcohol. C. A description of the health risks associated with the use

Napier, Terrence

157

Development and validation of a survey instrument for assessing prescribers' perception of computerized drug-drug interaction alerts  

PubMed Central

Objective To develop a theoretically informed and empirically validated survey instrument for assessing prescribers' perception of computerized drug–drug interaction (DDI) alerts. Materials and methods The survey is grounded in the unified theory of acceptance and use of technology and an adapted accident causation model. Development of the instrument was also informed by a review of the extant literature on prescribers' attitude toward computerized medication safety alerts and common prescriber-provided reasons for overriding. To refine and validate the survey, we conducted a two-stage empirical validation study consisting of a pretest with a panel of domain experts followed by a field test among all eligible prescribers at our institution. Results The resulting survey instrument contains 28 questionnaire items assessing six theoretical dimensions: performance expectancy, effort expectancy, social influence, facilitating conditions, perceived fatigue, and perceived use behavior. Satisfactory results were obtained from the field validation; however, a few potential issues were also identified. We analyzed these issues accordingly and the results led to the final survey instrument as well as usage recommendations. Discussion High override rates of computerized medication safety alerts have been a prevalent problem. They are usually caused by, or manifested in, issues of poor end user acceptance. However, standardized research tools for assessing and understanding end users' perception are currently lacking, which inhibits knowledge accumulation and consequently forgoes improvement opportunities. The survey instrument presented in this paper may help fill this methodological gap. Conclusion We developed and empirically validated a survey instrument that may be useful for future research on DDI alerts and other types of computerized medication safety alerts more generally. PMID:21486876

Fear, Kathleen; Chaffee, Bruce W; Zimmerman, Christopher R; Karls, Edward M; Gatwood, Justin D; Stevenson, James G; Pearlman, Mark D

2011-01-01

158

Development of a cell-based assay system considering drug metabolism and immune- and inflammatory-related factors for the risk assessment of drug-induced liver injury.  

PubMed

Drug-induced liver injury (DILI) is a major safety concern in drug development and clinical pharmacotherapy. However, prediction of DILI is difficult because the underlying mechanisms are not fully understood. To establish a novel cell-based screening system to suggest drugs with hepatotoxic potential in preclinical drug development, comprehensive gene expression analyses during in vivo DILI are necessary. Using in vivo mouse DILI models and 4 sets of hepatotoxic positive and non-hepatotoxic drugs, we found that the hepatic mRNA levels of S100A8; S100A9; "NATCH, LRR, and pyrin domain-containing protein 3" (NALP3); interleukin (IL)-1?; and the receptor for advanced glycation endproducts (RAGE) were commonly increased in hepatotoxic drug-administered mice compared to non-hepatotoxic drug-administered mice. To clarify whether these 5 in vivo biomarkers can be applied to a cell-based screening system, we adapted human liver microsomes (HLM) in the presence of NADPH to assess the metabolic activation reaction, and we also adapted human monocytic leukemia cells HL-60, K562, KG-1 and THP-1 to assess the effects on mRNA expression of immune- and inflammatory-related factors. We investigated 30 clinical drugs with different safety profiles with regard to DILI and found that the total sum score of gene expression levels of S100A8, S100A9, RAGE, NALP3 and IL-1? mRNA in HL-60 or K562 cells incubated with HLM, could identify drugs at high risk for hepatotoxicity. We proposed the use of the total sum score of gene expression level for assessing metabolic activation by drug-metabolizing enzymes and immune- and inflammatory-related factors for the risk assessment of DILI in preclinical drug development. PMID:24747151

Yano, Azusa; Oda, Shingo; Fukami, Tatsuki; Nakajima, Miki; Yokoi, Tsuyoshi

2014-07-01

159

Modifying the intensity distribution by assessing the reliability  

NASA Astrophysics Data System (ADS)

This article presents an application of a procedure to modify the intensity distribution by assessing the reliability. There are two potential possibilities that may influence the intensity distribution: (1) For the interpolation error, we generate a measured grid across the calculation region. When the point to station spacing is <5 km, we consider the results precise; however, some points have less precision because these are farther from the corresponding stations. When the spacing is between 5 and 50 km, we consider the results imprecise and define a reliability factor that correlates with the distance. (2) Some records may have errors that result from local site conditions, equipment problems, or some disturbance such as lightning stroke, which will lead to some grid points having an incorrect intensity. We regress the attenuation relation for sites with abnormal intensities and consider the results to be accurate when the standard deviation (STD) is < ? and inaccurate when the STD is > 2?. We then define a reliability factor to correlate with STD between ? and 2?, such that the intensity distribution is in accord with both wave propagation theory and the investigation intensity.

Kang, Lan-chi; Jin, Xing; Wei, Yong-xiang

2013-12-01

160

Impact of the September 11th attacks in New York City on drug users: a preliminary assessment  

Microsoft Academic Search

An exploratory assessment of the impact of the September 11th attacks in New York City on drug users, including their perceptions\\u000a of changes in drug use, drug availability, police activities, and access to services, was undertaken. Methods included focus\\u000a groups with drug users and acquired immunodeficiency syndrome (AIDS) outreach worker supervisors and surveys of service providers.\\u000a Results indicated that, while

Sherry Deren; Michele Shedlin; Thomas Hamilton; Holly Hagan

2002-01-01

161

Self-assessment Tool for Drug Information Advanced Pharmacy Practice Experience  

PubMed Central

Objective To describe the use of student self-assessments as a measure of the effectiveness of a drug information advanced pharmacy practice experience (APPE) and to determine whether other APPEs reinforced information-related skills. Design Students taking a drug information APPE completed a self-assessment survey instrument focusing on key information-related skills on the first day and again on the last day of that APPE. Findings were used to determine the effect of this and other APPEs on perceived information skills. Student ratings were compared with faculty ratings for items with similar wording. Assessment Student self-ratings improved after completing the drug information APPE. Other APPEs, gender, and course grade did not significantly impact student perceptions of their information-related knowledge and skills. Student and faculty ratings were similar, although individual variability occurred. Conclusion Student self-assessments, along with other direct and indirect data, can provide useful information needed to assess and change aspects of the experiential program and curriculum. PMID:17429502

Blommel, Matthew L.

2007-01-01

162

An interventional study on intensive care unit drug therapy assessment in a rural district hospital in India  

PubMed Central

Background: Intensive care unit is a potential area for drug-related problems. As many of the patients treated are complex patients, clinical pharmacy intervention could find drug therapy problems. Materials and Methods: Drug information liaisons daily attended ward rounds with intensivists and screened the patient for drug therapy assessment using the American Society for Health-System Pharmacists clinical skills competition DTA format. This was a prospective study done for 6 months from August 2012 to January 2013. Simple statistics were used to tabulate the drug-related problems assessed. Results: A total of 72 patients were screened for drug therapy problems, for which 947 drug doses were prescribed in the study period. The total number of prescriptions was 148. The average number of drugs per prescription was 6.39 and the average number of drugs per patient was 13.15. A total of 243 problems were identified; on an average, 1.67 problems were present per prescription. The total number of drug interactions identified was N = 192 (78.2%); majority of them (61.4%) were of type C (not serious). So, 55.73% of them were monitored and not stopped or substituted. The second type of problem was a correlation between drug therapy and medical problem (7.4%). Appropriate drug selection and drug regimen was the third problem, and the adverse drug reactions and therapeutic duplications accounted for approximately 2% of the drug-related problems identified. Conclusion: Drug interactions constituted the major problem of ICUs, but not many were serious or significant. Consensus in assessment of drug-related problems and convincing intensivists with good quality evidences are required for better acceptance of interventions. PMID:24808673

Pichala, Priyanka Tejashwani; Kumar, Bharani Mukkillapati; Zachariah, Seeba; Thomas, Dixon; Saunchez, Laura; Gerardo, Alvarez-Uria

2013-01-01

163

Assessing hERG Pore Models As Templates for Drug Docking Using Published Experimental Constraints: The Inactivated State in the Context of Drug Block  

PubMed Central

Many structurally and therapeutically diverse drugs interact with the human heart K+ channel hERG by binding within the K+ permeation pathway of the open channel, leading to drug-induced ‘long QT syndrome’. Drug binding to hERG is often stabilized by inactivation gating. In the absence of a crystal structure, hERG pore homology models have been used to characterize drug interactions. Here we assess potentially inactivated states of the bacterial K+ channel, KcsA, as templates for inactivated state hERG pore models in the context of drug binding using computational docking. Although Flexidock and GOLD docking produced low energy score poses in the models tested, each method selected a MthK K+ channel-based model over models based on the putative inactivated state KcsA structures for each of the 9 drugs tested. The variety of docking poses found indicates that an optimal arrangement for drug binding of aromatic side chains in the hERG pore can be achieved in several different configurations. This plasticity of the drug “binding site” is likely to be a feature of the hERG inactivated state. The results demonstrate that experimental data on specific drug interactions can be used as structural constraints to assess and refine hERG homology models. PMID:24471705

2014-01-01

164

Updating the French method for the causality assessment of adverse drug reactions.  

PubMed

The Imputability Working Group (CRI) updated the French drug reaction causality assessment method. This tripartite group is made up of staff from the French network of regional pharmacovigilance centres, pharmaceutical companies, and the French National Agency for the Safety of Medicines and Health Products (ANSM). After reviewing the strengths and weaknesses of the previous method, several ideas for improvement were proposed: a better-worded and more discriminating scale for certain chronological and semiological criteria, a larger scale for the intrinsic score (increased from 5 to 7 levels), a new bibliographical scale to differentiate between expected and unexpected adverse drug reactions, and a new informativeness scale. PMID:23773347

Arimone, Yannick; Bidault, Irène; Dutertre, Jean-Paul; Gérardin, Marie; Guy, Claire; Haramburu, Françoise; Hillaire-Buys, Dominique; Meglio, Carmine; Penfornis, Catherine; Théophile, Hélène; Valnet-Rabier, Marie-Blanche

2013-01-01

165

In silico assessment of drug safety in human heart applied to late sodium current blockers  

PubMed Central

Drug-induced action potential (AP) prolongation leading to Torsade de Pointes is a major concern for the development of anti-arrhythmic drugs. Nevertheless the development of improved anti-arrhythmic agents, some of which may block different channels, remains an important opportunity. Partial block of the late sodium current (INaL) has emerged as a novel anti-arrhythmic mechanism. It can be effective in the settings of free radical challenge or hypoxia. In addition, this approach can attenuate pro-arrhythmic effects of blocking the rapid delayed rectifying K+ current (IKr). The main goal of our computational work was to develop an in-silico tool for preclinical anti-arrhythmic drug safety assessment, by illustrating the impact of IKr/INaL ratio of steady-state block of drug candidates on “torsadogenic” biomarkers. The O’Hara et al. AP model for human ventricular myocytes was used. Biomarkers for arrhythmic risk, i.e., AP duration, triangulation, reverse rate-dependence, transmural dispersion of repolarization and electrocardiogram QT intervals, were calculated using single myocyte and one-dimensional strand simulations. Predetermined amounts of block of INaL and IKr were evaluated. “Safety plots” were developed to illustrate the value of the specific biomarker for selected combinations of IC50s for IKr and INaL of potential drugs. The reference biomarkers at baseline changed depending on the “drug” specificity for these two ion channel targets. Ranolazine and GS967 (a novel potent inhibitor of INaL) yielded a biomarker data set that is considered safe by standard regulatory criteria. This novel in-silico approach is useful for evaluating pro-arrhythmic potential of drugs and drug candidates in the human ventricle. PMID:23696033

Trenor, Beatriz; Gomis-Tena, Julio; Cardona, Karen; Romero, Lucia; Rajamani, Sridharan; Belardinelli, Luiz; Giles, Wayne R; Saiz, Javier

2013-01-01

166

Rapid, Serial, Non-invasive Assessment of Drug Efficacy in Mice with Autoluminescent Mycobacterium ulcerans Infection  

PubMed Central

Background Buruli ulcer (BU) caused by Mycobacterium ulcerans is the world's third most common mycobacterial infection. There is no vaccine against BU and surgery is needed for patients with large ulcers. Although recent experience indicates combination chemotherapy with streptomycin and rifampin improves cure rates, the utility of this regimen is limited by the 2-month duration of therapy, potential toxicity and required parenteral administration of streptomycin, and drug-drug interactions caused by rifampin. Discovery and development of drugs for BU is greatly hampered by the slow growth rate of M. ulcerans, requiring up to 3 months of incubation on solid media to produce colonies. Surrogate markers for evaluating antimicrobial activity in real-time which can be measured serially and non-invasively in infected footpads of live mice would accelerate pre-clinical evaluation of new drugs to treat BU. Previously, we developed bioluminescent M. ulcerans strains, demonstrating proof of concept for measuring luminescence as a surrogate marker for viable M. ulcerans in vitro and in vivo. However, the requirement of exogenous substrate limited the utility of such strains, especially for in vivo experiments. Methodology/Principal Finding For this study, we engineered M. ulcerans strains that express the entire luxCDABE operon and therefore are autoluminescent due to endogenous substrate production. The selected reporter strain displayed a growth rate and virulence similar to the wild-type parent strain and enabled rapid, real-time monitoring of in vitro and in vivo drug activity, including serial, non-invasive assessments in live mice, producing results which correlated closely with colony-forming unit (CFU) counts for a panel of drugs with various mechanisms of action. Conclusions/Significance Our results indicate that autoluminescent reporter strains of M. ulcerans are exceptional tools for pre-clinical evaluation of new drugs to treat BU due to their potential to drastically reduce the time, effort, animals, compound, and costs required to evaluate drug activity. PMID:24367713

Zhang, Tianyu; Li, Si-Yang; Converse, Paul J.; Grosset, Jacques H.; Nuermberger, Eric L.

2013-01-01

167

Drugs  

Microsoft Academic Search

Reviews 11 studies, published from the year 1917 to 1910, by Miles, Fiske, Graham, Rowe, Anderson, Marks, Stanley, Johnson, Macht, Isaacs, Greenberg and Lashley on the effects of alcohol, tobacco smoking, drug addiction, addiction to medicines like aspirin, and strychnine and caffeine.

A. T. Poffenberger

1919-01-01

168

Admixed Phylogenetic Distribution of Drug Resistant Mycobacterium tuberculosis in Saudi Arabia  

PubMed Central

Background The phylogeographical structure of Mycobacterium tuberculosis is generally bimodal in low tuberculosis (TB) incidence countries, where genetic lineages of the isolates generally differ with little strain clustering between autochthonous and foreign-born TB patients. However, less is known on this structure in Saudi Arabia—the most important hub of human migration as it hosts a total population of expatriates and pilgrims from all over the world which is equal to that of its citizens. Methodology We explored the mycobacterial phylogenetic structure and strain molecular clustering in Saudi Arabia by genotyping 322 drug-resistant clinical isolates collected over a 12-month period in a national drug surveillance survey, using 24 locus-based MIRU-VNTR typing and spoligotyping. Principal Findings In contrast to the cosmopolitan population of the country, almost all the known phylogeographic lineages of M. tuberculosis complex (with noticeable exception of Mycobacterium africanum/West-African 1 and 2) were detected, with Delhi/CAS (21.1%), EAI (11.2%), Beijing (11.2%) and main branches of the Euro-American super-lineage such as Ghana (14.9%), Haarlem (10.6%) and Cameroon (7.8%) being represented. Statistically significant associations of strain lineages were observed with poly-drug resistance and multi drug resistance especially among previously treated cases (p value of distribution of phylogenetic lineages (p?=?0.311). Moreover, 59.5% (22/37) of the strain molecular clusters were shared between the Saudi born and immigrant TB patients. Conclusions Specific distribution of M. tuberculosis phylogeographic lineages is not observed between the autochthonous and foreign-born populations. These observations might reflect both socially favored ongoing TB transmission between the two population groups, and historically deep-rooted, prolonged contacts and trade relations of the peninsula with other world regions. More vigorous surveillance and strict adherence to tuberculosis control policies are urgently needed in the country. PMID:23383340

Varghese, Bright; Supply, Philip; Allix-Beguec, Caroline; Shoukri, Mohammed; Al-Omari, Ruba; Herbawi, Mais; Al-Hajoj, Sahal

2013-01-01

169

Novel nanocarriers for topical drug delivery: investigating delivery efficiency and distribution in skin using two-photon microscopy  

NASA Astrophysics Data System (ADS)

The complex structure of skin represents an effective barrier against external environmental factors, as for example, different chemical and biochemical compounds, yeast, bacterial and viral infections. However, this impermeability prevents efficient transdermal drug delivery which limits the number of drugs that are able to penetrate the skin efficiently. Current trends in drug application through skin focus on the design and use of nanocarriers for transport of active compounds. The transport systems applied so far have several drawbacks, as they often have low payload, high toxicity, a limited variability of inclusion molecules, or long degradation times. The aim of these current studies is to investigate novel topical drug delivery systems, e.g. nanocarriers based on cyclic oligosaccharides - cyclodextrins (CD) or iron (III)-based metal-organic frameworks (MOF). Earlier studies on cell cultures imply that these drug nanocarriers show promising characteristics compared to other drug delivery systems. In our studies, we use two-photon microscopy to investigate the ability of the nanocarriers to deliver compounds through ex-vivo skin samples. Using near infrared light for excitation in the so called optical window of skin allows deep-tissue visualization of drug distribution and localization. In addition, it is possible to employ two-photon based fluorescence correlation spectroscopy for quantitative analysis of drug distribution and concentrations in different cell layers.

Kirejev, Vladimir; Guldbrand, Stina; Bauer, Brigitte; Smedh, Maria; Ericson, Marica B.

2011-03-01

170

Quantitative risk assessment in classification of drugs with identical API content.  

PubMed

When combating counterfeits it is equally important to recognize fakes and to avoid misclassification of genuine samples. This study presents a general approach to the problem using a newly-developed method called Data Driven Soft Independent Modeling of Class Analogy. The possibility to collect representative data for both training and validation is of great importance in classification modeling. When fakes are not available, we propose to compose the test set using the legitimate drug's analogs, manufactured by various producers. These analogs should have the identical API and a similar composition of excipients. The approach shows satisfactory results both in revealing counterfeits and in accounting for the future variability of the target class drugs. The presented case studies demonstrate that theoretically predicted misclassification errors can be successfully employed for the science-based risk assessment in drug identification. PMID:24929870

Rodionova, O Ye; Balyklova, K S; Titova, A V; Pomerantsev, A L

2014-09-01

171

In vivo assessment of drug sensitivity of African trypanosomes using the akinetoplastic induction test.  

PubMed

Following treatment of mice infected with Trypanosoma congolense or T brucei brucei with various doses of isometamidium chloride or diminazene aceturate, the induction of akinetoplastic (AK) forms was observed in the trypomastigotes of both species within 10 hours of drug administration. The levels of AK-induction were closely correlated with the levels of resistance to each compound found using a standard in vivo drug assay in mice. In general, ineffective doses of either compound conferred AK-induction rates of less than 30 per cent; relapsing cases had between 30 and 50 per cent while curative doses had AK-induction rates of 50 per cent or more. In vivo determination of AK-induction rates using ordinary light microscopy is thus a potentially feasible alternative indicator to the conventional use of mice infection and treatment methods for assessing drug sensitivity in African trypanosomes. PMID:1374928

Chitambo, H; Arakawa, A; Ono, T

1992-03-01

172

Drug-induced modulation of Tc-99m pyrophosphate tissue distribution: what is involved  

SciTech Connect

More than ten years after their introduction, Tc-99m-labeled phosphates and phosphonates (TcP) continue to be of interest to the investigator and to hold promise for new clinical applications in the future. Initially, TcP compounds were valued because of their bone-seeking properties. Emphasis shifted from bone to soft tissue when Bonte et al. introduced Tc-99m-labeled pyrophosphate (TcPPi) for myocardial infarct scanning. Detailed information about TcPPi uptake in ischemic and necrotic myocardial tissue at the subcellular level has accumulated. Therefore, understanding of the mechanism of TcPPi uptake in infarcted myocardium is more detailed than understanding of uptake by bone. A new, and potentially powerful, approach to the use of TcP is being proposed by Carr et al. The authors attempt to modulate favorably the tissue distribution of TcPPi by prior administration of drugs in pharmacological quantities. The authors demonstrate that uptake of TcPPi can be enhanced in the necrotic myocardium, uptake by bone can be reduced, and the lesion-to-blood ratio can be altered favorably when vitamin D/sub 3/ or desoxycorticosterone acetate (DOCA) is administered in pharmacological doses before the TcPPi injection. A short review is presented of background information helpful for interpreting the drug effects on TcPPi uptake in bone or necrotic myocardial tissue.

Wahner, H.W.; Dewanjee, M.K.

1981-06-01

173

In Vitro Release Kinetics of Antituberculosis Drugs from Nanoparticles Assessed Using a Modified Dissolution Apparatus  

PubMed Central

The aim of this study was to assess the in vitro release kinetics of antituberculosis drug-loaded nanoparticles (NPs) using a “modified” cylindrical apparatus fitted with a regenerated cellulose membrane attached to a standard dissolution apparatus (modifiedcylinder method). The model drugs that were used were rifampicin (RIF) and moxifloxacin hydrochloride (MX). Gelatin and polybutyl cyanoacrylate (PBCA) NPs were evaluated as the nanocarriers, respectively. The dissolution and release kinetics of the drugs from loaded NPs were studied in different media using the modified cylinder method and dialysis bag technique was used as the control technique. The results showed that use of the modified cylinder method resulted in different release profiles associated with unique release mechanisms for the nanocarrier systems investigated. The modified cylinder method also permitted discrimination between forced and normal in vitro release of the model drugs from gelatin NPs in the presence or absence of enzymatic degradation. The use of dialysis bag technique resulted in an inability to differentiate between the mechanisms of drug release from the NPs in these cases. This approach offers an effective tool to investigate in vitro release of RIF and MX from NPs, which further indicate that this technique can be used for performance testing of nanosized carrier systems. PMID:23936771

Gao, Yuan; Zuo, Jieyu; Bou-Chacra, Nadia; Pinto, Terezinha de Jesus Andreoli; Clas, Sophie-Dorothee; Walker, Roderick B.; Lobenberg, Raimar

2013-01-01

174

Establishing the validity of the personality assessment inventory drug and alcohol scales in a corrections sample.  

PubMed

Although not originally designed for implementation in correctional settings, researchers and clinicians have begun to use the Personality Assessment Inventory (PAI) to assess offenders. A relatively small number of studies have made attempts to validate the alcohol and drug abuse scales of the PAI, and only a very few studies have validated those scales in nonclinical correctional samples. The current study examined evidence of convergent and discriminant validity for the substance abuse scales on the PAI in a large, nonclinical sample of offenders. The net sample for the current study consisted of 1,120 federal inmates. Both the drug abuse and alcohol scales showed good convergent validity through high correlations with relevant proximal and distal indicators of substance use across multiple measures from several data sources. Discriminant validity was established as neither scale showed any "erroneous" correlations after controlling for the other scale. Implications for future research and practice are discussed. PMID:20484714

Patry, Marc W; Magaletta, Philip R; Diamond, Pamela M; Weinman, Beth A

2011-03-01

175

Neighborhood History as a Factor Shaping Syringe Distribution Networks Among Drug Users at a U.S. Syringe Exchange1  

PubMed Central

Throughout the US, high-visibility drug markets are concentrated in neighborhoods with few economic opportunities, while drug buyers/users are widely dispersed. A study of Pittsburgh Syringe Exchange participants provides data on travel between and network linkages across neighborhoods with different levels of drug activity. There are distinct racial patterns to syringe distribution activity within networks and across neighborhoods. Pittsburgh’s history suggests these patterns emerge from historical patterns of social and economic development. Study data demonstrate the ability of IDUs to form long term social ties across racial and geographic boundaries and use them to reduce the risk of HIV transmission. PMID:19578475

Braine, Naomi; Acker, Caroline; Goldblatt, Cullen; Yi, Huso; Friedman, Samuel; DesJarlais, Don C.

2008-01-01

176

COMPARING DISTRIBUTIONS OF SHELF LIVES FOR DRUG PRODUCTS WITH TWO COMPONENTS UNDER DIFFERENT DESIGNS  

Microsoft Academic Search

To reduce the cost of stability testing in drug research and development, both bracketing and matrixing designs are recommended in the U.S. Food and Drug Administration's (FDA) guidelines for drug products with a single active ingredient (component). When the drug product contains multiple active components, the naïve approach is to take the minimum of shelf lives obtained from individual components

Annpey Pong; Damaraju Raghavarao

2002-01-01

177

Raman and infrared techniques for fighting drug-related crime: a preliminary assessment  

NASA Astrophysics Data System (ADS)

A proof-of-concept hand-held Raman spectrometer and a commercial portable system based on Attenuated Total Reflectance Fourier Transform Infrared spectroscopy (ATR-FTIR) were assessed for the rapid, "at scene" analysis of illicit drugs. The objectives of such an assessment were twofold: 1) to determine the suitability of the systems in practical forensic casework and 2) to determine the potential of the use of such systems in covert operations. Data obtained are promising and demonstrate the potential advantages and limitations of the use of these techniques in these fields of operation.

Valussi, Silvia; Underhill, Mark

2006-09-01

178

Evaluation of higher distribution and/or utilization voltages. Fourth interim report (August 1980): assessment of optimum distribution configuration  

SciTech Connect

This interim report provides documentation on the fourth task, Assessment of Optimum Distribution Configuration, of DOE Contract No. ET-78-C-01-2866, Evaluation of Higher Distribution and/or Utilization Voltages. The work performed under this task includes the development of a computer model for assessment of life cycle costs for the distribution and utilization systems, the development of an optimization algorithm to enable distribution system configuration optimization and a net energy analysis to determine potential net energy savings. Input data for this task derive from Task 3. The major output of this task is a documented computer code.

Not Available

1981-04-01

179

Applying Linear and Non-Linear Methods for Parallel Prediction of Volume of Distribution and Fraction of Unbound Drug  

PubMed Central

Volume of distribution and fraction unbound are two key parameters in pharmacokinetics. The fraction unbound describes the portion of free drug in plasma that may extravasate, while volume of distribution describes the tissue access and binding of a drug. Reliable in silico predictions of these pharmacokinetic parameters would benefit the early stages of drug discovery, as experimental measuring is not feasible for screening purposes. We have applied linear and nonlinear multivariate approaches to predict these parameters: linear partial least square regression and non-linear recursive partitioning classification. The volume of distribution and fraction of unbound drug in plasma are predicted in parallel within the model, since the two are expected to be affected by similar physicochemical drug properties. Predictive models for both parameters were built and the performance of the linear models compared to models included in the commercial software Volsurf+. Our models performed better in predicting the unbound fraction (Q2 0.54 for test set compared to 0.38 with Volsurf+ model), but prediction accuracy of the volume of distribution was comparable to the Volsurf+ model (Q2 of 0.70 for test set compared to 0.71 with Volsurf+ model). The nonlinear classification models were able to identify compounds with a high or low volume of distribution (sensitivity 0.81 and 0.71, respectively, for test set), while classification of fraction unbound was less successful. The interrelationship between the volume of distribution and fraction unbound is investigated and described in terms of physicochemical descriptors. Lipophilicity and solubility descriptors were found to have a high influence on both volume of distribution and fraction unbound, but with an inverse relationship. PMID:24116008

del Amo, Eva M.; Ghemtio, Leo; Xhaard, Henri; Yliperttula, Marjo; Urtti, Arto; Kidron, Heidi

2013-01-01

180

Applicability Domain ANalysis (ADAN): a robust method for assessing the reliability of drug property predictions.  

PubMed

We report a novel method called ADAN (Applicability Domain ANalysis) for assessing the reliability of drug property predictions obtained by in silico methods. The assessment provided by ADAN is based on the comparison of the query compound with the training set, using six diverse similarity criteria. For every criterion, the query compound is considered out of range when the similarity value obtained is larger than the 95th percentile of the values obtained for the training set. The final outcome is a number in the range of 0-6 that expresses the number of unmet similarity criteria and allows classifying the query compound within seven reliability categories. Such categories can be further exploited to assign simpler reliability classes using a traffic light schema, to assign approximate confidence intervals or to mark the predictions as unreliable. The entire methodology has been validated simulating realistic conditions, where query compounds are structurally diverse from those in the training set. The validation exercise involved the construction of more than 1000 models. These models were built using a combination of training set, molecular descriptors, and modeling methods representative of the real predictive tasks performed in the eTOX project (a project whose objective is to predict in vivo toxicological end points in drug development). Validation results confirm the robustness of the proposed assessment methodology, which compares favorably with other classical methods based solely on the structural similarity of the compounds. ADAN characteristics make the method well-suited for estimate the quality of drug predictions obtained in extremely unfavorable conditions, like the prediction of drug toxicity end points. PMID:24821140

Carrió, Pau; Pinto, Marta; Ecker, Gerhard; Sanz, Ferran; Pastor, Manuel

2014-05-27

181

Statistical and regulatory considerations in assessments of interchangeability of biological drug products.  

PubMed

When the patent of a brand-name, marketed drug expires, new, generic products are usually offered. Small-molecule generic and originator drug products are expected to be chemically identical. Their pharmaceutical similarity can be typically assessed by simple regulatory criteria such as the expectation that the 90% confidence interval for the ratio of geometric means of some pharmacokinetic parameters be between 0.80 and 1.25. When such criteria are satisfied, the drug products are generally considered to exhibit therapeutic equivalence. They are then usually interchanged freely within individual patients. Biological drugs are complex proteins, for instance, because of their large size, intricate structure, sensitivity to environmental conditions, difficult manufacturing procedures, and the possibility of immunogenicity. Generic and brand-name biologic products can be expected to show only similarity but not identity in their various features and clinical effects. Consequently, the determination of biosimilarity is also a complicated process which involves assessment of the totality of the evidence for the close similarity of the two products. Moreover, even when biosimilarity has been established, it may not be assumed that the two biosimilar products can be automatically substituted by pharmacists. This generally requires additional, careful considerations. Without declaring interchangeability, a new product could be prescribed, i.e. it is prescribable. However, two products can be automatically substituted only if they are interchangeable. Interchangeability is a statistical term and it means that products can be used in any order in the same patient without considering the treatment history. The concepts of interchangeability and prescribability have been widely discussed in the past but only in relation to small molecule generics. In this paper we apply these concepts to biosimilars and we discuss: definitions of prescribability and interchangeability and their statistical implementation; the relation between bioequivalence and interchangeability for small-molecule drug products; regulatory requirements and expectations of biosimilar products in various jurisdictions; possible statistical approaches to establish the similarity and interchangeability of biologic drug products; definition of other technical terms such as switchability and automatic substitution. The paper will be concluded with a discussion of the anticipated future use of interchangeability of biological drug products. PMID:24832831

Tóthfalusi, Lászlo; Endrényi, László; Chow, Shein-Chung

2014-05-01

182

The practice of pre-marketing safety assessment in drug development.  

PubMed

The last 15 years have seen a substantial increase in efforts devoted to safety assessment by statisticians in the pharmaceutical industry. While some of these efforts were driven by regulations and public demand for safer products, much of the motivation came from the realization that there is a strong need for a systematic approach to safety planning, evaluation, and reporting at the program level throughout the drug development life cycle. An efficient process can help us identify safety signals early and afford us the opportunity to develop effective risk minimization plan early in the development cycle. This awareness has led many pharmaceutical sponsors to set up internal systems and structures to effectively conduct safety assessment at all levels (patient, study, and program). In addition to process, tools have emerged that are designed to enhance data review and pattern recognition. In this paper, we describe advancements in the practice of safety assessment during the premarketing phase of drug development. In particular, we share examples of safety assessment practice at our respective companies, some of which are based on recommendations from industry-initiated working groups on best practice in recent years. PMID:23331218

Chuang-Stein, Christy; Xia, H Amy

2013-01-01

183

Principles of laboratory assessment of drug abuse liability and implications for clinical development  

PubMed Central

Abuse liability testing plays an important role in informing drug development, regulatory processes, and clinical practice. This paper describes the current “gold standard” methodologies that are used for laboratory assessments of abuse liability in non-human and human subjects. Particular emphasis is given to procedures such as non-human drug discrimination, self-administration, and physical dependence testing, and human dose effect abuse liability studies that are commonly used in regulatory submissions to governmental agencies. The potential benefits and risks associated with the inclusion of measures of abuse liability in industry-sponsored clinical trials is discussed. Lastly, it is noted that many factors contribute to patterns of drug abuse and dependence outside of the laboratory setting and positive or negative signals in abuse liability studies do not always translate to high or low levels of actual abuse or dependence. Well-designed patient and physician education, pharmacovigilance, and postmarketing surveillance can reduce the diversion and misuse of drugs with abuse liability and can effectively foster the protection and promotion of public health. PMID:19443137

Carter, Lawrence P.; Griffiths, Roland R.

2009-01-01

184

Understanding the Assessment of Psychotropic Drug Harms in Clinical Trials to Improve Social Workers' Role in Medication Monitoring  

ERIC Educational Resources Information Center

The purpose of this integrative review is to facilitate social work practitioners' understanding of how psychotropic drug harms are assessed in clinical trials and to make specific suggestions for social workers' increased involvement in detecting drug harms in their clients. The authors undertook a comprehensive review of interdisciplinary…

Hughes, Shannon; Cohen, David

2010-01-01

185

Landslide Probability Assessment by the Derived Distributions Technique  

NASA Astrophysics Data System (ADS)

Landslides are potentially disastrous events that bring along human and economic losses; especially in cities where an accelerated and unorganized growth leads to settlements on steep and potentially unstable areas. Among the main causes of landslides are geological, geomorphological, geotechnical, climatological, hydrological conditions and anthropic intervention. This paper studies landslides detonated by rain, commonly known as "soil-slip", which characterize by having a superficial failure surface (Typically between 1 and 1.5 m deep) parallel to the slope face and being triggered by intense and/or sustained periods of rain. This type of landslides is caused by changes on the pore pressure produced by a decrease in the suction when a humid front enters, as a consequence of the infiltration initiated by rain and ruled by the hydraulic characteristics of the soil. Failure occurs when this front reaches a critical depth and the shear strength of the soil in not enough to guarantee the stability of the mass. Critical rainfall thresholds in combination with a slope stability model are widely used for assessing landslide probability. In this paper we present a model for the estimation of the occurrence of landslides based on the derived distributions technique. Since the works of Eagleson in the 1970s the derived distributions technique has been widely used in hydrology to estimate the probability of occurrence of extreme flows. The model estimates the probability density function (pdf) of the Factor of Safety (FOS) from the statistical behavior of the rainfall process and some slope parameters. The stochastic character of the rainfall is transformed by means of a deterministic failure model into FOS pdf. Exceedance probability and return period estimation is then straightforward. The rainfall process is modeled as a Rectangular Pulses Poisson Process (RPPP) with independent exponential pdf for mean intensity and duration of the storms. The Philip infiltration model is used along with the soil characteristic curve (suction vs. moisture) and the Mohr-Coulomb failure criteria in order to calculate the FOS of the slope. Data from two slopes located on steep tropical regions of the cities of Medellín (Colombia) and Rio de Janeiro (Brazil) where used to verify the model's performance. The results indicated significant differences between the obtained FOS values and the behavior observed on the field. The model shows relatively high values of FOS that do not reflect the instability of the analyzed slopes. For the two cases studied, the application of a more simple reliability concept (as the Probability of Failure - PR and Reliability Index - ?), instead of a FOS could lead to more realistic results.

Muñoz, E.; Ochoa, A.; Martínez, H.

2012-12-01

186

Decision biases and persistent illicit drug use: an experimental study of distributed choice and addiction  

Microsoft Academic Search

This experiment tested the hypothesis that differences in drug use are correlated with differences in decision making. The subjects were 22 drug clinic patients who had used either opiates or stimulants for an average of 10 years, and 21 community residents who reported that they had rarely used illicit addictive drugs. The procedure consisted of a series of binary choices

Gene M Heyman; Brian Dunn

2002-01-01

187

Distribution of Risk Factors and Prophylactic Drug Usage in Turkish Patients with Angiographically Established Coronary Artery Disease  

Microsoft Academic Search

Background Coronary artery disease (CAD) is the leading cause of adult deaths in our country. In clinical practice, an adequate level of secondary prevention towards CAD primarily requires full recognition of the distribution of risk factors. The aim of our study was to determine the prevalence of coronary risk factors and the use of prophylactic drugs among patients who have

Kenan Sonmez; Ahmet Akcay; Mustafa Akcakoyun; Durmus Demir; Oman Hakan Elonu; Selcuk Pala; Nilüfer Eksi Duran; Murat Gencbay; Muzaffer Degertekin; Fikret Turan

2002-01-01

188

Dear Colleagues, The following is the UM Alcohol and Other Drugs Policy, which is being distributed to all faculty, staff and  

E-print Network

Dear Colleagues, The following is the UM Alcohol and Other Drugs Policy, which is being distributed a student's alcohol or other drug use, please refer them to Counseling and Psychological Services, which System University of Michigan Health System University of Michigan Alcohol and Other Drugs (AOD) Policy

Eustice, Ryan

189

The mastermind approach to CNS drug therapy: translational prediction of human brain distribution, target site kinetics, and therapeutic effects  

PubMed Central

Despite enormous advances in CNS research, CNS disorders remain the world’s leading cause of disability. This accounts for more hospitalizations and prolonged care than almost all other diseases combined, and indicates a high unmet need for good CNS drugs and drug therapies. Following dosing, not only the chemical properties of the drug and blood–brain barrier (BBB) transport, but also many other processes will ultimately determine brain target site kinetics and consequently the CNS effects. The rate and extent of all these processes are regulated dynamically, and thus condition dependent. Therefore, heterogenious conditions such as species, gender, genetic background, tissue, age, diet, disease, drug treatment etc., result in considerable inter-individual and intra-individual variation, often encountered in CNS drug therapy. For effective therapy, drugs should access the CNS “at the right place, at the right time, and at the right concentration”. To improve CNS therapies and drug development, details of inter-species and inter-condition variations are needed to enable target site pharmacokinetics and associated CNS effects to be translated between species and between disease states. Specifically, such studies need to include information about unbound drug concentrations which drive the effects. To date the only technique that can obtain unbound drug concentrations in brain is microdialysis. This (minimally) invasive technique cannot be readily applied to humans, and we need to rely on translational approaches to predict human brain distribution, target site kinetics, and therapeutic effects of CNS drugs. In this review the term “Mastermind approach” is introduced, for strategic and systematic CNS drug research using advanced preclinical experimental designs and mathematical modeling. In this way, knowledge can be obtained about the contributions and variability of individual processes on the causal path between drug dosing and CNS effect in animals that can be translated to the human situation. On the basis of a few advanced preclinical microdialysis based investigations it will be shown that the “Mastermind approach” has a high potential for the prediction of human CNS drug effects. PMID:23432852

2013-01-01

190

Uterotonic drug quality: an assessment of the potency of injectable uterotonic drugs purchased by simulated clients in three districts in Ghana  

PubMed Central

Objectives Given use of uterotonics for postpartum haemorrhage and other obstetric indications, the importance of potent uterotonics is indisputable. This study evaluated access to and potency of injectable uterotonics in Ghana. Design Study design involved research assistants simulating clients to purchase oxytocin and ergometrine from different sources. Drug potency was measured via chemical assay by the Ghana Food and Drugs Board. Setting The study was conducted in three contrasting districts in Ghana. Outcome measure The per cent of active pharmaceutical ingredient was measured to assess the quality of oxytocin and ergometrine. Results 69 formal points of sale were visited, from which 55 ergometrine ampoules and 46 oxytocin ampoules were purchased. None of the ergometrine ampoules were within British Pharmacopoeia specification for active ingredient, none were expired and one showed 0% active ingredient, suggestive of a counterfeit drug. Among oxytocin ampoules purchased, only 11 (26%) were within British Pharmacopoeia specification for active ingredient and two (4%) were expired. The median percentages of active ingredients were 64% and 50% for oxytocin and ergometrine, respectively. Conclusions The quality of injectable uterotonics in three contrasting districts in Ghana is a serious problem. Restrictions regarding the sale of unregistered drugs, and of registered drugs from unlicensed shops, are inadequately enforced. These problems likely exist elsewhere but are not assessed, as postmarketing drug quality surveillance is generally restricted to well-funded disease-specific programmes relying on antiretroviral, antimalarial and antibiotic drugs. Maternal health programmes must adopt and fund the same approach to drug quality as is standard in programmes addressing infectious disease. PMID:22556159

Koski, Alissa; Cofie, Patience; Mirzabagi, Ellie; Grady, Breanne L; Brooke, Steve

2012-01-01

191

Impact of different tissue-simulating hydrogel compartments on in vitro release and distribution from drug-eluting stents.  

PubMed

In vitro drug release testing is an appropriate approach to identify critical parameters helping to predict drug release from drug-eluting stents (DES) prior to studying drug release behavior under in vivo conditions. Drug release and distribution from DES coated with a fluorescent model substance were studied in vitro using the vessel-simulating flow-through cell equipped with different long-term stable hydrogel compartments composed of agarose, polyacrylamide or poly(vinyl alcohol). The obtained experimental results were compared with the results of finite-element modeling obtained using experimentally determined diffusion coefficients and partition coefficients. In spite of differences regarding these parameters, experimental and mathematical data yielded only minor differences between the different gels regarding the release and distribution behavior and reasonable agreement between the modeling and the experiment was obtained. In an attempt to further elucidate the dosage form behavior, the diffusion coefficients in the gel as well as in the stent coating were systematically varied in the finite-element model. Changes in the diffusivity in the stent coating mainly impacted on the initial concentrations. Slower diffusion inside the hydrogel yielded a retarded elution from the stent coating and a higher model substance accumulation in the gel compartment at late time points. PMID:24801065

Semmling, Beatrice; Nagel, Stefan; Sternberg, Katrin; Weitschies, Werner; Seidlitz, Anne

2014-08-01

192

The Washington Needle Depot: fitting healthcare to injection drug users rather than injection drug users to healthcare: moving from a syringe exchange to syringe distribution model.  

PubMed

Needle exchange programs chase political as well as epidemiological dragons, carrying within them both implicit moral and political goals. In the exchange model of syringe distribution, injection drug users (IDUs) must provide used needles in order to receive new needles. Distribution and retrieval are co-existent in the exchange model. Likewise, limitations on how many needles can be received at a time compel addicts to have multiple points of contact with professionals where the virtues of treatment and detox are impressed upon them. The centre of gravity for syringe distribution programs needs to shift from needle exchange to needle distribution, which provides unlimited access to syringes. This paper provides a case study of the Washington Needle Depot, a program operating under the syringe distribution model, showing that the distribution and retrieval of syringes can be separated with effective results. Further, the experience of IDUs is utilized, through paid employment, to provide a vulnerable population of people with clean syringes to prevent HIV and HCV. PMID:20047690

Small, Dan; Glickman, Andrea; Rigter, Galen; Walter, Thia

2010-01-01

193

Independent Orbiter Assessment (IOA): Assessment of the electrical power distribution and control subsystem, volume 3  

NASA Technical Reports Server (NTRS)

The results of the Independent Orbiter Assessment (IOA) of the Failure Modes and Effects Analysis (FMEA) and Critical Items List (CIL) are presented. The IOA first completed an analysis of the Electrical Power Distribution and Control (EPD and C) hardware, generating draft failure modes and potential critical items. To preserve independence, this analysis was accomplished without reliance upon the results contained within the NASA FMEA/CIL documentation. The IOA results were then compared to the NASA FMEA/CIL baseline with proposed Post 51-L updates included. A resolution of each discrepancy from the comparison is provided through additional analysis as required. This report documents the results of that comparison for the Orbiter EPD and C hardware. Volume 3 continues the presentation of IOA worksheets and contains the potential critical items list and the NASA FMEA to IOA worksheet cross reference and recommendations.

Schmeckpeper, K. R.

1988-01-01

194

Independent Orbiter Assessment (IOA): Assessment of the Electrical Power Distribution and Control Subsystem, Volume 2  

NASA Technical Reports Server (NTRS)

The results of the Independent Orbiter Assessment (IOA) of the Failure Modes and Effects Analysis (FMEA) and Critical Items List (CIL) are presented. The IOA first completed an analysis of the Electrical Power Distribution and Control (EPD and C) hardware, generating draft failure modes and potential critical items. To preserve independence, this analysis was accomplished without reliance upon the results contained within the NASA FMEA/CIL documentation. The IOA results were then compared to the NASA FMEA/CIL baseline with proposed Post 51-L updates included. A resolution of each discrepancy from the comparison is provided through additional analysis as required. This report documents the results of that comparison for the Orbiter EPD and C hardware. Volume 2 continues the presentation of IOA worksheets.

Schmeckpeper, K. R.

1988-01-01

195

Towards the Assessment of Distributed Vulnerabilities in Autonomic Networks and Systems  

E-print Network

Towards the Assessment of Distributed Vulnerabilities in Autonomic Networks and Systems Mart autonomic networks and systems. Distributed vul- nerabilities must be assessed over a consolidated view]. In this context, autonomic networks and systems are responsible for their own management. They have to adapt

Paris-Sud XI, Université de

196

Are Drug Companies Living Up to Their Human Rights Responsibilities? Moving Toward Assessment  

PubMed Central

Background to the debate The human rights responsibilities of drug companies have been considered for years by nongovernmental organizations, but were most sharply defined in a report by the UN Special Rapporteur on the right to health, submitted to the United Nations General Assembly in August 2008. The “Human Rights Guidelines for Pharmaceutical Companies in relation to Access to Medicines” include responsibilities for transparency, management, monitoring and accountability, pricing, and ethical marketing, and against lobbying for more protection in intellectual property laws, applying for patents for trivial modifications of existing medicines, inappropriate drug promotion, and excessive pricing. Two years after the release of the Guidelines, the PLoS Medicine Debate asks whether drug companies are living up to their human rights responsibilities. Sofia Gruskin and Zyde Raad from the Harvard School of Public Health say more assessment is needed of such responsibilities; Geralyn Ritter, Vice President of Global Public Policy and Corporate Responsibility at Merck & Co. argues that multiple stakeholders could do more to help States deliver the right to health; and Paul Hunt and Rajat Khosla introduce Mr. Hunt's work as the UN Special Rapporteur on the right to the highest attainable standard of health, regarding the human rights responsibilities of pharmaceutical companies and access to medicines. PMID:20927356

Gruskin, Sofia; Raad, Zyde

2010-01-01

197

Drug release-modulating mechanism of hydrophilic hydroxypropylmethylcellulose matrix tablets: distribution of atoms and carrier and texture analysis.  

PubMed

Although release profiles of drug from hydrophilic matrices have been well recognized, the visual distribution of hydroxypropylmethylcellulose (HPMC) and atoms inside of internal structures of hydrophilic HPMC matrices has not been characterized. In this paper, drug release mechanism from HPMC matrix tablet was investigated based on the release behaviors of HPMC, physical properties of gelled HPMC tablet and atomic distributions of formulation components using diverse instruments. A matrix tablet consisting of hydroxypropyl methylcellulose (HPMC 6, 4,000 and 100,000 mPa·s), chlorpheniramine maleate (CPM) as a model and fumed silicon dioxide (Aerosil(®) 200) was prepared via direct compression. The distribution of atoms and HPMC imaging were characterized using scanning electron microscope (SEM)/ energy-dispersive X-ray spectroscopy (EDX), and near-infrared (NIR) analysis, respectively as a function of time. A texture analyzer was also used to characterize the thickness and maintenance of gel layer of HPMC matrix tablet. The HPMC matrix tablets showed Higuchi release kinetics with no lag time against the square root of time. High viscosity grades of HPMC gave retarded release rate because of the greater swelling and gel thickness as characterized by texture analyzer. According to the NIR imaging, low-viscosity-grade HPMC (6 mPa·s) quickly leached out onto the surface of the tablet, while the high-viscosity-grade HPMC (4000 mPa·s) formed much thicker gel layer around the tablet and maintained longer via slow erosion, resulting in retarded drug release. The atomic distribution of the drug (chlorine, carbon, oxygen), HPMC (carbon, oxygen) and silicon dioxide (silica, oxygen) and NIR imaging of HPMC corresponded with the dissolution behaviors of drug as a function of time. The use of imaging and texture analyses could be applicable to explain the release- modulating mechanism of hydrophilic HPMC matrix tablets. PMID:23855499

Park, Jun-Bom; Lim, Jisung; Kang, Chin-Yang; Lee, Beom-Jin

2013-12-01

198

Drug Use Prevention Data, Missing Assessments and Survival Jennifer M. Bacik1, Susan A. Murphy1, AND James C. Anthony2  

E-print Network

Drug Use Prevention Data, Missing Assessments and Survival Analysis Jennifer M. Bacik1, Susan A of interest to investigate the incidence of initial drug experimentation or other drug use milestones;1. INTRODUCTION In many drug use prevention studies, researchers are interested in the relationship between

Murphy, Susan A.

199

Pervasive Technology in Distributed Healthcare: Simultaneous Assessment of Multiple Individuals  

Microsoft Academic Search

The current paradigm of clinic-focused healthcare is challenged by growing numbers of aging baby boomers and the concomitant cost of managing chronic health conditions. We have begun investigating an alternative to clinic-based health assessments, in which pervasive technologies are used to enable continuous monitoring and assessment of patients in a variety of settings outside of hospitals. There are many outstanding

Tamara L. Hayes; Misha Pavel; Andre Adami; Nicole Larimer; Ann Tsay

2006-01-01

200

Further assessment of Mirazid as antischistosomal drug in experimental schistosomiasis hematobium.  

PubMed

Conflicting reports are found in the literature about the efficacy of Mirazid (MZ), which is a special formulation of myrrh obtained from the stem of Commiphora molmol (Nees), Engl. tree (Burseraceae), as an antischistosomal drug. This initiated the present study to further assess this drug in experimental schistosomiasis hematobium. The drug was administered orally to hamsters infected with Schistosoma hematobium ( Bilharz, 1852 ) using 500 mg/kg body weight for six successive days on an empty stomach. The drug effect was examined after three periods: 4, 8 and 12 weeks post-treatment. Emphasis was given to certain parameters such as change in worm load, number of ova/mg tissue, oogram pattern and number of ova/g stool, and tegumental changes in the worms by electron microscopy after prolonged observation periods. The results showed very slight 3.4% worm reduction by MZ after the longest evaluation period (12 weeks), versus very high reduction (100%) by the reference drug praziquantel (PZQ). In comparison with the untreated control no change was found in the number of ova/mg tissue in MZ-treated hamsters regardless of the date of observation (4-12 weeks), versus significantly high reduction (99.6%) observed in the case of PZQ treatment. However, a significant decrease (22%) in the ratio of immature and increase in dead ova in tissues of MZ-treated hamsters was obvious at 12 weeks post treatment. In MZ-treated animals, a slight reduction (18.3%) in the number of stool eggs versus absence of eggs in PZQ-treated animals 12 weeks after treatment. Scanning electron microscopic examination of S. hematobium worms revealed intact tubercles, spines and sensory bulbs and no effect of the ventral side after MZ treatment. Meanwhile, PZQ treatment revealed extensive disruption of the tegument worm. Therefore, this experimental study gives extra support to previously reported negative evaluation about the effectiveness of this drug in the treatment of schistosomiasis against many other published positive results. This controversy about the efficacy of MZ may be attributed to inconsistency of its material which is obtained from natural origin. PMID:20645776

Ramzy, Fatem; Mahmoud, Soheir; William, Samia

2010-07-01

201

Development of a high-throughput brain slice method for studying drug distribution in the central nervous system.  

PubMed

New, more efficient methods of estimating unbound drug concentrations in the central nervous system (CNS) combine the amount of drug in whole brain tissue samples measured by conventional methods with in vitro estimates of the unbound brain volume of distribution (V(u,brain)). Although the brain slice method is the most reliable in vitro method for measuring V(u,brain), it has not previously been adapted for the needs of drug discovery research. The aim of this study was to increase the throughput and optimize the experimental conditions of this method. Equilibrium of drug between the buffer and the brain slice within the 4 to 5 h of incubation is a fundamental requirement. However, it is difficult to meet this requirement for many of the extensively binding, lipophilic compounds in drug discovery programs. In this study, the dimensions of the incubation vessel and mode of stirring influenced the equilibration time, as did the amount of brain tissue per unit of buffer volume. The use of cassette experiments for investigating V(u,brain) in a linear drug concentration range increased the throughput of the method. The V(u,brain) for the model compounds ranged from 4 to 3000 ml . g brain(-1), and the sources of variability are discussed. The optimized setup of the brain slice method allows precise, robust estimation of V(u,brain) for drugs with diverse properties, including highly lipophilic compounds. This is a critical step forward for the implementation of relevant measurements of CNS exposure in the drug discovery setting. PMID:19299522

Fridén, Markus; Ducrozet, Frederic; Middleton, Brian; Antonsson, Madeleine; Bredberg, Ulf; Hammarlund-Udenaes, Margareta

2009-06-01

202

Assessment of PEG on polymeric particles surface, a key step in drug carrier translation.  

PubMed

Injectable drug nanocarriers have greatly benefited in their clinical development from the addition of a superficial hydrophilic corona to improve their cargo pharmacokinetics. The most studied and used polymer for this purpose is poly(ethylene glycol), PEG. However, in spite of its wide use for over two decades now, there is no general consensus on the optimum PEG chain coverage-density and size required to escape from the mononuclear phagocyte system and to extend the circulation time. Moreover, cellular uptake and active targeting may have conflicting requirements in terms of surface properties of the nanocarriers which complicate even more the optimization process. These persistent issues can be largely attributed to the lack of straightforward characterization techniques to assess the coverage-density, the conformation or the thickness of a PEG layer grafted or adsorbed on a particulate drug carrier and is certainly one of the main reasons why so few clinical applications involving PEG coated particle-based drug delivery systems are under clinical trial so far. The objective of this review is to provide the reader with a brief description of the most relevant techniques used to assess qualitatively or quantitatively PEG chain coverage-density, conformation and layer thickness on polymeric nanoparticles. Emphasis has been made on polymeric particle (solid core) either made of copolymers containing PEG chains or modified after particle formation. Advantages and limitations of each technique are presented as well as methods to calculate PEG coverage-density and to investigate PEG chains conformation on the NP surface. PMID:24768790

Rabanel, Jean-Michel; Hildgen, Patrice; Banquy, Xavier

2014-07-10

203

Assessment of excess fluid distribution in chronic hemodialysis patients using bioimpedance spectroscopy  

Microsoft Academic Search

Assessment of excess fluid distribution in chronic hemodialysis patients using bioimpedance spectroscopy. Sodium and water homeostasis is abnormal in hemodialysis (HD) patients, however, the distribution of the excess fluid (extracellular vs. intracellular) has not been fully characterized. We studied the distribution of fluid using bioimpedance spectroscopy to determine if HD patients have an excess of fluid in any specific compartment

Bruce J Fisch; David M Spiegel

1996-01-01

204

Assessment and Implications of Bacterial Regrowth in Water Distribution Systems.  

National Technical Information Service (NTIS)

Two water distribution systems were studied over a 1-year period. Temporal fluctuations in a number of physical, chemical and biological parameters were examined. Total and pigmented bacterial counts, total coliforms, and fecal coliforms were determined a...

B. H. Olson

1982-01-01

205

Uses and misuses of epidemiology in shaping and assessing drug policy  

Microsoft Academic Search

Seven ways that epidemiology can be used in the analysis of drug policy are identified, as follows: to determine the causes of drug use and abuse; to monitor the levels of drug use and abuse in our communities; to identify trends over time in drug use and abuse; to complete the clinical picture of drug use and abuse; to identify

David F. Duncan

1997-01-01

206

Computational modeling of drug distribution in the posterior segment of the eye: effects of device variables and positions.  

PubMed

A computational model was developed to simulate drug distribution in the posterior segment of the eye after intravitreal injection and ocular implantation. The effects of important factors in intravitreal injection such as injection time, needle gauge and needle angle on the ocular drug distribution were studied. Also, the influences of the position and the type of implant on the concentration profile in the posterior segment were investigated. Computational Fluid Dynamics (CFD) calculations were conducted to describe the 3D convective-diffusive transport. The geometrical model was constructed based on the human eye dimensions. To simulate intravitreal injection, unlike previous studies which considered the initial shape of the injected drug solution as a sphere or cylinder, the more accurate shape was obtained by level-set method in COMSOL. The results showed that in intravitreal injection the drug concentration profile and its maximum value depended on the injection time, needle gauge and penetration angle of the needle. Considering the actual shape of the injected solution was found necessary to obtain the real concentration profile. In implant insertion, the vitreous cavity received more drugs after intraocular implantation, but this method was more invasive compared to the periocular delivery. Locating the implant in posterior or anterior regions had a significant effect on local drug concentrations. Also, the shape of implant influenced on concentration profile inside the eye. The presented model is useful for optimizing the administration variables to ensure optimum therapeutic benefits. Predicting and quantifying different factors help to reduce the possibility of tissue toxicity and to improve the treatment efficiency. PMID:24946303

Jooybar, Elaheh; Abdekhodaie, Mohammad J; Farhadi, Fatolla; Cheng, Yu-Ling

2014-09-01

207

Intelligent Assessment of Distributed Security in TCP\\/IP Networks  

Microsoft Academic Search

\\u000a With the increase of the dynamics of networks interconnection, security issues became a critical point that needs to be considered.\\u000a The widely adopted solution considers a mix of routers, switches, firewalls and virtual private networks (VPNs) together with\\u000a the deployment of intrusion detection systems (IDSs) and vulnerability assessment tools. In a proactive approach for intrusions,\\u000a vulnerability assessment tools allow the

Rui Costa Cardoso; Mário Marques Freire

2004-01-01

208

Direct estimation of multidimensional perceptual distributions: Assessing hue and form  

Microsoft Academic Search

The procedures developed to assess the perceptual and decisional processes associated with detection in multidimensional space\\u000a all require specialized statistical skills and analysis programs. The present article describes a regression model, designed\\u000a to assess dimensional interactions, that is both computationally simpler and more accessible than those procedures. The paper\\u000a validates the regression model by comparing the perceptual space associated with

Dale J. Cohen

2003-01-01

209

[An approach to the assessment of the effectiveness of a drug use prevention program in secondary education in Andalusia].  

PubMed

This article examines the analysis of drug use among Secondary Education students in Andalusia from two different studies: the Health Behavior in School-aged Children Study (HBSC), in its 2006 edition, and a study assessing the implementation of the Prevenir para Vivir ("Prevent to Live") drug use prevention program in the education field. To this end, on the one hand the paper analyzes the use of tobacco, alcohol and cannabis among Andalusian adolescents on the HBSC Study, and on the other, selects two groups of adolescents to examine and compare their drug use: a group from the HBSC Study who had not participated in any drug use prevention program and in whose schools the staff had not received training in relation to these issues (called HBSC Control Group), and a group of adolescents who had participated in the Prevenir para Vivir drug use prevention program working with specialized staff (called Prevenir para Vivir Experimental Group). The results indicate, first, higher levels of drug use in older students than in younger ones; and, second, on comparing the two groups, that adolescents who have received drug prevention programs with specialized staff are not always those most likely to present healthier drug use. These results must therefore be interpreted as offering only limited support to drug use prevention programs. PMID:20802988

Jiménez-Iglesias, Antonia; Moreno, Carmen; Oliva, Alfredo; Ramos, Pilar

2010-01-01

210

A secure distributed logistic regression protocol for the detection of rare adverse drug events  

PubMed Central

Background There is limited capacity to assess the comparative risks of medications after they enter the market. For rare adverse events, the pooling of data from multiple sources is necessary to have the power and sufficient population heterogeneity to detect differences in safety and effectiveness in genetic, ethnic and clinically defined subpopulations. However, combining datasets from different data custodians or jurisdictions to perform an analysis on the pooled data creates significant privacy concerns that would need to be addressed. Existing protocols for addressing these concerns can result in reduced analysis accuracy and can allow sensitive information to leak. Objective To develop a secure distributed multi-party computation protocol for logistic regression that provides strong privacy guarantees. Methods We developed a secure distributed logistic regression protocol using a single analysis center with multiple sites providing data. A theoretical security analysis demonstrates that the protocol is robust to plausible collusion attacks and does not allow the parties to gain new information from the data that are exchanged among them. The computational performance and accuracy of the protocol were evaluated on simulated datasets. Results The computational performance scales linearly as the dataset sizes increase. The addition of sites results in an exponential growth in computation time. However, for up to five sites, the time is still short and would not affect practical applications. The model parameters are the same as the results on pooled raw data analyzed in SAS, demonstrating high model accuracy. Conclusion The proposed protocol and prototype system would allow the development of logistic regression models in a secure manner without requiring the sharing of personal health information. This can alleviate one of the key barriers to the establishment of large-scale post-marketing surveillance programs. We extended the secure protocol to account for correlations among patients within sites through generalized estimating equations, and to accommodate other link functions by extending it to generalized linear models. PMID:22871397

El Emam, Khaled; Samet, Saeed; Arbuckle, Luk; Tamblyn, Robyn; Earle, Craig; Kantarcioglu, Murat

2013-01-01

211

"Herbal incense": designer drug blends as cannabimimetics and their assessment by drug discrimination and other in vivo bioassays.  

PubMed

Recently, synthetic cannabinoids originally designed for testing in the laboratory only have found use recreationally in designer herbal blends, originally called "Spice". The myriad of compounds found are for the most part potent full agonists of the cannabinoid receptor 1, producing effects similar to tetrahydrocannabinol (THC) and marijuana. Drug discrimination of these compounds offers a specific behavioral test that can help determine whether these new synthetic compounds share a similar "subjective high" with the effects of marijuana/THC. By utilization of drug discrimination and other behavioral techniques, a better understanding of these new "designer" cannabinoids may be reached to assist in treating both the acute and chronic effects of these drugs. The paper provides a brief exposé of modern cannabinoid research as a backdrop to the recreational use of designer herbal blend cannabimimetics. PMID:23891559

Järbe, Torbjörn U C; Gifford, Roger S

2014-02-27

212

Assessment of a Candidate Marker Constituent Predictive of a Dietary Substance-Drug Interaction: Case Study with Grapefruit Juice and CYP3A4 Drug Substrates.  

PubMed

Dietary substances, including herbal products and citrus juices, can perpetrate interactions with conventional medications. Regulatory guidances for dietary substance-drug interaction assessment are lacking. This deficiency is due in part to challenges unique to dietary substances, a lack of requisite human-derived data, and limited jurisdiction. An in vitro-in vivo extrapolation (IVIVE) approach to help address some of these hurdles was evaluated using the exemplar dietary substance grapefruit juice (GFJ), the candidate marker constituent 6',7'-dihydroxybergamottin (DHB), and the purported victim drug loperamide. First, the GFJ-loperamide interaction was assessed in 16 healthy volunteers. Loperamide (16 mg) was administered with 240 ml of water or GFJ; plasma was collected from 0 to 72 hours. Relative to water, GFJ increased the geometric mean loperamide area under the plasma concentration-time curve (AUC) significantly (1.7-fold). Second, the mechanism-based inhibition kinetics for DHB were recovered using human intestinal microsomes and the index CYP3A4 reaction, loperamide N-desmethylation (KI [concentration needed to achieve one-half kinact], 5.0 ± 0.9 µM; kinact [maximum inactivation rate constant], 0.38 ± 0.02 minute(-1)). These parameters were incorporated into a mechanistic static model, which predicted a 1.6-fold increase in loperamide AUC. Third, the successful IVIVE prompted further application to 15 previously reported GFJ-drug interaction studies selected according to predefined criteria. Twelve of the interactions were predicted to within the 25% predefined criterion. Results suggest that DHB could be used to predict the CYP3A4-mediated effect of GFJ. This time- and cost-effective IVIVE approach could be applied to other dietary substance-drug interactions to help prioritize new and existing drugs for more advanced (dynamic) modeling and simulation and clinical assessment. PMID:25253884

Ainslie, Garrett R; Wolf, Kristina K; Li, Yingxin; Connolly, Elizabeth A; Scarlett, Yolanda V; Hull, J Heyward; Paine, Mary F

2014-12-01

213

Characterization of Lung's Emphysema Distribution: Numerical Assessment of Disease Development  

E-print Network

, Egypt. Abstract--Chronic Obstructive Pulmonary Disease (COPD) refers to a group of lung diseases are the two main conditions that make up COPD, but COPD can also refer to damage caused by chronic asthmatic- Digital image treatments, air density distribution and emphysema characterizations. I. INTRODUCTION

Paris-Sud XI, Université de

214

Particle Size Distribution to Assess the Performance of Trickling Filters  

Microsoft Academic Search

Particle size distributions by laser scatter analysis were compared with other solids settlement performance indicators from trickling filters. Field and laboratory pilot plant data indicated smaller less flocculated solids from trickling filters than activated sludge or rotating biological contractors (RBC). Analysis of utility company treatment plants indicated settlement characteristics were linked to less consistent performance from the trickling filters compared

R. Marquet; N. Muhammad; K. Vairavamoorthy; A. Wheatley

2007-01-01

215

Assessing a Tornado Climatology from Global Tornado Intensity Distributions  

Microsoft Academic Search

Recent work demonstrated that the shape of tornado intensity distributions from various regions worldwide is well described by Weibull functions. This statistical modeling revealed a strong correlation between the fit parameters c for shape and b for scale regardless of the data source. In the present work it is shown that the quality of the Weibull fits is optimized if

Bernold Feuerstein; Nikolai Dotzek; Jürgen Grieser

2005-01-01

216

Using the Quality of Well-Being Scale to Assess Quality of Life in Out-of-Treatment Drug Users  

Microsoft Academic Search

The Quality of Well-Being Scale (QWB) was developed for use with diverse patient and general population samples. This study investigated its use with a sample of out-of-treatment drug users. The QWB was administered to 75 out-of-treatment drug users. A linear regression model was developed using the QWB score as the dependent variable and items from the Risk Behavior Assessment (RBA)

Grace L. Reynolds; Dennis G. Fisher; Jennifer A. Klahn; Michele M. Wood

2003-01-01

217

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

PubMed

The plant alkaloid ibogaine has promising anti-addictive properties. Albeit not licensed as a therapeutic drug, and despite hints that ibogaine may perturb the heart rhythm, this alkaloid is used to treat drug addicts. We have recently reported that ibogaine inhibits human ERG (hERG) potassium channels at concentrations similar to the drugs affinity for several of its known brain targets. Thereby the drug may disturb the heart's electrophysiology. Here, to assess the drug's cardiac ion channel profile in more detail, we studied the effects of ibogaine and its congener 18-Methoxycoronaridine (18-MC) on various cardiac voltage-gated ion channels. We confirmed that heterologously expressed hERG currents are reduced by ibogaine in low micromolar concentrations. Moreover, at higher concentrations, the drug also reduced human Nav1.5 sodium and Cav1.2 calcium currents. Ion currents were as well reduced by 18-MC, yet with diminished potency. Unexpectedly, although blocking hERG channels, ibogaine did not prolong the action potential (AP) in guinea pig cardiomyocytes at low micromolar concentrations. Higher concentrations (? 10 ?M) even shortened the AP. These findings can be explained by the drug's calcium channel inhibition, which counteracts the AP-prolonging effect generated by hERG blockade. Implementation of ibogaine's inhibitory effects on human ion channels in a computer model of a ventricular cardiomyocyte, on the other hand, suggested that ibogaine does prolong the AP in the human heart. We conclude that therapeutic concentrations of ibogaine have the propensity to prolong the QT interval of the electrocardiogram in humans. In some cases this may lead to cardiac arrhythmias. PMID:23707769

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

2013-12-01

218

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

PubMed Central

The plant alkaloid ibogaine has promising anti-addictive properties. Albeit not licenced as a therapeutic drug, and despite hints that ibogaine may perturb the heart rhythm, this alkaloid is used to treat drug addicts. We have recently reported that ibogaine inhibits human ERG (hERG) potassium channels at concentrations similar to the drugs affinity for several of its known brain targets. Thereby the drug may disturb the heart's electrophysiology. Here, to assess the drug's cardiac ion channel profile in more detail, we studied the effects of ibogaine and its congener 18-Methoxycoronaridine (18-MC) on various cardiac voltage-gated ion channels. We confirmed that heterologously expressed hERG currents are reduced by ibogaine in low micromolar concentrations. Moreover, at higher concentrations, the drug also reduced human Nav1.5 sodium and Cav1.2 calcium currents. Ion currents were as well reduced by 18-MC, yet with diminished potency. Unexpectedly, although blocking hERG channels, ibogaine did not prolong the action potential (AP) in guinea pig cardiomyocytes at low micromolar concentrations. Higher concentrations (? 10 ?M) even shortened the AP. These findings can be explained by the drug's calcium channel inhibition, which counteracts the AP-prolonging effect generated by hERG blockade. Implementation of ibogaine's inhibitory effects on human ion channels in a computer model of a ventricular cardiomyocyte, on the other hand, suggested that ibogaine does prolong the AP in the human heart. We conclude that therapeutic concentrations of ibogaine have the propensity to prolong the QT interval of the electrocardiogram in humans. In some cases this may lead to cardiac arrhythmias. PMID:23707769

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

2013-01-01

219

Assessment of QT-prolonging drugs in the isolated normal and failing rabbit hearts.  

PubMed

Lengthening of QTc is the usual signal to indicate torsadogenic potential of a therapeutic agent. The ICH S7B guideline recommends that new chemical entities should be assessed for potential of delayed ventricular repolarization in animal models. The aim of this study was to determine a feasibility of using isolated failing heart rabbit to assess the QT-lengthening drugs in comparison with their effects on isolated normal heart rabbits. Heart failure was induced by ligation of the left anterior descending and descending branch of left circumflex coronary arteries. One month after ligation, all rabbits were anesthetized and the hearts were removed quickly, and they were perfused with the oxygenated Krebs-Henseleit solution to which escalating concentrations of QT-lengthening compounds were added. RR, QT, and QTc(F) were not significantly different, at rest, between failing and normal hearts. During baseline, dP/dtmax was lower and dP/dtmin was higher for failing hearts than for normals. In responses to all three QT-lengthening compounds, RR, QT and QTc(F) lengthened similarly in a dose-response manner in both the failing and normal hearts. Neither the failing nor the normal hearts developed fatal arrhythmias, torsades de pointes. Langendorff preparations of failing hearts are as good as normal isolated hearts and can be use to assess the potential of delayed ventricular repolarization of test articles. PMID:22687985

Kijtawornrat, Anusak; Sawangkoon, Suwanakiet; Hamlin, Robert L

2012-01-01

220

[New system for diagnosing acute circulatory disorders and assessing drug choice and dosage].  

PubMed

The assessment of the status of a patient and diagnosis are first made strictly algorithmically. At the same time the procedure is monitored by a physician in terms of his experience and knowledge. The dialogue is made on the basis of a model and images which reflect the pattern of blood circulation. The diagnosis is made by isolating the key pathophysiological link and interpreting it by means of a clinico-mathematical classification. The usual wording based on the evaluation of the severity and stage of a pathological process is supplemented with assessments of compensatory, protective, and other adaptive changes which greatly influence the choice of a therapy. The action of drugs is evaluated by their cumulative effects on the changes in physiological functions determining their properties, direction and magnitude of alterations of the weakest link. The clinical experience has shown that the procedure is beneficial for rapid detection of clinically significant changes, choice and assessment of therapeutical efforts just during an operation and in the early postoperative period. PMID:8148177

Burakovski?, V I; Lishchuk, V A; Gazizova, D Sh

1993-01-01

221

COMMENT ON: APPLYING SPECIES-SENSITIVITY DISTRIBUTIONS IN ECOLOGICAL RISK ASSESSMENT: ASSUMPTION OF DISTRIBUTION TYPE AND SUFFICIENT NUMBER OF SPECIES  

EPA Science Inventory

Newman et al. (2000) addressed some important issues regarding the characterization of species-sensitivity distributions (SSDs) used in ecological risk assessments. A common assumption is that SSDs are log-normal, and this allows data sets to be analyzed by standard parametric me...

222

Duplex quantitative Reverse-Transcriptase PCR for simultaneous assessment of drug activity against Leishmania intracellular amastigotes and their host cells?  

PubMed Central

Currently available drugs for treatment of Leishmania infections are highly toxic and drug resistance to first line therapies has been observed. New, safer and more effective drugs are urgently needed to improve clinical resolution of the disease and reduce the risks associated with it. High-throughput screening of new compounds against cultured promastigotes is easy to perform, but the results are poorly predictive of in vivo efficacy. Intra-macrophage amastigote models provide a better proxy of the clinically relevant stage of disease and should be routinely implemented in the search for new anti-leishmanial agents, despite being labor intensive. This study describes the use of a duplex quantitative Reverse-Transcriptase PCR (qRT-PCR) for assessment of drug activity against Leishmania intracellular amastigotes and their host cells. The assay simultaneously quantifies Leishmania 18S ribosomal RNA and the human ?2-microglobulin (?-2M) mRNA, used for monitoring drug cytotoxicity and test performance. Accurate determination of parasite viability by the newly developed qRT-PCR was confirmed by parallel assessment of compound performance against standard microscopy. Highly reproducible anti-leishmanial activities were obtained with a set of structurally- and pharmacologically-diverse compounds, whose toxicity against host cells correlated with a low ?-2M amplification. Sensitive and versatile, this duplex qRT-PCR offers a valuable tool for assessment of drug activities against Leishmania amastigotes and their host cells. PMID:24596664

van den Bogaart, Erika; Schoone, Gerard J.; Adams, Emily R.; Schallig, Henk D.F.H.

2013-01-01

223

Assessment of non-steroidal anti-inflammatory drug (NSAID) damage in the human gastrointestinal tract  

PubMed Central

Aspirin is widely prescribed and confers considerable benefit to patients by reducing cardiovascular and cerebrovascular morbidity and mortality. Nonsteroidal anti-inflammatory drugs (NSAIDs) are effective analgesics, antipyretics and reduce the inflammatory component in conditions such as rheumatoid arthritis. However, both agents are associated with an increased risk of gastrointestinal symptoms and the potentially serious consequences of gastroduodenal ulceration, bleeding and perforation. The introduction of highly selective cyclo-oxygenase (COX)-2 inhibitors or the coprescription gastroprotective agents with nonselective NSAIDs have offered strategies to reduce the incidence of such events. This review article analyzes the quantitative techniques that can be employed by clinical pharmacologists and the clinical studies performed to assess NSAID damage in the gastrointestinal tract. PMID:12895187

James, Martin W; Hawkey, Christopher J

2003-01-01

224

Assessment of Distributed Generation Potential in JapaneseBuildings  

SciTech Connect

To meet growing energy demands, energy efficiency, renewable energy, and on-site generation coupled with effective utilization of exhaust heat will all be required. Additional benefit can be achieved by integrating these distributed technologies into distributed energy resource (DER) systems (or microgrids). This research investigates a method of choosing economically optimal DER, expanding on prior studies at the Berkeley Lab using the DER design optimization program, the Distributed Energy Resources Customer Adoption Model (DER-CAM). DER-CAM finds the optimal combination of installed equipment from available DER technologies, given prevailing utility tariffs, site electrical and thermal loads, and a menu of available equipment. It provides a global optimization, albeit idealized, that shows how the site energy loads can be served at minimum cost by selection and operation of on-site generation, heat recovery, and cooling. Five prototype Japanese commercial buildings are examined and DER-CAM applied to select the economically optimal DER system for each. The five building types are office, hospital, hotel, retail, and sports facility. Based on the optimization results, energy and emission reductions are evaluated. Furthermore, a Japan-U.S. comparison study of policy, technology, and utility tariffs relevant to DER installation is presented. Significant decreases in fuel consumption, carbon emissions, and energy costs were seen in the DER-CAM results. Savings were most noticeable in the sports facility (a very favourable CHP site), followed by the hospital, hotel, and office building.

Zhou, Nan; Marnay, Chris; Firestone, Ryan; Gao, Weijun; Nishida,Masaru

2005-05-25

225

Novel hydrophilic drug polymer nano-conjugates of Cisplatin showing long blood retention profile: its release kinetics, cellular uptake and bio-distribution.  

PubMed

The present study evaluates the efficacy of drug polymer self folding nano-conjugates of pectin-cisplatin to enhance blood circulating levels of cisplatin. The binding of nano-conjugate was confirmed by a peak-shift in UV-spectra. Physical characterization was done by DLS and TEM. Pharmacokinetics and bio-distribution of the nano-conjugates were performed at various time points in normal, Balb-c mice. Zeta Potential showed the shielding effect on the negative potential of pectin that was approximately 7 times more than the pectin chains when conjugated with cisplatin. TEM confirmed the formation of a hydrophilic, easily re-dispersible nano-conjugate in the size range of 100 nm. Release kinetics in plasma showed that the pectin-cisplatin conjugate is a stable, slow and sustained system with no burst effect. Immuno-fluorescence analysis of J-774, a mouse macrophage cell line, was assessed after incubating the cells with pectin chains tagged with FITC as well as Pectin-Cisplatin-FITC conjugates. With the cellular uptake of these particles in J-774, 40% of the cells showed an uptake post 30 min of incubation. However, Pectin chains were clearly eliminated. The plasma proteins facilitate the release of cisplatin with 85-89% of the drug being released in 17 days, and only 57% of drug was released in approximately 30 days without plasma. The reduced negative charge on the conjugate helps in adhesion to the cell surface and subsequent uptake by cells as evidenced by cell uptake studies on J-774 cell line. Nano-conjugates showed long blood retention profile in mice and the cisplatin was found in circulation even after 24 hrs. Pharmacokinetic study clearly indicates that it can form a novel anticancer drug that possesses good efficacy and has a safer profile than cisplatin. PMID:18393814

Verma, Anita K; Sachin, K

2008-04-01

226

Diagnostic Accuracy of Kato-Katz and FLOTAC for Assessing Anthelmintic Drug Efficacy  

PubMed Central

Background Sensitive diagnostic tools are required for an accurate assessment of prevalence and intensity of helminth infections in areas undergoing regular deworming, and for monitoring anthelmintic drug efficacy. We compared the diagnostic accuracy of the Kato-Katz and FLOTAC techniques in the frame of a drug efficacy trial. Methodology/Principal Findings Stool samples from 343 Zanzibari children were subjected to duplicate Kato-Katz thick smears and the FLOTAC basic technique in a baseline screening in early 2009. The FLOTAC showed a higher sensitivity than the Kato-Katz method for the diagnosis of Trichuris trichiura (95% vs. 88%, p?=?0.012) and Ascaris lumbricoides (88% vs. 68%, p?=?0.098), but a lower sensitivity for hookworm diagnosis (54% vs. 81%, p?=?0.006). Considering the combined results from both methods as ‘gold’ standard, the prevalences of T. trichiura, hookworm and A. lumbricoides were 71% (95% confidence interval (CI): 66–75%), 22% (95% CI: 17–26%) and 12% (95% CI: 8–15%), respectively. At follow-up, 3–5 weeks after 174 among the 269 re-examined children were administered anthelmintic drugs, we observed cure rates (CRs) against A. lumbricoides, hookworm and T. trichiura of 91% (95% CI: 80–100%), 61% (95% CI: 48–75%) and 41% (95% CI: 34–49%), respectively, when using the Kato-Katz method. FLOTAC revealed lower CRs against A. lumbricoides (83%, 95% CI: 67–98%) and T. trichiura (36%, 95% CI: 29–43%), but a higher CR against hookworm (69%, 95% CI: 57–82%). These differences, however, lacked statistical significance. Considerable differences were observed in the geometric mean fecal egg counts between the two methods with lower egg reduction rates (ERRs) determined by FLOTAC. Conclusion/Significance Our results suggest that the FLOTAC technique, following further optimization, might become a viable alternative to the Kato-Katz method for anthelmintic drug efficacy studies and for monitoring and evaluation of deworming programs. The lower CRs and ERRs determined by FLOTAC warrant consideration and could strategically impact future helminth control programs. PMID:21532740

Knopp, Stefanie; Speich, Benjamin; Hattendorf, Jan; Rinaldi, Laura; Mohammed, Khalfan A.; Khamis, I. Simba; Mohammed, Alisa S.; Albonico, Marco; Rollinson, David; Marti, Hanspeter; Cringoli, Giuseppe; Utzinger, Jurg

2011-01-01

227

Magnetic Field Distribution and Application of a Transcranial Magnetic Stimulation for Drug Addicts  

Microsoft Academic Search

This article introduces the property of magnetic field distribution and application of TMS developed by BJUT. The TMS generates time-varying magnetic field to stimulate the particular area in human brain. To obtain the distribution of magnetic density, we carried out survey by utilizing a Gauss meter, from three aspects: the distribution of magnetic density in axial direction, in radial direction

Yu Chang; Miao Song; Bin Gao; Ningning Chen; Ling Li; Hongxing Wang

2009-01-01

228

Assessing the spatial distribution of nitrogen dioxide in London, Ontario.  

PubMed

Land use regression (LUR) models have been widely used to characterize the spatial distribution of urban air pollution and estimate exposure in epidemiologic studies. However, spatial patterns of air pollution vary greatly between cities due to local source type and distribution. London, Ontario, Canada, is a medium-sized city with relatively few and isolated industrial point sources, which allowed the study to focus on the contribution of different transportation sectors to urban air pollution. This study used LUR models to estimate the spatial distribution of nitrogen dioxide (NO2) and to identify local sources influencing NO2 concentrations in London, ON. Passive air sampling was conducted at 50 locations throughout London over a 2-week period in May-June 2010. NO2 concentrations at the monitored locations ranged from 2.8 to 8.9 ppb, with a median of 5.2 ppb. Industrial land use, dwelling density, distance to highway, traffic density, and length of railways were significant predictors of NO2 concentrations in the final LUR model, which explained 78% of NO2 variability in London. Traffic and dwelling density explained most of the variation in NO2 concentrations, which is consistent with LUR models developed in other Canadian cities. We also observed the importance of local characteristics. Specifically, 17% of the variation was explained by distance to highways, which included the impacts of heavily traveled corridors transecting the southern periphery of the city. Two large railway yards and railway lines throughout central areas of the city explained 9% of NO2 variability. These results confirm the importance of traditional LUR variables and highlight the importance of including a broader array of local sources in LUR modeling. Finally, future analyses will use the model developed in this study to investigate the association between ambient air pollution and cardiovascular disease outcomes, including plaque burden, cholesterol, and hypertension. PMID:23210225

Oiamo, Tor H; Luginaah, Isaac N; Buzzelli, Michael; Tang, Kathy; Xu, Xiaohong; Brook, Jeffrey R; Johnson, Markey

2012-11-01

229

Application of distribution coefficients to radiological assessment models  

SciTech Connect

A field and laboratory investigation of the transport of fallout radionuclides in natural, organic rich ecosystems has been initiated. Mountain-top peat bogs in Pennsylvania, New York and Virginia were sampled by coring, dated by Pb-210 methods and measured for bomb-produced Sr-90, Pu-239, 240, and Cs-137; laboratory measurements of the distribution coefficients for Cs-137, Sr-85, Ru-106, Am-241, and Co-57 by the constant shaking method have been made. These natural terrestrial ecosystems are labeled with fallout radionuclides from nuclear weapons tests which are environmental tracers of element transport. To explain the differences between the input from fallout and the distribution of Cs-137 in peat cores, a simple ''theoretical plate'' transport model has been used. Each year of growth is assumed to be a ''theoretical plate'' and Cs-137 deposited is transferred between plates by advection and mixing processes. The annual deposition of Cs-137 occurs on the (then) uppermost layer and is proportional to the atmospheric input. The theoretical plate model finds values of the advection and mixing coefficients which give the best fit between Cs-137 profile in the bog and the atmospherically-derived Cs-137. For the three bogs tested so far, the advection coefficients indicate an upward movement of Cs-137 as well as downward transport. Values for the diffusion coefficient range from 10E/sup -7/ to 10E/sup -9/ cm/sup 2/ s/sup -1/ depending on organic content and porosity. The mass transport values from the model are compared to laboratory measurements of distribution coefficients in simulated acid rain conditions. Based on the diffusion coefficients calculated from the model, a thickness of 8 to 20 cm of peat surrounding a leaking cannister of Cs-137 would not allow the radionuclide to enter an aquifer for 300 years from a low level waste disposal site.

Schell, W.R.; Sanchez, A.L.; Underhill, D.W.; Thomas, E.

1985-01-01

230

Pathway-dependent inhibition of paclitaxel hydroxylation by kinase inhibitors and assessment of drug-drug interaction potentials.  

PubMed

Paclitaxel is often used in combination with small molecule kinase inhibitors to enhance antitumor efficacy against various malignancies. Because paclitaxel is metabolized by CYP2C8 and CYP3A4, the possibility of drug-drug interactions mediated by enzyme inhibition may exist between the combining agents. In the present study, a total of 12 kinase inhibitors were evaluated for inhibitory potency in human liver microsomes by monitoring the formation of CYP2C8 and CYP3A4 metabolites simultaneously. For reversible inhibition, nilotinib was found to be the most potent inhibitor against both CYP2C8 and CYP3A4, and the inhibition potency could be explained by strong hydrogen binding based on molecular docking simulations and type II binding based on spectral analysis. Comparison of K(i) values revealed that the CYP2C8 pathway was more sensitive toward some kinase inhibitors (such as axitinib), while the CYP3A4 pathway was preferentially inhibited by others (such as bosutinib). Pathway-dependent inactivation (time-dependent inhibition) was also observed for a number of kinase inhibitors against CYP3A4 but not CYP2C8. Further studies showed that axitinib had a K(I) of 0.93 ?M and k(inact) of 0.0137 min(-1), and the observed inactivation toward CYP3A4 was probably due to the formation of reactive intermediate(s). Using a static model, a reasonably accurate prediction of drug-drug interactions was achieved by incorporating parallel pathways and hepatic extraction ratio. The present results suggest that potent and pathway-dependent inhibition of CYP2C8 and/or CYP3A4 pathways by kinase inhibitors may alter the ratio of paclitaxel metabolites in vivo, and that such changes can be clinically relevant as differential metabolism has been linked to paclitaxel-induced neurotoxicity in cancer patients. PMID:24476576

Wang, Yedong; Wang, Meiyu; Qi, Huixin; Pan, Peichen; Hou, Tingjun; Li, Jiajun; He, Guangzhao; Zhang, Hongjian

2014-04-01

231

Assessing mechanical vulnerability in water distribution networks under multiple failures  

NASA Astrophysics Data System (ADS)

mechanical vulnerability of water distribution networks (WDN) is of direct relevance for water utilities since it entails two different purposes. On the one hand, it might support the identification of severe failure scenarios due to external causes (e.g., natural or intentional events) which result into the most critical consequences on WDN supply capacity. On the other hand, it aims at figure out the WDN portions which are more prone to be affected by asset disruptions. The complexity of such analysis stems from the number of possible scenarios with single and multiple simultaneous shutdowns of asset elements leading to modifications of network topology and insufficient water supply to customers. In this work, the search for the most disruptive combinations of multiple asset failure events is formulated and solved as a multiobjective optimization problem. The higher vulnerability failure scenarios are detected as those causing the lower supplied demand due to the lower number of simultaneous failures. The automatic detection of WDN topology, subsequent to the detachments of failed elements, is combined with pressure-driven analysis. The methodology is demonstrated on a real water distribution network. Results show that, besides the failures causing the detachment of reservoirs, tanks, or pumps, there are other different topological modifications which may cause severe WDN service disruptions. Such information is of direct relevance to support planning asset enhancement works and improve the preparedness to extreme events.

Berardi, Luigi; Ugarelli, Rita; Røstum, Jon; Giustolisi, Orazio

2014-03-01

232

Characterisation of neutron fields: challenges in assessing the directional distribution.  

PubMed

The SCK·CEN has carried out neutron field characterisation campaigns at several nuclear reactors. The main goal of these measurement campaigns was to evaluate the performance of different neutron personal dosemeters. To be able to evaluate the performance of neutron personal dosemeters in terms of Hp(10), knowledge of the directional distribution is indispensable. This distribution was estimated by placing several personal dosemeters on all six sides of a slab phantom. The interpretation and conversion of this information into a reliable value for Hp(10) requires great care. The data were analysed using three methods. In the first approach, a linear interpolation was performed on three perpendicular axes. In the other two approaches, an icosahedron was used to model the angle of incidence of the neutrons and a linear interpolation or a Bayesian analysis was performed. This study describes the limitations and advantages of each of these methods and provides recommendations for their use to estimate the personal dose equivalent Hp(10) for neutron dosimetry. PMID:24966340

Cauwels, Vanessa; Vanhavere, Filip; Reginatto, Marcel

2014-10-01

233

Microneedle-Based Intradermal Delivery Enables Rapid Lymphatic Uptake and Distribution of Protein Drugs  

Microsoft Academic Search

Purpose  The purpose of this research was to examine the pharmacokinetics (PK) of drug uptake for microneedle-based intradermal (ID)\\u000a delivery of several classes of protein drugs compared to standard subcutaneous (SC) administration.\\u000a \\u000a \\u000a \\u000a \\u000a Methods  Systemic absorption kinetics of various proteins were analyzed following microneedle-based ID delivery and standard injection\\u000a methods in the swine model. Comparative PK data were determined using standard non-compartmental techniques

Alfred J. Harvey; Scott A. Kaestner; Diane E. Sutter; Noel G. Harvey; John A. Mikszta; Ronald J. Pettis

2011-01-01

234

Di-22:6-bis(monoacylglycerol)phosphate: A clinical biomarker of drug-induced phospholipidosis for drug development and safety assessment.  

PubMed

The inability to routinely monitor drug-induced phospholipidosis (DIPL) presents a challenge in pharmaceutical drug development and in the clinic. Several nonclinical studies have shown di-docosahexaenoyl (22:6) bis(monoacylglycerol) phosphate (di-22:6-BMP) to be a reliable biomarker of tissue DIPL that can be monitored in the plasma/serum and urine. The aim of this study was to show the relevance of di-22:6-BMP as a DIPL biomarker for drug development and safety assessment in humans. DIPL shares many similarities with the inherited lysosomal storage disorder Niemann-Pick type C (NPC) disease. DIPL and NPC result in similar changes in lysosomal function and cholesterol status that lead to the accumulation of multi-lamellar bodies (myeloid bodies) in cells and tissues. To validate di-22:6-BMP as a biomarker of DIPL for clinical studies, NPC patients and healthy donors were classified by receiver operator curve analysis based on urinary di-22:6-BMP concentrations. By showing 96.7-specificity and 100-sensitivity to identify NPC disease, di-22:6-BMP can be used to assess DIPL in human studies. The mean concentration of di-22:6-BMP in the urine of NPC patients was 51.4-fold (p ? 0.05) above the healthy baseline range. Additionally, baseline levels of di-22:6-BMP were assessed in healthy non-medicated laboratory animals (rats, mice, dogs, and monkeys) and human subjects to define normal reference ranges for nonclinical/clinical studies. The baseline ranges of di-22:6-BMP in the plasma, serum, and urine of humans and laboratory animals were species dependent. The results of this study support the role of di-22:6-BMP as a biomarker of DIPL for pharmaceutical drug development and health care settings. PMID:24967688

Liu, Nanjun; Tengstrand, Elizabeth A; Chourb, Lisa; Hsieh, Frank Y

2014-09-15

235

Characterization of four new designer drugs, 5-chloro-NNEI, NNEI indazole analog, ?-PHPP and ?-POP, with 11 newly distributed designer drugs in illegal products.  

PubMed

Our continuous survey of illegal products in Japan revealed the new distribution of 15 designer drugs. We identified four synthetic cannabinoids, i.e., NNEI (1), 5-fluoro-NNEI (2), 5-chloro-NNEI (3) and NNEI indazole analog (4), and seven cathinone derivatives, i.e., MPHP (5), ?-PHPP (6), ?-POP (7), 3,4-dimethoxy-?-PVP (8), 4-fluoro-?-PVP (9), ?-ethylaminopentiophenone (10) and N-ethyl-4-methylpentedrone (11). We also determined LY-2183240 (12) and its 2'-isomer (13), which were reported to inhibit endocannabinoid uptake, a methylphenidate analog, 3,4-dichloromethylphenidate (14), and an MDA analog, 5-APDB (15). No chemical and pharmaceutical data for compounds 3, 4, 6 and 7 had been reported, making this the first report on these compounds. PMID:24769262

Uchiyama, Nahoko; Matsuda, Satoru; Kawamura, Maiko; Shimokawa, Yoshihiko; Kikura-Hanajiri, Ruri; Aritake, Kosuke; Urade, Yoshihiro; Goda, Yukihiro

2014-10-01

236

Condition Assessment of Ferrous Water Transmission and Distribution Systems State of Technology Review Report  

EPA Science Inventory

This White Paper was developed to serve as the basis for discussion at a Technology Forum on Condition Assessment of Water Transmission and Distribution Systems that was held on September 9 and 10, 2008, at Edison, NJ. It was distributed to the Forum participants for review in a...

237

Can Brazil play a more important role in global tuberculosis drug production? An assessment of current capacity and challenges  

PubMed Central

Background Despite the existence of effective treatment, tuberculosis is still a global public health issue. The World Health Organization recommends a six-month four-drug regimen in fixed-dose combination formulation to treat drug sensitive tuberculosis, and long course regimens with several second-line drugs to treat multi-drug resistant tuberculosis. To achieve the projected tuberculosis elimination goal by 2050, it will be essential to ensure a non-interrupted supply of quality-assured tuberculosis drugs. However, quality and affordable tuberculosis drug supply is still a significant challenge for National Tuberculosis Programs. Discussion Quality drug production requires a combination of complex steps. The first challenge is to guarantee the quality of tuberculosis active pharmaceutical ingredients, then ensure an adequate manufacturing process, according to international standards, to guarantee final product´s safety, efficacy and quality. Good practices for storage, transport, distribution and quality control procedures must follow. In contrast to other high-burden countries, Brazil produces tuberculosis drugs through a strong network of public sector drug manufacturers regulated by a World Health Organization-certified national sanitary authority. The installed capacity for production surpasses the 71,000 needed treatments in the country. However, in order to be prepared to act as a global supplier, important bottlenecks are to be overcome. This article presents an in-depth analysis of the current status of production of tuberculosis drugs in Brazil and the bottlenecks and opportunities for the country to sustain national demand and play a role as a potential global supplier. Raw material and drug production, quality control, international certification and pre-qualification, political commitment and regulatory aspects are discussed, as well recommendations for tackling these bottlenecks. This discussion becomes more important as new drugs and regimens to treat tuberculosis are expected in a close future. Summary International manufacturers of raw material for tuberculosis treatment should undergo certification and pre-qualify their active pharmaceutical ingredients as a first step to ensure quality of tuberculosis drugs. At the country level, Brazilian public manufacturers should apply for international certification and tuberculosis drugs should be pre-qualified by international organisms. Finally, only with political commitment and large-scale production will Brazilian public sector manufacturers be able to partially supply the global market. PMID:23537151

2013-01-01

238

A distributed, collaborative intelligent agent system approach for proactive postmarketing drug safety surveillance  

Microsoft Academic Search

Discovering unknown adverse drug reactions (ADRs) in postmarketing surveillance as early as possible is of great importance. The current approach to postmarketing surveillance primarily relies on spontaneous reporting. It is a passive surveillance system and limited by gross underreporting (<10% reporting rate), latency, and inconsistent reporting. We propose a novel team-based intelligent agent software system approach for proactively monitoring and

Yanqing Ji; Hao Ying; Margo S. Farber; John Yen; Peter Dews; Richard E. Miller; R. Michael Massanari

2010-01-01

239

A distributed, collaborative intelligent agent system approach for proactive postmarketing drug safety surveillance.  

PubMed

Discovering unknown adverse drug reactions (ADRs) in postmarketing surveillance as early as possible is of great importance. The current approach to postmarketing surveillance primarily relies on spontaneous reporting. It is a passive surveillance system and limited by gross underreporting (<10% reporting rate), latency, and inconsistent reporting. We propose a novel team-based intelligent agent software system approach for proactively monitoring and detecting potential ADRs of interest using electronic patient records. We designed such a system and named it ADRMonitor. The intelligent agents, operating on computers located in different places, are capable of continuously and autonomously collaborating with each other and assisting the human users (e.g., the food and drug administration (FDA), drug safety professionals, and physicians). The agents should enhance current systems and accelerate early ADR identification. To evaluate the performance of the ADRMonitor with respect to the current spontaneous reporting approach, we conducted simulation experiments on identification of ADR signal pairs (i.e., potential links between drugs and apparent adverse reactions) under various conditions. The experiments involved over 275,000 simulated patients created on the basis of more than 1000 real patients treated by the drug cisapride that was on the market for seven years until its withdrawal by the FDA in 2000 due to serious ADRs. Healthcare professionals utilizing the spontaneous reporting approach and the ADRMonitor were separately simulated by decision-making models derived from a general cognitive decision model called fuzzy recognition-primed decision (RPD) model that we recently developed. The quantitative simulation results show that 1) the number of true ADR signal pairs detected by the ADRMonitor is 6.6 times higher than that by the spontaneous reporting strategy; 2) the ADR detection rate of the ADRMonitor agents with even moderate decision-making skills is five times higher than that of spontaneous reporting; and 3) as the number of patient cases increases, ADRs could be detected significantly earlier by the ADRMonitor. PMID:20007038

Ji, Yanqing; Ying, Hao; Farber, Margo S; Yen, John; Dews, Peter; Miller, Richard E; Massanari, R Michael

2010-05-01

240

Can vesicle size distributions assess eruption intensity during volcanic activity?  

NASA Astrophysics Data System (ADS)

We studied three-dimensional (3-D) vesicle size distributions by X-ray microtomography in scoria collected during the relatively quiescent Phase II of the April-May 2010 eruption at Eyjafjallajökull volcano, Iceland. Our goal was to compare cumulative vesicle size distributions (VSDs) measured in these samples with those found in Stromboli volcano, Italy. Stromboli was chosen because its VSDs are well-characterized and show a correlation with eruption intensity: typical Strombolian activity produces VSDs with power-law exponents near 1, whereas larger and more energetic vulcanian-type explosions and Plinian eruptions produce VSDs with power-law exponents near 1.5. The first hypothesis to be tested was whether or not the samples studied in this work would contain VSDs similar to normal Strombolian products, display higher power-law exponents, or be described by exponential functions. Before making this comparison, we tested a second hypothesis, which was that the magma-water interactions in the Eyjafjallajökull eruption might have a significant effect on the VSDs. We performed 1 bar bubble-growth experiments in which the samples were inundated with water and compared them to similar control experiments without water inundation. No significant differences between the VSDs of the two sets of experiments were found, and the second hypothesis is not supported by the experimental evidence. The Phase II Eyjafjallajökull VSDs are described by power-law exponents of ~0.8, typical of normal Strombolian eruptions, and support the first hypothesis. The comparable VSDs and behavior of Phase II of the Eyjafjallajökull 2010 eruption to Stromboli are interpreted to be a reflection of similar conduit systems in both volcanoes that are being constantly fed by the ascent of mingled/mixed magma from depth. Such behavior implies that continued activity during Phase II of the Eyjafjallajökull eruption could be expected and would have been predicted, had our VSDs been measured in real time during the eruption. However, the products studied show no peculiar feature that could herald the renewed eruption intensity observed in the following Phase III of the eruption.

LaRue, A.; Baker, D. R.; Polacci, M.; Allard, P.; Sodini, N.

2013-10-01

241

Assessing the impact of tumor evolution on oncology drug development and commercialization  

E-print Network

This thesis investigates the commercial viability of developing and commercializing targeted oncology drugs directed at a specific tumor mutation instead of all forms and mutations of a single target. While oncologic drugs ...

Sterk, Joseph P. (Sterk, Joseph Phillip)

2011-01-01

242

The role of health technology assessment bodies in shaping drug development  

PubMed Central

The use of health technology assessment (HTA) to inform policy-making is established in most developed countries. Compared to licensing agencies, HTA agencies have different interests and, therefore, different evidence requirements. Criteria for coverage or reimbursement decisions on pharmaceutical compounds vary; however, it is common to include, as part of the HTA, a comparative effectiveness evaluation. This type of clinical data might go beyond that required for market authorization, thus creating an additional evidence gap between the regulatory and the reimbursement submission. The relevance of submissions to HTA agencies is consistently increasing in a pharmaceutical company’s perspective, as market prospects are strongly influenced by third-party payers’ coverage. In this study, we aim to describe current HTA activities with a potential impact throughout the drug development process of pharmaceuticals, with a comparative emphasis on the systems in place in Italy and in the UK. Based on an extensive literature and website review, we identified three major classes of HTA activities, beyond mainstream HTA, with the potential to influence the drug development program: 1) horizon scanning and early HTA; 2) bipartite and tripartite early dialogue between manufacturers, regulators, and HTA assessors; and 3) managed market entry agreements. From early stages of clinical research up to postauthorization studies, there is a trend toward increased collaboration between parties, anticipation of market access evidence collection, and postmarketing risk-sharing. Heterogeneity of HTA practices increases the complexity of the market access environment. Overall, there are signals that market access departments are gaining importance in the pharmaceutical companies, but there is still a lack of evidence and reporting on how the increasing relevance of HTA has reshaped the way clinical development is designed and managed.

Ciani, Oriana; Jommi, Claudio

2014-01-01

243

Transmission Assessment Surveys (TAS) to Define Endpoints for Lymphatic Filariasis Mass Drug Administration: A Multicenter Evaluation  

PubMed Central

Background Lymphatic filariasis (LF) is targeted for global elimination through treatment of entire at-risk populations with repeated annual mass drug administration (MDA). Essential for program success is defining and confirming the appropriate endpoint for MDA when transmission is presumed to have reached a level low enough that it cannot be sustained even in the absence of drug intervention. Guidelines advanced by WHO call for a transmission assessment survey (TAS) to determine if MDA can be stopped within an LF evaluation unit (EU) after at least five effective rounds of annual treatment. To test the value and practicality of these guidelines, a multicenter operational research trial was undertaken in 11 countries covering various geographic and epidemiological settings. Methodology The TAS was conducted twice in each EU with TAS-1 and TAS-2 approximately 24 months apart. Lot quality assurance sampling (LQAS) formed the basis of the TAS survey design but specific EU characteristics defined the survey site (school or community), eligible population (6–7 year olds or 1st–2nd graders), survey type (systematic or cluster-sampling), target sample size, and critical cutoff (a statistically powered threshold below which transmission is expected to be no longer sustainable). The primary diagnostic tools were the immunochromatographic (ICT) test for W. bancrofti EUs and the BmR1 test (Brugia Rapid or PanLF) for Brugia spp. EUs. Principal Findings/Conclusions In 10 of 11 EUs, the number of TAS-1 positive cases was below the critical cutoff, indicating that MDA could be stopped. The same results were found in the follow-up TAS-2, therefore, confirming the previous decision outcome. Sample sizes were highly sex and age-representative and closely matched the target value after factoring in estimates of non-participation. The TAS was determined to be a practical and effective evaluation tool for stopping MDA although its validity for longer-term post-MDA surveillance requires further investigation. PMID:24340120

Chu, Brian K.; Deming, Michael; Biritwum, Nana-Kwadwo; Bougma, Windtare R.; Dorkenoo, Ameyo M.; El-Setouhy, Maged; Fischer, Peter U.; Gass, Katherine; Gonzalez de Pena, Manuel; Mercado-Hernandez, Leda; Kyelem, Dominique; Lammie, Patrick J.; Flueckiger, Rebecca M.; Mwingira, Upendo J.; Noordin, Rahmah; Offei Owusu, Irene; Ottesen, Eric A.; Pavluck, Alexandre; Pilotte, Nils; Rao, Ramakrishna U.; Samarasekera, Dilhani; Schmaedick, Mark A.; Settinayake, Sunil; Simonsen, Paul E.; Supali, Taniawati; Taleo, Fasihah; Torres, Melissa; Weil, Gary J.; Won, Kimberly Y.

2013-01-01

244

Development of an Adverse Drug Reaction Risk Assessment Score among Hospitalized Patients with Chronic Kidney Disease  

PubMed Central

Background Adverse drug reactions (ADRs) represent a major burden on the healthcare system. Chronic kidney disease (CKD) patients are particularly vulnerable to ADRs because they are usually on multiple drug regimens, have multiple comorbidities, and because of alteration in their pharmacokinetics and pharmacodynamic parameters. Therefore, one step towards reducing this burden is to identify patients who are at increased risk of an ADR. Objective To develop a method of identifying CKD patients who are at increased risk for experiencing ADRs during hospitalisation. Materials and Methods Factors associated with ADRs were identified by using demographic, clinical and laboratory variables of patients with CKD stages 3 to 5 (estimated glomerular filtration rate, 10–59 ml/min/1.73 m2) who were admitted between January 1, 2012, and December 31, 2012, to the renal unit of Dubai Hospital. An ADR risk score was developed by constructing a series of logistic regression models. The overall model performance for sequential models was evaluated using Akaike Information Criterion for goodness of fit. Odd ratios of the variables retained in the best model were used to compute the risk scores. Results Of 512 patients (mean [SD] age, 60 [16] years), 62 (12.1%) experienced an ADR during their hospitalisation. An ADR risk score included age 65 years or more, female sex, conservatively managed end-stage renal disease, vascular disease, serum level of C-reactive protein more than 10 mg/L, serum level of albumin less than 3.5 g/dL, and the use of 8 medications or more during hospitalization. The C statistic, which assesses the ability of the risk score to predict ADRs, was 0.838; 95% CI, 0.784–0.892). Conclusion A score using routinely available patient data can be used to identify CKD patients who are at increased risk of ADRs. PMID:24755778

Saheb Sharif-Askari, Fatemeh; Syed Sulaiman, Syed Azhar; Saheb Sharif-Askari, Narjes; Al Sayed Hussain, Ali

2014-01-01

245

Cortical EEG oscillations and network connectivity as efficacy indices for assessing drugs with cognition enhancing potential.  

PubMed

Synchronization of electroencephalographic (EEG) oscillations represents a core mechanism for cortical and subcortical networks, and disturbance in neural synchrony underlies cognitive processing deficits in neurological and neuropsychiatric disorders. Here, we investigated the effects of cognition enhancers (donepezil, rivastigmine, tacrine, galantamine and memantine), which are approved for symptomatic treatment of dementia, on EEG oscillations and network connectivity in conscious rats chronically instrumented with epidural electrodes in different cortical areas. Next, EEG network indices of cognitive impairments with the muscarinic receptor antagonist scopolamine were modeled. Lastly, we examined the efficacy of cognition enhancers to normalize those aberrant oscillations. Cognition enhancers elicited systematic ("fingerprint") enhancement of cortical slow theta (4.5-6 Hz) and gamma (30.5-50 Hz) oscillations correlated with lower activity levels. Principal component analysis (PCA) revealed a compact cluster that corresponds to shared underlying mechanisms as compared to different drug classes. Functional network connectivity revealed consistent elevated coherent slow theta activity in parieto-occipital and between interhemispheric cortical areas. In rats instrumented with depth hippocampal CA1-CA3 electrodes, donepezil elicited similar oscillatory and coherent activities in cortico-hippocampal networks. When combined with scopolamine, the cognition enhancers attenuated the leftward shift in coherent slow delta activity. Such a consistent shift in EEG coherence into slow oscillations associated with altered slow theta and gamma oscillations may underlie cognitive deficits in scopolamine-treated animals, whereas enhanced coherent slow theta and gamma activity may be a relevant mechanism by which cognition enhancers exert their beneficial effect on plasticity and cognitive processes. The findings underscore that PCA and network connectivity are valuable tools to assess efficacy of novel therapeutic drugs with cognition enhancing potential. PMID:25181033

Ahnaou, A; Huysmans, H; Jacobs, T; Drinkenburg, W H I M

2014-11-01

246

Environmental justice, impact assessment and the politics of knowledge: The implications of assessing the social distribution of environmental outcomes  

SciTech Connect

Claims of environmental injustice have increasingly become part of environmental conflicts, both explicitly through the work of environmental justice campaigning groups and implicitly through the arguments deployed about the rights and wrongs of a given situation. Such claims can centre on different notions of justice, including those concerned with questions of distribution and procedure. This paper focuses on distributional or outcome justice and explores what implications follow when the distributional concerns of environmental justice are included in the practice of impact assessment processes, including through social impact assessment (SIA). The current use of impact assessment methods in the UK is reviewed showing that although practices are evolving there is a little routine assessment of distributional inequalities. It is argued that whilst this should become part of established practice to ensure that inequalities are revealed and matters of justice are given a higher profile, the implications for conflict within decision making processes are not straightforward. On the one hand, there could be scope for conflict to be ameliorated by analysis of inequalities informing the debate between stakeholders, and facilitating the implementation of mitigation and compensation measures for disadvantaged groups. On the other hand, contestation over how evidence is produced and therefore what it shows, and disagreement as to the basis on which justice and injustice are to be determined, means that conflict may also be generated and sustained within what are essentially political and strategic settings.

Walker, Gordon, E-mail: g.p.walker@lancaster.ac.u [Lancaster Environment Centre, Lancaster University, Lancaster, LA1 4YQ (United Kingdom)

2010-09-15

247

Assessment and Continued Validation of the Malaria SYBR Green I-Based Fluorescence Assay for Use in Malaria Drug Screening  

Microsoft Academic Search

Several new fluorescence malaria in vitro drug susceptibility microtiter plate assays that detect the presence of malarial DNA in infected erythrocytes have recently been reported, in contrast to traditional isotopic screens that involve radioactive substrate incorporation to measure in vitro malaria growth inhibition. We have assessed and further characterized the malaria SYBR Green I-based fluorescence (MSF) assay for its ability

Jacob D. Johnson; Richard A. Dennull; Lucia Gerena; Miriam Lopez-Sanchez; Norma E. Roncal; Norman C. Waters

2007-01-01

248

Simple pharmacological test battery to assess efficacy and side effect profile of centrally acting muscle relaxant drugs  

Microsoft Academic Search

Introduction: Centrally muscle relaxants (CMRs) are used mainly for treating muscle spasticities of neurological origin, and painful muscle spasms due to rheumatologic conditions. Their use is frequently associated with dose-limiting adverse effects. New drugs with improved side-effect characteristics are badly needed. However, there is no general agreement in the pharmacological literature on what methods are adequate to assess CMR effect

Sándor Farkas; Pál Berzsenyi; Egon Kárpáti; Pál Kocsis; István Tarnawa

2005-01-01

249

Some US Food and Drug Administration perspectives on data mining for pediatric safety Assessment  

Microsoft Academic Search

Background: The US Food and Drug Administration's (FDA's) large spontaneous reporting database contains >110,000 voluntary reports of adverse drug events (ADEs) observed during postmarketing pediatric practice and submitted to the FDA by manufacturers, health care providers, or consumers. These reports may provide evidence about known or unknown harm associated with single or combination drug treatments in pediatric patients. We recently

Robert T. O'Neill; Ana Szarfman

2001-01-01

250

Distributional Assumptions in Educational Assessments Analysis: Normal Distributions versus Generalized Beta Distribution in Modeling the Phenomenon of Learning  

ERIC Educational Resources Information Center

This paper introduces the generalized beta (GB) model as a new modeling tool in the educational assessment area and evaluation analysis, specifically. Unlike normal model, GB model allows us to capture some real characteristics of data and it is an important tool for understanding the phenomenon of learning. This paper develops a contrast with the…

Campos, Jose Alejandro Gonzalez; Moraga, Paulina Saavedra; Del Pozo, Manuel Freire

2013-01-01

251

Assessment of spatial distribution of fallout radionuclides through geostatistics concept.  

PubMed

After introducing geostatistics concept and its utility in environmental science and especially in Fallout Radionuclide (FRN) spatialisation, a case study for cesium-137 ((137)Cs) redistribution at the field scale using geostatistics is presented. On a Canadian agricultural field, geostatistics coupled with a Geographic Information System (GIS) was used to test three different techniques of interpolation [Ordinary Kriging (OK), Inverse Distance Weighting power one (IDW1) and two (IDW2)] to create a (137)Cs map and to establish a radioisotope budget. Following the optimization of variographic parameters, an experimental semivariogram was developed to determine the spatial dependence of (137)Cs. It was adjusted to a spherical isotropic model with a range of 30 m and a very small nugget effect. This (137)Cs semivariogram showed a good autocorrelation (R(2)=0.91) and was well structured ('nugget-to-sill' ratio of 4%). It also revealed that the sampling strategy was adequate to reveal the spatial correlation of (137)Cs. The spatial redistribution of (137)Cs was estimated by Ordinary Kriging and IDW to produce contour maps. A radioisotope budget was established for the 2.16 ha agricultural field under investigation. It was estimated that around 2 x 10(7)Bq of (137)Cs were missing (around 30% of the total initial fallout) and were exported by physical processes (runoff and erosion processes) from the area under investigation. The cross-validation analysis showed that in the case of spatially structured data, OK is a better interpolation method than IDW1 or IDW2 for the assessment of potential radioactive contamination and/or pollution. PMID:17673340

Mabit, L; Bernard, C

2007-01-01

252

Network Capacity Assessment of CHP-based Distributed Generation on Urban Energy Distribution Networks  

NASA Astrophysics Data System (ADS)

The combined heat and power (CHP)-based distributed generation (DG) or dis-tributed energy resources (DERs) are mature options available in the present energy market, considered to be an effective solution to promote energy efficiency. In the urban environment, the electricity, water and natural gas distribution networks are becoming increasingly interconnected with the growing penetration of the CHP-based DG. Subsequently, this emerging interdependence leads to new topics meriting serious consideration: how much of the CHP-based DG can be accommodated and where to locate these DERs, and given preexisting constraints, how to quantify the mutual impacts on operation performances between these urban energy distribution networks and the CHP-based DG. The early research work was conducted to investigate the feasibility and design methods for one residential microgrid system based on existing electricity, water and gas infrastructures of a residential community, mainly focusing on the economic planning. However, this proposed design method cannot determine the optimal DG sizing and siting for a larger test bed with the given information of energy infrastructures. In this context, a more systematic as well as generalized approach should be developed to solve these problems. In the later study, the model architecture that integrates urban electricity, water and gas distribution networks, and the CHP-based DG system was developed. The proposed approach addressed the challenge of identifying the optimal sizing and siting of the CHP-based DG on these urban energy networks and the mutual impacts on operation performances were also quantified. For this study, the overall objective is to maximize the electrical output and recovered thermal output of the CHP-based DG units. The electricity, gas, and water system models were developed individually and coupled by the developed CHP-based DG system model. The resultant integrated system model is used to constrain the DG's electrical output and recovered thermal output, which are affected by multiple factors and thus analyzed in different case studies. The results indicate that the designed typical gas system is capable of supplying sufficient natural gas for the DG normal operation, while the present water system cannot support the complete recovery of the exhaust heat from the DG units.

Zhang, Xianjun

253

Geographic distribution of human immunodeficiency virus markers in parenteral drug abusers.  

PubMed Central

Drug abuse treatment programs in six regions of the United States collaborated in a study aimed at monitoring trends in the seroprevalence of human immunodeficiency virus (HIV) antibodies. The wide disparities in HIV seroprevalence in the face of similarities in drug using behavior have important implications for prevention. In the New York City area (Harlem, Brooklyn), 61 per cent of samples (N = 280) obtained in late 1986 were positive, up from 50 per cent of samples (N = 585) in early 1985. In Baltimore, Maryland, 29 per cent of samples (N = 184) representing 11 programs were positive. In contrast, samples from programs distant from the Northeast corridor had far lower rates: Denver, Colorado 5 per cent (N = 100); San Antonio, Texas 2 per cent (N = 106); Southern California, 1.5 per cent (N = 413); and Tampa, Florida, 0 per cent (N = 102). Contrary to expectations, there was no corresponding difference in reported lifetime needle sharing experiences, which ranged from 70 per cent in New York to 99 per cent in San Antonio. HIV seropositivity was associated only with geographic location and ethnicity; however, because needle sharing is practiced by parenteral drug abusers in areas where seroprevalence is still relatively low, these areas are potentially vulnerable to the same catastrophic spread seen in the Northeast. A window of opportunity exists where prompt, vigorous, and aggressive efforts at prevention could have major impact. PMID:3348473

Lange, W R; Snyder, F R; Lozovsky, D; Kaistha, V; Kaczaniuk, M A; Jaffe, J H

1988-01-01

254

Does mass drug administration for the integrated treatment of neglected tropical diseases really work? Assessing evidence for the control of schistosomiasis and soil-transmitted helminths in Uganda  

PubMed Central

Background Less is known about mass drug administration [MDA] for neglected tropical diseases [NTDs] than is suggested by those so vigorously promoting expansion of the approach. This paper fills an important gap: it draws upon local level research to examine the roll out of treatment for two NTDs, schistosomiasis and soil-transmitted helminths, in Uganda. Methods Ethnographic research was undertaken over a period of four years between 2005-2009 in north-west and south-east Uganda. In addition to participant observation, survey data recording self-reported take-up of drugs for schistosomiasis, soil-transmitted helminths and, where relevant, lymphatic filariasis and onchocerciasis was collected from a random sample of at least 10% of households at study locations. Data recording the take-up of drugs in Ministry of Health registers for NTDs were analysed in the light of these ethnographic and social survey data. Results The comparative analysis of the take-up of drugs among adults revealed that although most long term residents have been offered treatment at least once since 2004, the actual take up of drugs for schistosomiasis and soil-transmitted helminths varies considerably from one district to another and often also within districts. The specific reasons why MDA succeeds in some locations and falters in others relates to local dynamics. Issues such as population movement across borders, changing food supply, relations between drug distributors and targeted groups, rumours and conspiracy theories about the 'real' purpose of treatment, subjective experiences of side effects from treatment, alternative understandings of affliction, responses to social control measures and historical experiences of public health control measures, can all make a huge difference. The paper highlights the need to adapt MDA to local circumstances. It also points to specific generalisable issues, notably with respect to health education, drug distribution and more effective use of existing public health legislation. Conclusion While it has been an achievement to have offered free drugs to so many adults, current standard practices of monitoring, evaluation and delivery of MDA for NTDs are inconsistent and inadequate. Efforts to integrate programmes have exacerbated the difficulties. Improved assessment of what is really happening on the ground will be an essential step in achieving long-term overall reduction of the NTD burden for impoverished communities. PMID:21211001

2011-01-01

255

Prediction of human volume of distribution values for drugs using linear and nonlinear quantitative structure pharmacokinetic relationship models.  

PubMed

In the present study the volume of distribution values in humans of 121 drugs was estimated using quantitative structure pharmacokinetic relationship analysis. The multiple linear regression (MLR) method and nonlinear artificial neural network (ANN) and support vector machines (SVM) were employed for modeling. The theoretically calculated molecular descriptors were used for modeling and best set of descriptors selected by correlation based feature selection (CFS) method. The performance and predictive capability of linear method was investigated and compared with nonlinear method. The ANN gave better model with an average fold error of 1.66. The test set prediction accuracy shows human volume of distribution values could be predicted, on average, within 2-fold of the actual value. PMID:24464707

Louis, Bruno; Agrawal, Vijay K

2014-03-01

256

Assessment of surface concentrations in resorbable ocular implants: controlled drug delivery devices for 5-fluorouracil (5-FU)  

NASA Astrophysics Data System (ADS)

The antineoplastic drug 5-fluorouracil (5-fluoro- 2,4,(1H,3H)-pyrimidinedione; 5-FU) has been used to control proliferation of penetrating fibroblasts and to prevent channel closure following glaucoma filtration surgery (trabeculectomy) or laser sclerectomy. Because of the toxicity of the drug, administration of low dosages slowly over time, at the site of the desired treatment, is indicated for optimum efficacy. Repeated injections of low dosages of the drug represent an undesirable intervention and may also result in unwanted toxicity to the corneal epithelium. A suitable biocompatible and resorbable polymer matrix composed of a poly (D,L-lactic-co-glycolic acid: PLGA) has been admixed with varying amounts of 5-FU and cast as shapes suitable for intracorneal implantation. Slow biodegradation of this polymer over a one to two week period has been shown to result in an acceptably slow drug release mechanism. An issue arising during the clinical evaluation of the efficacy of this drug delivery system was how best to quantify the concentration of 5-FU and its distribution spatially in the solid implant. FT-IR and FT-Raman spectroscopies distinguishes between the drug and the polymer matrix and were used to differentiate and quantitate the 5-FU concentration of the implants.

Milne, Peter J.; Gautier, Sandrine; Parel, Jean-Marie A.; Jallet, Valerie

1997-05-01

257

The Effect of Antihypertensive Drugs on Endothelial Function as Assessed by Flow-Mediated Vasodilation in Hypertensive Patients  

PubMed Central

Endothelial dysfunction is found in hypertensive patients and may serve as a prognostic marker of future cardiovascular events. Endothelial function can be assessed noninvasively by flow-mediated vasodilation (FMD). The goal of this paper is to summarize comprehensively the clinical trials that investigated the effects of antihypertensive drugs on endothelial function assessed by FMD in hypertensive patients. A PubMed-based search found 38 clinical trial papers published from January 1999 to June 2011. Significant improvement of FMD after antihypertensive treatment was shown in 43 of 71 interventions (among 38 clinical trial papers). Angiotensin II receptor blockers and angiotensin converting enzyme inhibitors appeared to improve FMD more than other drug types. Antihypertensive treatment can improve endothelial dysfunction when assessed by FMD, although there are conflicting data that require further research. PMID:22489272

Miyamoto, Michiaki; Kotani, Kazuhiko; Ishibashi, Shun; Taniguchi, Nobuyuki

2012-01-01

258

Assessing directed evolution methods for the generation of biosynthetic enzymes with potential in drug biosynthesis.  

PubMed

To address the synthesis of increasingly structurally diverse small-molecule drugs, methods for the generation of efficient and selective biological catalysts are becoming increasingly important. 'Directed evolution' is an umbrella term referring to a variety of methods for improving or altering the function of enzymes using a nature-inspired twofold strategy of mutagenesis followed by selection. This article provides an objective assessment of the effectiveness of directed evolution campaigns in generating enzymes with improved catalytic parameters for new substrates from the last decade, excluding studies that aimed to select for only improved physical properties and those that lack kinetic characterization. An analysis of the trends of methodologies and their success rates from 81 qualifying examples in the literature reveals the average fold improvement for k (cat) (or V (max)), K (m) and k (cat)/K (m) to be 366-, 12- and 2548-fold, respectively, whereas the median fold improvements are 5.4, 3 and 15.6. Further analysis by enzyme class, library-generation methodology and screening methodology explores relationships between successful campaigns and the methodologies employed. PMID:21644826

Nannemann, David P; Birmingham, William R; Scism, Robert A; Bachmann, Brian O

2011-05-01

259

Assessing directed evolution methods for the generation of biosynthetic enzymes with potential in drug biosynthesis  

PubMed Central

To address the synthesis of increasingly structurally diverse small-molecule drugs, methods for the generation of efficient and selective biological catalysts are becoming increasingly important. ‘Directed evolution’ is an umbrella term referring to a variety of methods for improving or altering the function of enzymes using a nature-inspired twofold strategy of mutagenesis followed by selection. This article provides an objective assessment of the effectiveness of directed evolution campaigns in generating enzymes with improved catalytic parameters for new substrates from the last decade, excluding studies that aimed to select for only improved physical properties and those that lack kinetic characterization. An analysis of the trends of methodologies and their success rates from 81 qualifying examples in the literature reveals the average fold improvement for kcat (or Vmax), Km and kcat/Km to be 366-, 12- and 2548-fold, respectively, whereas the median fold improvements are 5.4, 3 and 15.6. Further analysis by enzyme class, library-generation methodology and screening methodology explores relationships between successful campaigns and the methodologies employed. PMID:21644826

Nannemann, David P; Birmingham, William R; Scism, Robert A; Bachmann, Brian O

2011-01-01

260

Causality, Severity and Preventability Assessment of Adverse Cutaneous Drug Reaction: A Prospective Observational Study in a Tertiary Care Hospital  

PubMed Central

Introduction: The number of subjects involved in a clinical trial are limited, whose findings cannot be extrapolated to the entire population.Due to the emergence of newer molecules the pattern of Adverse Cutaneous Drug Reaction(ACDR) also changes frequently. The need for this study is for early diagnosis, to reduce the morbidity and mortality due to ACDR and to ensure safety of the patients. Material and Methods: Forty one subjects with the diagnosis of ACDR were included in the study for a period of 12 months(Jan 2009- Dec 2009). The informations such as patient demographic details, drug history, associated comorbid conditions and pattern of the skin reaction were noted. Assessment was done for causality, severity and preventability using separate valid scales. Results: The most common ACDR was fixed drug eruption (43.9%) and the most common causative drug for the same was surprisingly found to be paracetamol. Antimicrobials were the most common causative drug group and two significant associated risk factors were multiple drug intake and history of allergy. Among the total reactions 78% were of probable category and 59% were of moderate level severity reaction. Out of which 12% of the cases were definitely preventable. PMID:24551632

S., Padmavathi; K., Manimekalai; S., Ambujam

2013-01-01

261

FEA study on the stress distributions in the polymer coatings of cardiovascular drug-eluting stent medical devices.  

PubMed

Cardiovascular drug-eluting stents (DES) are widely applied medical products to treat diseased narrowed arteries. Despite their wide application, there still are many clinical adverse effects associated with DES implantation. One of the major issues is that the coatings comprised of drug and polymer phases are often delaminated during the deployment of the stent, which can lead to more serious clinical complications. In the present work, we conducted a 3D finite-element analysis (FEA) computational study to quantitatively estimate the stress distributions in the coating components of DES devices. To adequately represent the skeleton design of modern DES products, we adopted the strut geometry of a SYNERGY stent along with a full coating of poly(lactic-co-glycolic) acid. The FEA computation results clearly indicate that the curved regions (i.e., kink) are subject to much higher stress accumulation in the coating. In addition, it was found that the local shear and normal stress distribution profiles in the polymer coatings are different from those based on von-Mises stresses near the kink area. PMID:24889717

Lee, Solki; Lee, Chang Woo; Kim, Chang-Soo

2014-09-01

262

Hepatitis C genotype distribution and homology among geographically disparate injecting drug users in Afghanistan.  

PubMed

Hepatitis C virus (HCV) prevalence is high among injecting drug users in Afghanistan, but transmission dynamics are poorly understood. Samples from HCV-infected injecting drug users were sequenced to determine circulating genotypes and potential transmission linkages. Serum samples were obtained from injecting drug user participants in Hirat, Jalalabad, and Mazar-i-Sharif between 2006 and 2008 with reactive anti-HCV rapid tests. Specimens with detected HCV viremia were amplified and underwent sequence analysis. Of 113 samples evaluated, 25 samples (35.2%) were only typeable in NS5B, nine samples (12.7%) were only typeable in CE1, and 37 samples (52.1%) were genotyped in both regions. Of those with typeable HCV, all were Afghan males with a mean age of 31.1 (standard deviation [SD]?±?8.0) years and mean duration of injecting of 3.9 (SD?±?4.3) years. Most reported residence outside Afghanistan in the last decade (90.1%) and prior incarceration (76.8%). HCV genotypes detected were: 1a, (35.2%, n?=?25), 3a (62.0%, n?=?44), and 1b (2.8%, n?=?2). Cluster formation was detected in NS5B and CE1 and were generally from within the same city. All participants within clusters reported being a refugee in Iran compared to 93.5% of those outside clusters. Only 22.2% (4/11) of those within clusters had been refugees in Pakistan and these four individuals had also been refugees in Iran. Predominance of genotype 3a and the association between HCV viremia and having been a refugee in Iran potentially reflects migration between Afghanistan and Iran among IDUs from Mazar-i-Sharif and Hirat and carry implications for harm reduction programs for this migratory population. PMID:23918535

Sanders-Buell, Eric; Rutvisuttinunt, Wiriya; Todd, Catherine S; Nasir, Abdul; Bradfield, Andrea; Lei, Esther; Poltavee, Kultida; Savadsuk, Hathairat; Kim, Jerome H; Scott, Paul T; de Souza, Mark; Tovanabutra, Sodsai

2013-07-01

263

Hepatitis C Viremia and Genotype Distribution among a sample of HCV-exposed Nonmedical Prescription Drug Users in Rural Appalachia  

PubMed Central

Research has demonstrated that hepatitis C (HCV) genotype distribution varies geographically and demographically. This exploratory study examines HCV viremia, viral concentration, and genotype distribution among anti-HCV positive, rural Appalachian nonmedical prescription drug users. The study population was randomly selected from a pool of 200 anti-HCV positive participants in a longitudinal study. Those randomly chosen were representative of the overall pool in terms of demographics, drug use, and other risk behaviors. Participants were tested serologically for HCV RNA, viral concentration, and genotype, and interview-administered questionnaires examined behavioral and demographic characteristics. Of the 81 participants, 69% tested RNA positive, 59% of which had viral loads exceeding 800,000 IU/mL. Approximately 66% of the RNA positive sample had genotype 1a; types 2b (16%) and 3a (13%) were less common. RNA positive participants were not significantly different than RNA negative participants demographically or behaviorally. Likewise, with the exception of education, genotype 1 participants were not significantly different than those with genotype 2 or 3. The prevalence of active HCV infection highlights a need for prevention and treatment in this population. However, the predominance of genotype 1 may present challenges due to its association with decreased responsiveness to drug treatment, although the novel class of direct-acting antivirals such as telaprevir and boceprevir offer new hope in this regard. The prevalence of genotype 1 may also foreshadow heightened burden of hepatocellular carcinoma and elevated healthcare expenditures. More research is needed to characterize HCV infection and genotype in this population. PMID:22825816

Young, April M.; Crosby, Richard A.; Oser, Carrie B.; Leukefeld, Carl G.; Stephens, Dustin B.; Havens, Jennifer R.

2012-01-01

264

Drug use assessment and risk evaluation in pregnancy--the PEGASUS-project.  

PubMed

Since the thalidomide tragedy it is well accepted that drugs can have adverse effects on the unborn child. Although numerous studies show that drug use during pregnancy is widespread, there still is a serious lack of comprehensive and valid data on the risks of drug use during pregnancy. One objective of the PEGASUS-project, which focuses on Munich, is to enlarge the knowledge on embryo- and fetotoxic properties of drugs by prospectively recording information on drug exposure during pregnancy and analysing these data with regard to untoward fetal outcome. First results of PEGASUS confirm that drug utilization during pregnancy is rather common-85% of women use at least one preparation. The most frequent groups are haematologicals, minerals, iodide, and vitamins. Randomized studies have shown that periconceptional folic acid supplementation considerably reduces the risk of neural tube defects. However, only very few women in the PEGASUS-project recorded folic acid intake during the critical period or in sufficient dosage. PMID:15073753

Irl, C; Kipferler, P; Hasford, J

1997-10-01

265

Usefulness of charge-transfer complexation for the assessment of sympathomimetic drugs: Spectroscopic properties of drug ephedrine hydrochloride complexed with some ?-acceptors  

NASA Astrophysics Data System (ADS)

Recently, ephedrine (Eph) assessment in food products, pharmaceutical formulations, human fluids of athletes and detection of drug toxicity and abuse, has gained a growing interest. To provide basic data that can be used to assessment of Eph quantitatively based on charge-transfer (CT) complexation, the CT complexes of Eph with 7?,8,8?-tetracyanoquinodimethane (TCNQ), dichlorodicyanobenzoquinone (DDQ), 1,3-dinitrobenzene (DNB) or tetrabromothiophene (TBT) were synthesized and spectroscopically investigated. The newly synthesized complexes have been characterized via elemental analysis, IR, Raman, 1H NMR, and UV-visible spectroscopy. The formation constant (KCT), molar extinction coefficient (?CT) and other spectroscopic data have been determined using the Benesi-Hildebrand method and its modifications. The sharp, well-defined Bragg reflections at specific 2? angles have been identified from the powder X-ray diffraction patterns. Thermal decomposition behavior of these complexes was also studied, and their kinetic thermodynamic parameters were calculated with Coats-Redfern and Horowitz-Metzger equations.

Refat, Moamen S.; Ibrahim, Omar B.; Saad, Hosam A.; Adam, Abdel Majid A.

2014-05-01

266

Report of the Workshop on Selecting Input Distributions For Probabilistic Assessments  

NSDL National Science Digital Library

The Environmental Protection Agency provides online access to the Report of the Workshop on Selecting Input Distributions for Probabilistic Assessments. This report highlights the main points discussed at an EPA workshop held in April 1998 by the Eastern Research Group. The goal of the workshop and report was to "assist EPA in developing a framework and guidance for selecting input distributions for probabilistic risk assessments." The abstract can be viewed in HTML format, while the full-text article is available in .pdf format.

1999-01-01

267

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

ERIC Educational Resources Information Center

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,…

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

2003-01-01

268

Computational molecular docking assessment of hormone receptor adjuvant drugs: Breast cancer as an example  

Microsoft Academic Search

For the maintenance therapy of breast cancer, drugs which act as antagonists\\/partial agonists of hormone receptors against the breast tissue are used in the conventional clinical practices. However, during the course of treatment the patients may encounter systems related complications. Drugs like tamoxifen, which block the action of estrogens at its receptors in mammary gland; and the recently designed antiestrogens

Sayan Mukherjee; Durjoy Majumder

2009-01-01

269

Assessing maternal perceptions of harmful effects of drug use during pregnancy.  

PubMed

Research has shown that perceived risk is an important predictor of health behavior change. In turn, drug use risk education is a vital component of many health campaigns. In pregnant women, perceived risk studies have focused primarily on alcohol and tobacco use. Little is known about perceived risks associated with prenatal exposure to illicit drugs. The present study compared drug use attitude (DUA) in both treatment-seeking and non-treatment-seeking drug-using pregnant women as well as a comparison group of non-drug-using pregnant women. The results suggest that non-treatment-seekers are less knowledgeable about specific potential risks of perinatal substance use. In addition, compared to treatment seekers and non-users, non-treatment-seekers were more likely to endorse cutting down on drug use rather than quitting as a means of reducing harm to the developing child. Results of the present study suggest drug-using women may benefit from additional education about harmful effects of drug use. PMID:12661976

Perry, Bridget L; Jones, Hendree; Tuten, Michelle; Svikis, Dace S

2003-01-01

270

Issues Surrounding the Assessment of the Genetic Determinants of Drugs as Reinforcing Stimuli  

Microsoft Academic Search

A wide variety of drugs used in medicine and on a non-prescription basis have abuse liability. However, not all psychoactive drugs have demonstrable reinforcing properties either in animal models or in humans. In order to predict the abuse liability of a compound or to understand determinants of the abuse liability, several animal testing procedures have been developed. These procedures include

John M. Carney; Meng-Shan Cheng; Cao Wu; Thomas W. Seale

1991-01-01

271

Human placental perfusion method in the assessment of transplacental passage of antiepileptic drugs  

SciTech Connect

Epilepsy is one of the most common neurological diseases, affecting about 0.5 to 1% of pregnant women. It is commonly accepted that older antiepileptic drugs bear teratogenic potential. So far, no agreement has been reached about the safest antiepileptic drug during pregnancy. It is known that nearly all drugs cross the placenta at least to some extent. Nowadays, there is very little information available of the pharmacokinetics of drugs in the feto-placental unit. Detailed information about drug transport across the placenta would be valuable for the development of safe and effective treatments. For reasons of safety, human studies on placental transfer are restricted to a limited number of drugs. Interspecies differences limit the extrapolation of animal data to humans. Several in vitro methods for the study of placental transfer have been developed over the past decades. The placental perfusion method is the only experimental method that has been used to study human placental transfer of substances in organized placental tissue. The aim of this article is to review human placental perfusion data on antiepileptic drugs. According to perfusion data, it seems that most of the antiepileptic drugs are transferred across the placenta meaning significant fetal exposure.

Myllynen, Paeivi [Department of Pharmacology and Toxicology, University of Oulu, PO Box 5000, 90014 Oulu (Finland)]. E-mail: paivi.k.myllynen@oulu.fi; Pienimaeki, Paeivi [Department of Pharmacology and Toxicology, University of Oulu, PO Box 5000, 90014 Oulu (Finland); Vaehaekangas, Kirsi [Department of Pharmacology and Toxicology, University of Oulu, PO Box 5000, 90014 Oulu (Finland); Department of Pharmacology and Toxicology, University of Kuopio, PO Box 1627, 70211 Kuopio (Finland)

2005-09-01

272

Modulation of Taste Aversions by a Pentobarbital Drug State: An Assessment of Its Transfer Properties  

Microsoft Academic Search

In a drug-discrimination procedure using conditioned taste aversions, a pentobarbital injection signaled a taste–toxin pairing while the vehicle injection signaled the same taste in the absence of the toxin. In transfer tests, drug states transferred control over consumption to other targets. If the training target was a fluid (saccharin), then transfer occurred to other fluids (both novel and familiar) but

Darlene M. Skinner

2000-01-01

273

Porcine Ear Skin as a Model for the Assessment of Transdermal Drug Delivery to Premature Neonates  

Microsoft Academic Search

Purpose. The purpose of this study was (i) to validate differentially tape-stripped, porcine skin as an in vitro model for the evaluation of transdermal drug delivery (TDD) to premature neonates, (ii) to determine whether the model could estimate neonatal skin permeability as a function of postconceptional age (PCA), and (iii) to demonstrate that iontophoretic delivery permits precise control of drug

Nabila Sekkat; Yogeshvar N. Kalia; Richard H. Guy

2004-01-01

274

Assessment of Pseudomonas aeruginosa N5,N10-Methylenetetrahydrofolate Dehydrogenase - Cyclohydrolase as a Potential Antibacterial Drug Target  

PubMed Central

The bifunctional enzyme methylenetetrahydrofolate dehydrogenase – cyclohydrolase (FolD) is identified as a potential drug target in Gram-negative bacteria, in particular the troublesome Pseudomonas aeruginosa. In order to provide a comprehensive and realistic assessment of the potential of this target for drug discovery we generated a highly efficient recombinant protein production system and purification protocol, characterized the enzyme, carried out screening of two commercial compound libraries by differential scanning fluorimetry, developed a high-throughput enzyme assay and prosecuted a screening campaign against almost 80,000 compounds. The crystal structure of P. aeruginosa FolD was determined at 2.2 Å resolution and provided a template for an assessment of druggability and for modelling of ligand complexes as well as for comparisons with the human enzyme. New FolD inhibitors were identified and characterized but the weak levels of enzyme inhibition suggest that these compounds are not optimal starting points for future development. Furthermore, the close similarity of the bacterial and human enzyme structures suggest that selective inhibition might be difficult to attain. In conclusion, although the preliminary biological data indicates that FolD represents a valuable target for the development of new antibacterial drugs, indeed spurred us to investigate it, our screening results and structural data suggest that this would be a difficult enzyme to target with respect to developing the appropriate lead molecules required to underpin a serious drug discovery effort. PMID:22558288

Maluf, Fernando V.; McElroy, Stuart; James, Daniel; Frearson, Julie; Gray, David; Hunter, William N.

2012-01-01

275

Assessing the Long-Term Impact of Drug Court Participation on Recidivism with Generalized Estimating Equations  

PubMed Central

Drug courts are one of the most common strategies for dealing with the large proportion of criminal offenders who are drug-involved, yet methodological limitations limit the conclusions that can be drawn from many existing evaluations of their effectiveness. The current study examined the long-term impact of drug court participation compared to regular probation on the recidivism of 475 drug-involved offenders under supervision in Hillsborough County, Florida. Using a combination of self-reported data (collected through in-person interviews at baseline, i.e., the beginning of supervision) and administrative records, the study employed a repeated measures framework (examining five six-month time periods from baseline to 30 months post-baseline) and generalized estimating equations to compare the likelihood of being arrested between drug court participants and a matched sample of comparison offenders. The results indicate that participation in drug court was associated with a significant decrease in the likelihood of being arrested in the 12 to 18 months post-baseline time period. Although the drug court effect was somewhat delayed (it was not significant prior to 12 months) and short-lived (it was not significant after 18 months), the fact that significant program effects were observed during a time period that coincides with the conclusion of drug court participation for graduates and a time period well beyond initial program exposure, suggests that drug court participants are more likely than comparable offenders not exposed to drug court to remain arrest free when no longer under community supervision. PMID:17604918

Krebs, Christopher P.; Lindquist, Christine H.; Koetse, Willem; Lattimore, Pamela K.

2007-01-01

276

In vitro, in vivo and pharmacokinetic assessment of amikacin sulphate laden polymeric nanoparticles meant for controlled ocular drug delivery  

NASA Astrophysics Data System (ADS)

The rationale of current exploration was to formulate positively charged amikacin-loaded polymeric nanoparticles providing a controlled release attribute. Amikacin sulphate-loaded nanoparticles were prepared by w/o/w emulsification solvent evaporation approach succeeded by high-pressure homogenization. Two bioadhesive positively charged polymers, Eudragit® RS 100 and Eudragit® RL 100, were used in the blend, with variable ratios of drug and polymer. The formulations were assessed in terms of particle size and zeta potential. Thermal gravimetric analysis was brought out on the samples of drug, polymer and drug polymer complex. Drug loading and release attributes of the nanoparticles were scrutinized and antimicrobial activity in contrast to Staphylococcus aureus was appraised. Ocular irritation test, in vivo ocular retention study, in vivo release profile (permeation study) and in vivo antibacterial activity of polymeric nanosuspensions were executed. No rupture consequence but a lengthened drug release was contemplated from all formulations. Amikacin sulphate release from the polymeric nanoparticles reflected a better fit with Korsmeyer-Peppas model. In the course of the antibacterial activity of nanoparticles against S. aureus, formulation AE1 displays the most prominent inhibitory effect as compared with marketed formulation of amikacin sulphate.

Sharma, Upendra Kumar; Verma, Amita; Prajapati, Sunil Kuamr; Pandey, Himanshu; Pandey, Avinash C.

2014-03-01

277

Effect of varying drug loading on particle size distribution and drug release kinetics of verapamil hydrochloride microspheres prepared with cellulose esters.  

PubMed

Microspheres containing two different drug loadings of a calcium channel blocker, verapamil hydrochloride, were prepared with three different cellulose esters namely cellulose acetate (CA), cellulose acetate propionate (CAP) and cellulose acetate butyrate (CAB) of approximately similar molecular weights using the emulsion-solvent evaporation method. Increasing the drug loading from 33.3 to 50% w/w increased the geometric mean diameter of the microspheres as well as the T50% values, i.e. time required to release 50% of the drug from microspheres prepared with all the three cellulose esters. Drug release from the microspheres was affected by the nature of polymer. Mathematical modelling of drug release data by fitting the data to various equations revealed that the data did not fit the conventional Higuchi's and Baker-Lonsdale's models for drug release from spherical matrices. Instead, the data fitted the log-probability and the Weibull models quite well. PMID:7730959

Bhardwaj, S B; Shukla, A J; Collins, C C

1995-01-01

278

Revisiting the Isobole and Related Quantitative Methods for Assessing Drug Synergism  

PubMed Central

The isobole is well established and commonly used in the quantitative study of agonist drug combinations. This article reviews the isobole, its derivation from the concept of dose equivalence, and its usefulness in providing the predicted effect of an agonist drug combination, a topic not discussed in pharmacology textbooks. This review addresses that topic and also shows that an alternate method, called “Bliss independence,” is inconsistent with the isobolar approach and also has a less clear conceptual basis. In its simplest application the isobole is the familiar linear plot in Cartesian coordinates with intercepts representing the individual drug potencies. It is also shown that the isobole can be nonlinear, a fact recognized by its founder (Loewe) but neglected or rejected by virtually all other users. Whether its shape is linear or nonlinear the isobole is equally useful in detecting synergism and antagonism for drug combinations, and its theoretical basis leads to calculations of the expected effect of a drug combination. Numerous applications of isoboles in preclinical testing have shown that synergism or antagonism is not only a property of the two agonist drugs; the dose ratio is also important, a fact of potential importance to the design and testing of drug combinations in clinical trials. PMID:22511201

2012-01-01

279

A re-assessment of aerosol size distributions from Masaya volcano (Nicaragua)  

E-print Network

A re-assessment of aerosol size distributions from Masaya volcano (Nicaragua) R.S. Martinab E humidity in 2010. These results indicate that aerosol emissions from a volcano can vary in ionic; Cascade impactor 1. Aerosol emissions from quiescently degassing volcanoes Active volcanoes are a major

Paris-Sud XI, Université de

280

Assessment of the Impact of SFCL on Voltage Sags in Power Distribution System  

Microsoft Academic Search

This paper assesses and analyses the effects of super- conducting fault current limiter (SFCL) installed in power dis- tribution system on voltage sags. First of all, resistor-type SFCL is modeled using PSCAD\\/EMTDC to represent the quench and recovery characteristics based on the experimental results. Next, typical power distribution system of Korea is modeled. When the SFCLisinstalledinvariouslocationsfromthestartingpointtoend point of feeders, improvement

Jong-Fil Moon; Sung-Hun Lim; Jae-Chul Kim; Sang-Yun Yun

2011-01-01

281

Spatially distributed pesticide exposure assessment in the Central Valley, California, USA  

E-print Network

Spatially distributed pesticide exposure assessment in the Central Valley, California, USA Yuzhou of pesticide sources. a r t i c l e i n f o Article history: Received 24 September 2009 Received in revised level a b s t r a c t Field runoff is an important transport mechanism by which pesticides move

Zhang, Minghua

282

DEVELOPMENT OF STATISTICAL DISTRIBUTIONS OR RANGES OF STANDARD FACTORS USED IN EXPOSURE ASSESSMENTS  

EPA Science Inventory

This document is intended to support EPA's Exposure Assessment Guidelines by providing data and information on standard factors that are used to calculate human exposure to toxic substances. tatistical distributions or ranges of values were developed for body weight, skin surface...

283

MODELING OF SPECIES GEOGRAPHIC DISTRIBUTION FOR ASSESSING PRESENT NEEDS FOR THE ECOLOGICAL NETWORKS  

Microsoft Academic Search

In Japan, attention is currently focused on designing ecological networks for wildlife animals. However there is an obvious lack of the species spatial information. This study aims (a) to acquire the potential spatial distribution of Asiatic black bear and Japanese se- row to identify core areas, and (b) to propose a methodology for assessing needs for ecological networks. 1836 species'

T. Doko; F A. Kooiman; A. G. Toxopeus

284

Autoradiographic and biochemical studies of drug distribution in the liver III. [ 14 C] Aminotriazole  

Microsoft Academic Search

Summary  Whole body autoradiography revealed that the distribution pattern of [14C]aminotriazole in the mouse liver was homogeneous after intravenous administration of the labeled agent and then became heterogeneous\\u000a (or reticular). Microautoradiography by dry-moun-ting method revealed that the macroscopic heterogeneous pattern was due to\\u000a the central localization of the radioactive compound in the hepatic lobule.\\u000a \\u000a \\u000a The present studies indicated that the heterogeneous

Toshihiko Fujii; Hisashi Miyazaki; Masahisa Hashimoto

1984-01-01

285

Assessment of ion-selective optical nanosensors for drug screening applications  

E-print Network

Ion channels represent an important category of drug targets. They play a significant role in numerous physiological functions, from membrane excitation and signaling to fluid absorption and secretion. An ion-channel assay ...

Yun, Hannah

2007-01-01

286

Drug-induced glucose-6-phosphate dehydrogenase deficiency-related hemolysis risk assessment.  

PubMed

Glucose-6-phosphate dehydrogenase (G6PD) is an essential enzyme that protects human red blood cells from premature destruction caused by oxidative damage. People suffering from G6PD deficiency would be vulnerable to various oxidative substances, such as fava beans and oxidant drugs. Until now, many institutes, organizations or domain experts have compiled low-risk or high-risk drugs collection for patients with G6PD deficiency, mainly from the case report or clinical trails. Recently, we have explored a classification system to predict drug-induced hemolytic potential. In this paper, we screen the normally used over-the-counter (OTC) drugs for "high-risk" and "low-risk" ones to G6PD deficient patients by this system. PMID:21704265

Yang, Yang; Li, Zuofeng; Nan, Peng; Zhang, Xiaoyan

2011-06-01

287

Non-invasive assessment of diastolic function in hypertrophic cardiomyopathy on and off beta adrenergic blocking drugs.  

PubMed Central

Beta adrenergic blocking drugs in hypertrophic cardiomyopathy provide symptomatic relief but their effect on long-term prognosis is uncertain. Thirty patients were studied non-invasively by simultaneous recordings of echocardiogram, apex-cardiogram, phonocardiogram, and electrocardiogram in order to assess diastolic abnormalities on and off oral beta adrenergic blocking drugs. While on treatment these patients had a mean dose of propranolol 200 mg/day. The treatment was stopped for one week and then non-invasive assessment was repeated. The following diastolic time intervals were studied: isovolumic relaxation period (A2-mitral valve opening); rapid relaxation period (A2-O point of the apexcardiogram), and the period from mitral valve opening to the O point of the apexcardiogram (Mo-O) when most of the filling of the left ventricle occurs. The prolongation of the rapid relaxation period reflects a reduced rate of fall of the left ventricular pressure when the pressure differential does not change between A2 and the O point of the apexcardiogram, and in this study this period was prolonged in 19, shortened in eight, and remained the same in three patients after beta blockade. The Mo-O point was prolonged in 22, shortened in seven, and was unchanged in one patient after beta adrenergic blocking drugs. All these results were independent of heart rate. In conclusion the response of diastolic time intervals to beta blocking drugs in hypertrophic cardiomyopathy was variable but there was a significant number of patients in whom the time available for filling of the left ventricle was prolonged, suggesting better filling possibly because of improved distensibility of the left ventricle after beta adrenergic blocking drugs. PMID:6125160

Alvares, R F; Goodwin, J F

1982-01-01

288

An in vitro model for assessment of drug-induced torsade de pointes arrhythmia  

Microsoft Academic Search

Torsade de pointes (TdP) is a serious side effect of many drugs. We aimed to establish an in vitro TdP model for drug testing,\\u000a which includes typical risk factors, such as female gender, hypokalemia, low magnesium levels, and bradycardia. Isolated,\\u000a spontaneously beating rabbit hearts (female White New Zealand rabbits) were perfused according to the Langendorff technique\\u000a and submitted to conditions

Stefan Dhein; Franziska Perlitz; Friedrich-Wilhelm Mohr

2008-01-01

289

Distributions  

NSDL National Science Digital Library

This online, interactive lesson on distributions provides examples, exercises, and applets which explore the basic types of probability distributions and the ways distributions can be defined using density functions, distribution functions, and quantile functions.

Siegrist, Kyle

2008-12-24

290

Clinician uptake of obesity-related drug information: a qualitative assessment using continuing medical education activities  

PubMed Central

Background Medications necessary for disease management can simultaneously contribute to weight gain, especially in children. Patients with preexisting obesity are more susceptible to medication-related weight gain. How equipped are primary care practitioners at identifying and potentially reducing medication-related weight gain? To inform this question germane to public health we sought to identify potential gaps in clinician knowledge related to metabolic adverse drug effects of weight gain. Methods The study analyzed practitioner responses to the pre-activity questions of six continuing medical education (CME) activities from May 2009 through August 2010. Results The 20,705 consecutive, self-selected respondents indicated varied levels of familiarity with adverse metabolic effects and psychiatric indications of atypical antipsychotics. Correct responses were lower than predicted for drug indications pertaining to autism (?17% predicted); drug effects on insulin resistance (?62% predicted); chronic disease risk in mental illness (?34% predicted); and drug safety research (?40% predicted). Pediatrician knowledge scores were similar to other primary care practitioners. Conclusions Clinicians’ knowledge of medication-related weight gain may lead them to overestimate the benefits of a drug in relation to its metabolic risks. The knowledge base of pediatricians appears comparable to their counterparts in adult medicine, even though metabolic drug effects in children have only become prevalent recently. PMID:23575242

2013-01-01

291

Risk assessment of drug interaction potential and concomitant dosing pattern on targeted toxicities in pediatric cancer patients.  

PubMed

This investigation evaluated the impact of potential drug interactions on the incidence of reported toxicities seen with common dosing patterns in children with cancer, with the intent of being able to screen and reduce the incidence of adverse drug reactions (ADRs) in the future. Toxicity reported in pediatric cancer patients treated at the Children's Hospital of Philadelphia from 2004 to 2010 were abstracted from a cancer tumor registry and merged with drug order profiles from the medical record system. Analysis datasets were created in SAS and permutation algorithms were used to identify pairwise drug combinations associated with specific toxicity occurrence. Relative risk of toxicity based on dosing pattern was assessed via comparison to control patients. A total of 326 of 1,713 patients (19%) had reportable toxicities. Neutrophil count decreases and alanine aminotransferase increases represented the highest occurring, corresponding to 28.8% and 31.9% prevalence among patients reporting toxicity, respectively. Of coadministered drug pairs, acetaminophen-diphenhydramine occurred most frequently; however, methotrexate-vincristine was the highest occurring pair linked to a single toxicity (hepatotoxicity). Toxicity was highly associated with the diagnoses of leukemia (52.1%) or neuroblastoma (28.5%). Comparison of the dosing interval (?30 versus >30 min) suggested that risk of toxicity can be associated with the timing of coadministration, with ?30 min increasing the risk of hepatotoxicity with fentanyl-midazolam and methotrexate-midazolam combinations. Knowledge of drug interactions in children with cancer may help reduce the incidence of ADRs by providing pharmacotherapy options that may reduce the likelihood of toxicity. PMID:23595361

Barrett, Jeffrey S; Patel, Dimple; Dombrowsky, Erin; Bajaj, Gaurav; Skolnik, Jeffrey M

2013-07-01

292

Liquid extraction surface analysis mass spectrometry (LESA-MS) as a novel profiling tool for drug distribution and metabolism analysis: the terfenadine example.  

PubMed

Liquid extraction surface analysis mass spectrometry (LESA-MS) is a novel surface profiling technique that combines micro-liquid extraction from a solid surface with nano-electrospray mass spectrometry. One potential application is the examination of the distribution of drugs and their metabolites by analyzing ex vivo tissue sections, an area where quantitative whole body autoradiography (QWBA) is traditionally employed. However, QWBA relies on the use of radiolabeled drugs and is limited to total radioactivity measured whereas LESA-MS can provide drug- and metabolite-specific distribution information. Here, we evaluate LESA-MS, examining the distribution and biotransformation of unlabeled terfenadine in mice and compare our findings to QWBA, whole tissue LC/MS/MS and MALDI-MSI. The spatial resolution of LESA-MS can be optimized to ca. 1 mm on tissues such as brain, liver and kidney, also enabling drug profiling within a single organ. LESA-MS can readily identify the biotransformation of terfenadine to its major, active metabolite fexofenadine. Relative quantification can confirm the rapid absorption of terfendine after oral dosage, its extensive first pass metabolism and the distribution of both compounds into systemic tissues such as muscle, spleen and kidney. The elimination appears to be consistent with biliary excretion and only trace levels of fexofenadine could be confirmed in brain. We found LESA-MS to be more informative in terms of drug distribution than a comparable MALDI-MS imaging study, likely due to its favorable overall sensitivity due to the larger surface area sampled. LESA-MS appears to be a useful new profiling tool for examining the distribution of drugs and their metabolites in tissue sections. PMID:22095508

Eikel, Daniel; Vavrek, Marissa; Smith, Sheri; Bason, Carol; Yeh, Suzie; Korfmacher, Walter A; Henion, Jack D

2011-12-15

293

Variability in P-glycoprotein inhibitory potency (IC??) using various in vitro experimental systems: implications for universal digoxin drug-drug interaction risk assessment decision criteria.  

PubMed

A P-glycoprotein (P-gp) IC?? working group was established with 23 participating pharmaceutical and contract research laboratories and one academic institution to assess interlaboratory variability in P-gp IC?? determinations. Each laboratory followed its in-house protocol to determine in vitro IC?? values for 16 inhibitors using four different test systems: human colon adenocarcinoma cells (Caco-2; eleven laboratories), Madin-Darby canine kidney cells transfected with MDR1 cDNA (MDCKII-MDR1; six laboratories), and Lilly Laboratories Cells--Porcine Kidney Nr. 1 cells transfected with MDR1 cDNA (LLC-PK1-MDR1; four laboratories), and membrane vesicles containing human P-glycoprotein (P-gp; five laboratories). For cell models, various equations to calculate remaining transport activity (e.g., efflux ratio, unidirectional flux, net-secretory-flux) were also evaluated. The difference in IC?? values for each of the inhibitors across all test systems and equations ranged from a minimum of 20- and 24-fold between lowest and highest IC?? values for sertraline and isradipine, to a maximum of 407- and 796-fold for telmisartan and verapamil, respectively. For telmisartan and verapamil, variability was greatly influenced by data from one laboratory in each case. Excluding these two data sets brings the range in IC?? values for telmisartan and verapamil down to 69- and 159-fold. The efflux ratio-based equation generally resulted in severalfold lower IC?? values compared with unidirectional or net-secretory-flux equations. Statistical analysis indicated that variability in IC?? values was mainly due to interlaboratory variability, rather than an implicit systematic difference between test systems. Potential reasons for variability are discussed and the simplest, most robust experimental design for P-gp IC?? determination proposed. The impact of these findings on drug-drug interaction risk assessment is discussed in the companion article (Ellens et al., 2013) and recommendations are provided. PMID:23620485

Bentz, Joe; O'Connor, Michael P; Bednarczyk, Dallas; Coleman, Joann; Lee, Caroline; Palm, Johan; Pak, Y Anne; Perloff, Elke S; Reyner, Eric; Balimane, Praveen; Brännström, Marie; Chu, Xiaoyan; Funk, Christoph; Guo, Ailan; Hanna, Imad; Herédi-Szabó, Krisztina; Hillgren, Kate; Li, Libin; Hollnack-Pusch, Evelyn; Jamei, Masoud; Lin, Xuena; Mason, Andrew K; Neuhoff, Sibylle; Patel, Aarti; Podila, Lalitha; Plise, Emile; Rajaraman, Ganesh; Salphati, Laurent; Sands, Eric; Taub, Mitchell E; Taur, Jan-Shiang; Weitz, Dietmar; Wortelboer, Heleen M; Xia, Cindy Q; Xiao, Guangqing; Yabut, Jocelyn; Yamagata, Tetsuo; Zhang, Lei; Ellens, Harma

2013-07-01

294

Variability in P-Glycoprotein Inhibitory Potency (IC50) Using Various in Vitro Experimental Systems: Implications for Universal Digoxin Drug-Drug Interaction Risk Assessment Decision Criteria  

PubMed Central

A P-glycoprotein (P-gp) IC50 working group was established with 23 participating pharmaceutical and contract research laboratories and one academic institution to assess interlaboratory variability in P-gp IC50 determinations. Each laboratory followed its in-house protocol to determine in vitro IC50 values for 16 inhibitors using four different test systems: human colon adenocarcinoma cells (Caco-2; eleven laboratories), Madin-Darby canine kidney cells transfected with MDR1 cDNA (MDCKII-MDR1; six laboratories), and Lilly Laboratories Cells—Porcine Kidney Nr. 1 cells transfected with MDR1 cDNA (LLC-PK1-MDR1; four laboratories), and membrane vesicles containing human P-glycoprotein (P-gp; five laboratories). For cell models, various equations to calculate remaining transport activity (e.g., efflux ratio, unidirectional flux, net-secretory-flux) were also evaluated. The difference in IC50 values for each of the inhibitors across all test systems and equations ranged from a minimum of 20- and 24-fold between lowest and highest IC50 values for sertraline and isradipine, to a maximum of 407- and 796-fold for telmisartan and verapamil, respectively. For telmisartan and verapamil, variability was greatly influenced by data from one laboratory in each case. Excluding these two data sets brings the range in IC50 values for telmisartan and verapamil down to 69- and 159-fold. The efflux ratio-based equation generally resulted in severalfold lower IC50 values compared with unidirectional or net-secretory-flux equations. Statistical analysis indicated that variability in IC50 values was mainly due to interlaboratory variability, rather than an implicit systematic difference between test systems. Potential reasons for variability are discussed and the simplest, most robust experimental design for P-gp IC50 determination proposed. The impact of these findings on drug-drug interaction risk assessment is discussed in the companion article (Ellens et al., 2013) and recommendations are provided. PMID:23620485

Bentz, Joe; O'Connor, Michael P.; Bednarczyk, Dallas; Coleman, JoAnn; Lee, Caroline; Palm, Johan; Pak, Y. Anne; Perloff, Elke S.; Reyner, Eric; Balimane, Praveen; Brannstrom, Marie; Chu, Xiaoyan; Funk, Christoph; Guo, Ailan; Hanna, Imad; Heredi-Szabo, Krisztina; Hillgren, Kate; Li, Libin; Hollnack-Pusch, Evelyn; Jamei, Masoud; Lin, Xuena; Mason, Andrew K.; Neuhoff, Sibylle; Patel, Aarti; Podila, Lalitha; Plise, Emile; Rajaraman, Ganesh; Salphati, Laurent; Sands, Eric; Taub, Mitchell E.; Taur, Jan-Shiang; Weitz, Dietmar; Wortelboer, Heleen M.; Xia, Cindy Q.; Xiao, Guangqing; Yabut, Jocelyn; Yamagata, Tetsuo; Zhang, Lei

2013-01-01

295

Rapid Assessment and Response Studies of Injection Drug Use: Knowledge Gain, Capacity Building, and Intervention Development in a Multisite Study  

PubMed Central

Objectives. We evaluated the World Health Organization’s rapid assessment and response (RAR) method of assessing injection drug use and its associated health problems, focusing on knowledge gain, capacity building, and whether RAR leads to the development of interventions reducing the health effects of injection drug use. Methods. Data were derived from RAR studies conducted in Beijing, China; Bogotá, Colombia; Greater Rosario, Argentina; Hanoi, Vietnam; Kharkiv, Ukraine; Minsk, Belarus; Nairobi, Kenya; Penang, Malaysia; St. Petersburg, Russia; and Tehran, Iran. Results. Substantial gains in knowledge and response capacity were reported at all of the study sites. Before RAR initiation, prevention and intervention programs had been absent or inadequate at most of the sites. The RARs resulted in many new or modified interventions; 7 sites reported 24 health-related interventions that were subsequently developed and influenced by the RARs. Conclusions. RARs, which require relatively little external funding, appear to be effective in linking assessment to development of appropriate interventions. The present results add to the evidence that rapid assessment is an important public health tool. PMID:16380578

Stimson, Gerry V.; Fitch, Chris; Jarlais, Don Des; Poznyak, Vladimir; Perlis, Theresa; Oppenheimer, Edna; Rhodes, Tim

2006-01-01

296

COMPARISON OF IN VITRO METHODS AND THE IN VIVO METABOLISM OF LINDANE FOR ASSESSING THE EFFECTS OF REPEATED ADMINISTRATION OF ETHANOL ON HEPATIC DRUG METABOLISM  

EPA Science Inventory

In vitro methods of assessing alterations in drug metabolism and the measurement of lindane metabolites in urine were compared for their ability to determine the influence of ethanol on drug metabolism. Ethanol was administered to young adult female rats daily for seven days at d...

297

Biomarkers to assess the efficiency of treatment with platinum-based drugs: what can metallomics add?  

PubMed

Since the approval of cisplatin as an antineoplastic drug, the medical and the scientific communities have been concerned about the side effects of platinum-based drugs, and this has been the dose-limiting factor that leads to reduced treatment efficiency. Another important issue is the intrinsic or acquired resistance of some patients to treatment. Identifying proper biomarkers is crucial in evaluating the efficiency of a treatment, assisting physicians in determining, at early stages, whether or not the patient presents resistance to the drug, minimizing severe side effects, and allowing them to redirect the established course of chemotherapy. A great effort is being made to identify biomarkers that can be used to predict the outcome of the treatment of cancer patients with platinum-based drugs. In this context, the metallomic approach has not yet been used to its full potential. Since the basis of these drugs is platinum, the monitoring of biomarkers containing this metal should be the natural approach to evaluate treatment progress. This review intends to show where the research in this field stands and points out some gaps that can be filled by metallomics. PMID:25387565

Araujo, Thiago de O; Costa, Lilian T; Fernandes, Janaina; Aucélio, Ricardo Queiroz; de Campos, Reinaldo Calixto

2014-12-20

298

Standardization of Nomenclature and Causality Assessment in Drug-Induced Liver Injury: Summary of a Clinical Research Workshop  

PubMed Central

Idiosyncratic drug-induced liver injury (DILI) is an important but relatively infrequent cause of potentially severe acute and chronic liver injury. The aim of this clinical research workshop was to review and attempt to standardize the current nomenclature and terminology used in DILI research. Because DILI is a diagnosis of exclusion, selected elements of the medical history, laboratory tests, and previous reports were proposed to improve causality assessment. Definitions and diagnostic criteria regarding the onset of DILI, evolution of liver injury, risk factors, and mandatory testing versus optional testing for competing causes were reviewed. In addition, the role of intentional and inadvertent rechallenge, liver histology, and host genetic polymorphisms in establishing the diagnosis and prognosis of DILI were reviewed. Consensus was established regarding the need to develop a web-of-knowledge database that provides concise, reliable, and updated information on cases of liver injury due to drugs and herbal and dietary supplements. In addition, the need to develop drug-specific computerized causality assessment methods that are derived from prospectively phenotyped cases was a high priority. Proposed scales for grading DILI severity and assessing the likelihood of an agent causing DILI and written criteria for improving the reliability, accuracy, and reproducibility of expert opinion were reviewed. Finally, the unique challenges of assessing causality in children, patients with underlying liver disease, and subjects taking herbal and dietary supplements were discussed. Conclusion: Workshop participants concluded that multicenter referral networks enrolling patients with suspected DILI according to standardized methodologies are needed. These networks should also collect biological samples that may provide crucial insights into the mechanism(s) of DILI with the ultimate aim of preventing future cases of DILI. PMID:20564754

Fontana, Robert J.; Seeff, Leonard B.; Andrade, Raul J.; Bjornsson, Einar; Day, Christopher P.; Serrano, Jose; Hoofnagle, Jay H.

2013-01-01

299

Waste prevention in liquid detergent distribution: A comparison based on life cycle assessment.  

PubMed

The distribution of liquid detergents through self-dispensing systems has been adopted in some Italian retail stores over the last few years. By enabling the consumer to refill several times the same container, it is proposed as a less waste-generating and more environmentally friendly alternative to the traditional distribution with single-use plastic containers. For this reason, its implementation is encouraged by the national waste prevention programme recently adopted in Italy. In order to assess such claims, a life cycle assessment was carried out to evaluate whether detergent distribution through self-dispensing systems actually allows to achieve the expected reduction in waste generation and environmental impacts. The focus was on the distribution within the large-scale retail trade and on the categories of laundry detergents, fabric softeners and hand dishwashing detergents. For each of them, a set of baseline single-use scenarios were compared with two alternative waste prevention scenarios, where the detergent is distributed through self-dispensing systems. Beyond waste generation, also the Cumulative Energy Demand and thirteen midpoint-level potential impact indicators were calculated for the comparison. Results showed that a reduction in waste generation up to 98% can be achieved, depending on the category of detergent, on the baseline scenario of comparison and on the number of times the refillable container is used. A progressive reduction in the energy demand and in most of the potential impacts was also observed, starting from a minimum number of uses of the refillable container. PMID:25209251

Nessi, Simone; Rigamonti, Lucia; Grosso, Mario

2014-11-15

300

An injectable depot system for sustained intraperitoneal chemotherapy of ovarian cancer results in favorable drug distribution at the whole body, peritoneal and intratumoral levels.  

PubMed

The current study characterizes the impact of docetaxel (DTX) distribution on efficacy following sustained intraperitoneal (IP) chemotherapy in murine models of ovarian cancer. A polymer-lipid biodegradable depot (PoLigel) was used to deliver DTX in a sustained manner over 21-days following IP administration. Distribution and efficacy studies were carried out in SCID mice bearing SKOV3 IP solid tumors or C57BL/6 mice with ID8 IP ascites fluid. In addition, a subcutaneous (SC) SKOV3 model was used to determine whether systemic drug levels that result from IP administration of the PoLigel influence antitumor efficacy. Immunostained IP and SC SKOV3 tumor sections were used to study cell death, intratumoral drug distribution and tumor penetration. Sustained concentrations of DTX were observed in plasma, tissue, tumor and ascites over the entire study period. Drug accumulation was several fold greater in tumors and ascites when compared to plasma levels. Sustained chemotherapy resulted in significant reduction in tumor burden and ascites volume. IP tumors showed greater cell death compared to the SC tumors as seen by higher TUNEL and caspase-3 expression. At the intratumoral level, DTX distributed more towards the core of IP tumors compared to the SC tumors. Tumor penetration of drug from nearest blood vessel was 1.5 fold greater in the IP tumors than the SC tumors. Overall, favorable drug distribution at the whole-body, peritoneal and intratumoral levels in combination with local and systemic sustained drug exposure contribute to the high efficacy observed. These results encourage the clinical use of IP sustained chemotherapy for ovarian cancer. PMID:22154933

Zahedi, Payam; Stewart, James; De Souza, Raquel; Piquette-Miller, Micheline; Allen, Christine

2012-03-28

301

EO-199, a specific antagonist of antiarrhythmic drugs: Assessment by binding experiments and in vivo studies  

SciTech Connect

EO-199, a demethylated analog of the novel class I antiarrhythmic drug EO-122 was found to antagonize the antiarrhythmic activity of EO-122 and that of procainamide (Class I{sub A}). EO-199 did not block significantly the activity of a class I{sub B} antiarrhythmic agent, lidocaine. EO-199 also displaced the specific binding of ({sup 3}H)EO-122 to rate heart membranes similarly to procainamide whereas lidocaine did not. The correlation between binding experiments and pharmacological effects points to a possible subclassification of these drugs; the two chemical analogs EO-199 and EO-122, as well as procainamide (I{sub A}) but not lidocaine (I{sub B}), compete at the same site or the same state of the sodium channel. The availability of a specific antagonist might be useful for studying the mechanism of action of antiarrhythmic drugs as well as an antidote in cases of antiarrhythmics overdose intoxication.

Oppenheimer, E.; Harel, G.; Lipinsky, D.; Sarne, Y. (Tel-Aviv Univ. (Israel))

1991-01-01

302

Drug deposition and distribution in healthy and atherosclerotic arteries and in models of atherosclerosis following bulk or stent-based drug delivery  

E-print Network

Drug eluting stents have revolutionized the practice of medicine and the landscape of medical devices. Yet, more than four years after introduction clinical trial data and clinical use have still not fully clarified what ...

Vukmirovic, Neda

2007-01-01

303

An assessment of direct-to-consumer advertising of prescription drugs.  

PubMed

Advertising is widely seen by economists and regulators as beneficial to markets and consumers. The prescription drug market offers exceptional opportunities for direct-to-consumer advertising (DTCA) to provide new-product information, improve compliance, alleviate widespread underdiagnosis and undertreatment, and motivate new-product development.5 DTCA can also induce excess or even dangerous prescribing, however, partly because patients are poorly informed and usually pay far less than the full cost of drugs. Empirical research can help resolve these issues. PMID:17851572

Calfee, J E

2007-10-01

304

Preclinical Predictors of Anticancer Drug Efficacy: Critical Assessment with Emphasis on Whether Nanomolar Potency Should Be Required of Candidate Agents  

PubMed Central

In the current paradigm of anticancer drug development, candidate compounds are evaluated by testing their in vitro potency against molecular targets relevant to carcinogenesis, their effect on cultured cancer cells, and their ability to inhibit cancer growth in animal models. We discuss the key assumptions inherent in these approaches. In recent years, great emphasis has been placed on selecting for development compounds with nanomolar in vitro potency, expecting that they will be efficacious and safer based on the assumption that they can be used at lower doses (“the nanomolar rule”). However, this rule ignores critical parameters affecting efficacy and toxicity such as physiochemical and absorption, distribution, metabolism and excretion properties, off-target effects, and multitargeting activities. Thus, uncritical application of the nanomolar rule may reject efficacious compounds or select ineffective or toxic compounds. We present examples of efficacious chemotherapeutic (alkylating agents, hormonal agents, antimetabolites, thalidomide, and valproic acid) and chemopreventive (aspirin and sulindac) agents having millimolar potency and compounds with nanomolar potency (cyclooxygenase-2 inhibitors) that, nevertheless, failed or proved to be unsafe. The effect of candidate drugs on animal models of cancer is a better predictor of human drug efficacy; particularly useful are tumor xenografts. Given the cost of failure at clinical stages, it is imperative to keep in mind the limitations of the nanomolar rule and use relevant in vivo models early in drug discovery to prioritize candidates. Although in vivo models will continue having a major role in cancer drug development, more robust approaches that combine high predictive ability with simplicity and low cost should be developed. PMID:22448039

Wong, C. C.; Cheng, Ka-Wing

2012-01-01

305

Grapefruit juice-drug interaction studies as a method to assess the extent of intestinal availability: utility and limitations.  

PubMed

This study aims to assess utility and limitations of grapefruit juice (GFJ) interaction studies as alternative in vivo approach to estimate intestinal availability (F(G)) in comparison to the predominantly used i.v./oral method. The F(G) estimates were obtained from the ratio of AUC in the control and the GFJ group reported previously. Due to large variability in the study design, the following inclusion criteria were applied for the selection of clinical studies: no change in elimination half-life in the presence of GFJ, administration of GFJ with or up to 4 h before drug intake, and a reported significant increase in AUC in the presence of GFJ. Weighted mean F(G) values were compared to estimates from i.v./oral data. Additionally, inter-study and inter-individual variation of GFJ F(G) estimates was assessed by meta-analysis for drugs with multiple studies reported. F(G) values ranged from 0.07 to 0.92 for lovastatin and quinidine, respectively. Overall, the inter-individual variation in GFJ F(G) estimates (16-54%) was higher than the inter-study (5.7-39%) with the exception of nisoldipine and simvastatin where inter-study variations of 53-88% were observed. Weighted average GFJ F(G) estimates were comparable to i.v./oral, supporting the application of this approach as an alternative to i.v./oral data for predominantly metabolised drugs (r(2) = 0.65; n=10). In contrast, this approach is of limited use for drugs whose disposition is co-dependent on efflux/uptake transporters and metabolic enzymes. An area of high intestinal extraction (F(G) < or = 0.25) is identified as problematic, as availability of conclusive data is limited in this area. PMID:18855612

Gertz, Michael; Davis, John D; Harrison, Anthony; Houston, J Brian; Galetin, Aleksandra

2008-10-01

306

Zebrafish: an emerging technology for in vivo pharmacological assessment to identify potential safety liabilities in early drug discovery  

PubMed Central

The zebrafish is a well-established model organism used in developmental biology. In the last decade, this technology has been extended to the generation of high-value knowledge on safety risks of novel drugs. Indeed, the larval zebrafish appear to combine advantages of whole organism phenotypic assays and those (rapid production of results with minimal resource engagement) of in vitro high-throughput screening techniques. Thus, if appropriately evaluated, it can offer undeniable advantages in drug discovery for identification of target and off-target effects. Here, we review some applications of zebrafish to identify potential safety liabilities, particularly before lead/candidate selection. For instance, zebrafish cardiovascular system can be used to reveal decreases in heart rate and atrial–ventricular dissociation, which may signal human ether-a-go-go-related gene (hERG) channel blockade. Another main area of interest is the CNS, where zebrafish behavioural assays have been and are further being developed into screening platforms for assessment of locomotor activity, convulsant and proconvulsant liability, cognitive impairment, drug dependence potential and impaired visual and auditory functions. Zebrafish also offer interesting possibilities for evaluating effects on bone density and gastrointestinal function. Furthermore, available knowledge of the renal system in larval zebrafish can allow identification of potential safety issues of drug candidates on this often neglected area in early development platforms. Although additional validation is certainly needed, the zebrafish is emerging as a versatile in vivo animal model to identify off-target effects that need investigation and further clarification early in the drug discovery process to reduce the current, high degree of attrition in development. PMID:18552866

Barros, T P; Alderton, W K; Reynolds, H M; Roach, A G; Berghmans, S

2008-01-01

307

The assessment of renal function in relation to the use of drugs in elderly in nursing homes; a cohort study  

PubMed Central

Background Renal function decreases with age. Dosage adjustment according to renal function is indicated for many drugs, in order to avoid adverse reactions of medications and/or aggravation of renal impairment. There are several ways to assess renal function in the elderly, but no way is ideal. The aim of the study was to explore renal function in elderly subjects in nursing homes and the use of pharmaceuticals that may be harmful to patients with renal impairment. Methods 243 elderly subjects living in nursing homes were included. S-creatinine and s-cystatin c were analysed. Renal function was estimated using Cockcroft-Gault formula, Modification of Diet in Renal Disease (MDRD) and cystatin C-estimated glomerular filtration rate (GFR). Concomitant medication was registered and four groups of renal risk drugs were identified: metformin, nonsteroidal anti-inflammatory drugs (NSAID), angiotensin-converting enzyme -inhibitors/angiotensin receptor blockers and digoxin. Descriptive statistics and the Kappa test for concordance were used. Results Reduced renal function (cystatin C-estimated GFR < 60 ml/min) was seen in 53%. Normal s-creatinine was seen in 41% of those with renal impairment. Renal risk drugs were rather rarely prescribed, with exception for ACE-inhibitors. Poor concordance was seen between the GFR estimates as concluded by other studies. Conclusions The physician has to be observant on renal function when prescribing medications to the elderly patient and not only rely on s-creatinine level. GFR has to be estimated before prescribing renal risk drugs, but using different estimates may give divergence in the results. PMID:21223578

2011-01-01

308

21 CFR 809.40 - Restrictions on the sale, distribution, and use of OTC test sample collection systems for drugs...  

Code of Federal Regulations, 2010 CFR

...Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES IN VITRO DIAGNOSTIC PRODUCTS FOR HUMAN USE Requirements for Manufacturers and Producers § 809.40 Restrictions on the...

2010-04-01

309

A meta-analysis of the hepatitis C virus distribution in diverse racial/ethnic drug injector groups  

PubMed Central

Hepatitis C virus (HCV) is mostly transmitted through blood-to-blood contact during injection drug use via shared contaminated syringes/needles or injection paraphernalia. This paper used meta-analytic methods to assess whether HCV prevalence and incidence varied across different racial/ethnic groups of injection drug users (IDUs) sampled internationally. The 29 prevalence and 11 incidence studies identified as part of the HCV Synthesis Project were categorized into subgroups based on similar racial/ethnic comparisons. The effect estimate used was the odds or risk ratio comparing HCV prevalence or incidence rates in racial/ethnic minority groups versus those of majority status. For prevalence studies, the clearest disparity in HCV status was observed in the Canadian and Australian Aboriginal versus White comparison, followed by the US non-White versus White categories. Overall, Hispanic IDUs had greater HCV prevalence, and HCV prevalence in African-Americans was not significantly greater than that of Whites in the US. Aboriginal groups showed higher HCV seroconversion rates when compared to others, and African-Americans had lower seroconversion rates compared to other IDUs in the US. The findings suggest that certain minority groups have elevated HCV rates in comparison to other IDUs, which may be a consequence of stigma, discrimination, different risk behaviors or decreased access to health care, services and preventive education. Future research should seek to explicitly explore and explain racial/ethnic variations in HCV prevalence and incidence, and define the groups more precisely to allow for more accurate detection of possible racial/ethnic differences in HCV rates. PMID:19062148

Lelutiu-Weinberger, Corina; Pouget, Enrique R.; Des Jarlais, Don D.C.; Cooper, Hannah L.; Scheinmann, Roberta; Stern, Rebecca; Strauss, Shiela M.; Hagan, Holly

2013-01-01

310

Assessment of soil organic carbon distribution in Europe scale by spatio-temporal data and geostatistics  

NASA Astrophysics Data System (ADS)

Accuracy in assessing the distribution of soil organic carbon (SOC) is an important issue because SOC is an important soil component that plays key roles in the functions of both natural ecosystems and agricultural systems. The SOC content varies from place to place and it is strongly related with climate variables (temperature and rainfall), terrain features, soil texture, parent material, vegetation, land-use types, and human management (management and degradation) at different spatial scales. Geostatistical techniques allow for the prediction of soil properties using soil information and environmental covariates. In this study, assessment of SOC distribution has been predicted using combination of LUCAS soil samples with local soil data and ten spatio-temporal predictors (slope, aspect, elevation, CTI, CORINE land-cover classification, parent material, texture, WRB soil classification, average temperature and precipitation) with Regression-Kriging method in Europe scale. Significant correlation between the covariates and the organic carbon dependent variable was found.

Aksoy, Ece; Panagos, Panos; Montanarella, Luca

2013-04-01

311

Assessment of benzimidazole resistance in Haemonchus contortus in sheep flocks in Ontario, Canada: comparison of detection methods for drug resistance.  

PubMed

In 2011, a field study was conducted to assess drug resistance of gastro-intestinal nematodes in sheep flocks in Ontario, Canada. Benzimidazole resistance in Haemonchus contortus was assessed by genetic analysis of eggs; measurement of resistant allele percentages at codons 167, 198 and 200 in the ?-tubulin gene was determined on pools of H. contortus eggs using pyrosequencing. Susceptibility to benzimidazoles in gastro-intestinal nematodes was also determined using a Faecal Egg Count Reduction Test (FECRT) and a Larval Development Assay (LDA). In total, 16 farms were assessed with the genetic test. Based on resistant allele frequencies, all of the farms (16/16) tested had benzimidazole resistance in H. contortus; the overall percentage of benzimidazole-resistant H. contortus (estimated prior to treatment using the Hardy-Weinberg formula) was 68.5%. The FECRT and LDA were performed on 11 and 13 farms, respectively. Resistance to fenbendazole was detected on 100% (11/11) of the farms where the FECRT was performed. The LDA revealed the presence of thiabendazole resistance in H. contortus in 92% (12/13) of the farms. Estimated percentages of resistant parasites in H. contortus populations obtained with the two biological tests and the genetic test were compared. The results of the genetic test were in agreement with the biological tests and confirmed that benzimidazole resistance in H. contortus is present in Ontario sheep flocks. Differences between the different methods of drug resistance detection are discussed in terms of cost, time and sampling. PMID:23993632

Barrere, V; Falzon, L C; Shakya, K P; Menzies, P I; Peregrine, A S; Prichard, R K

2013-11-15

312

The International Intravitreal Bevacizumab Safety Survey: using the internet to assess drug safety worldwide  

Microsoft Academic Search

Aim: Off-label intravitreal injections of bevacizumab (Avastin) have been given for the treatment of neovascular and exudative ocular diseases since May 2005. Since then, the use of intravitreal bevacizumab has spread worldwide, but the drug-related adverse events associated with its use have been reported only in a few retrospective reviews. The International Intravitreal Bevacizumab Safety Survey was initiated to gather

A E Fung; P J Rosenfeld; E Reichel

2006-01-01

313

Assessment of laser-induced release of drugs from liposomes: An in vitro study  

SciTech Connect

We evaluated the characteristics of laser-induced release of an antimetabolite (cytosine arabinoside) from temperature-sensitive liposomes. Previous work had shown that a laser would induce breakdown of liposomes when a dye was encapsulated within the liposomes. The present investigation was performed to determine if release could be induced from liposomes that did not contain dye. In vitro, dynamic studies of the release of the drug from liposomes diluted in blood (flowing in a capillary tube at 40 microns/min) were conducted using an argon dye laser operating either in the blue-green mode (488/514 nm) or in the dye mode (577 nm). A radio-labeled marker was used to monitor the drug release. The results showed that the drug could indeed be released from liposomes that did not contain dye, at energy levels that are not likely to be harmful to the tissue. At identical power levels, the release of the drug was greater at 577 nm than at 488/514 nm, probably owing to the greater light absorbance of hemoglobin at the longer wavelength. The results indicate the potential for the site-specific release of a variety of molecules in the ocular vasculature.

Khoobehi, B.; Char, C.A.; Peyman, G.A. (Louisiana State Univ. Medical Center School of Medicine, New Orleans (USA))

1990-01-01

314

Assessment of (mu)grid distributed energy resource potential using DER-CAM and GIS  

Microsoft Academic Search

This report outlines an approach to assess the local potential for deployment of distributed energy resources (DER), small power-generation installations located close to the point where the energy they produce will be consumed. Although local restraints, such as zoning, building codes, and on-site physical barriers are well-known frustrations to DER deployment, no analysis method has been developed to address them

Jennifer L. Edwards; Chris Marnay; Emily Bartholomew; Boubekeur Ouaglal; Afzal S. Siddiqui; Kristina S. H. LaCommare

2002-01-01

315

Differences in distribution and drug sensitivity of pathogens in lower respiratory tract infections between general wards and RICU  

PubMed Central

Background Lower respiratory tract infections (LRTIs) are common among patients in hospitals worldwide, especially in patients over the age of 60. This study investigates the differences in distribution and drug sensitivity of pathogens in LRTIs. Methods The clinical and laboratory data of 4,762 LRTI patients in the general ward and respiratory intensive care unit (RICU) of Xiangya Hospital (Changsha) were retrospectively analyzed. Results The infection rate of Gram-negative bacteria was significantly higher than that of Gram-positive bacteria in both the general ward and RICU (P<0.05). The incidence of Gram-negative bacteria infection was significantly higher in the RICU than in the general ward (P<0.05), whereas the incidence of Gram-positive bacteria infection is less in the RICU than in the general ward (P<0.05). In the general ward, the incidence of Gram-negative bacteria infection significantly increased (P<0.05) over time, whereas the incidence of Gram-positive bacteria infection significantly decreased from 1996 to 2011 (P<0.05). In the RICU, the incidence of Gram-positive bacteria infection decreased, while Gram-negative bacteria infections increased without statistical significance (P>0.05). Staphylococcus pneumoniae and Staphylococcus aureus were found to be the predominant Gram-positive strains in the general ward (34.70-41.18%) and RICU (41.66-54.87%), respectively (P>0.05). Pseudomonas aeruginosa and Acinetobacter baumannii were the predominant gram negative strains in the general ward (19.17-21.09%) and RICU (29.60-33.88%), respectively (P>0.05). Streptococcus pneumoniae is sensitive to most antibiotics with a sensitivity of more than 70%. Staphylococcus aureus is highly sensitive to vancomycin (100%), linezolid (100%), chloramphenicol (74.36-82.19%), doxycycline (69.57-77.33%), and sulfamethoprim (67.83-72.46%); however, its sensitivity to other antibiotics is low and decreased each year. Sensitivity of Pseudomonas aeruginosa to most ?-lactam, aminoglycoside, and quinolone group antibiotics decreased each year. Conclusions The distribution and drug sensitivity of LRTI pathogens exhibit a high divergence between the general ward and RICU. Streptococcus pneumoniae may not be the predominant pathogen in LRTIs in some areas of China. PMID:25364517

He, Ruoxi; Luo, Bailing; Hu, Chengping; Li, Ying

2014-01-01

316

Rapid dynamic R1 /R2 */temperature assessment: a method with potential for monitoring drug delivery.  

PubMed

Local drug delivery by hyperthermia-induced drug release from thermosensitive liposomes (TSLs) may reduce the systemic toxicity of chemotherapy, whilst maintaining or increasing its efficacy. Relaxivity contrast agents can be co-encapsulated with the drug to allow the visualization of the presence of liposomes, by means of R2 *, as well as the co-release of the contrast agent and the drug, by means of R1, on heating. Here, the mathematical method used to extract both R2 * and R1 from a fast dynamic multi-echo spoiled gradient echo (ME-SPGR) is presented and analyzed. Finally, this method is used to monitor such release events. R2 * was obtained from a fit to the ME-SPGR data. Absolute R1 was calculated from the signal magnitude changes corrected for the apparent proton density changes and a baseline Look-Locker R1 map. The method was used to monitor nearly homogeneous water bath heating and local focused ultrasound heating of muscle tissue, and to visualize the release of a gadolinium chelate from TSLs in vitro. R2 *, R1 and temperature maps were measured with a 5-s temporal resolution. Both R2 *and R1 measured were found to change with temperature. The dynamic R1 measurements after heating agreed with the Look-Locker R1 values if changes in equilibrium magnetization with temperature were considered. Release of gadolinium from TSLs was detected by an R1 increase near the phase transition temperature, as well as a shallow R2 * increase. Simultaneous temperature, R2 * and R1 mapping is feasible in real time and has the potential for use in image-guided drug delivery studies. Copyright © 2014 John Wiley & Sons, Ltd. PMID:25208052

Lorenzato, Cyril; Oerlemans, Chris; Cernicanu, Alexandru; Ries, Mario; Denis de Senneville, Baudouin; Moonen, Chrit; Bos, Clemens

2014-11-01

317

Independent Orbiter Assessment (IOA): Analysis of the Electrical Power Distribution and Control Subsystem, Volume 2  

NASA Technical Reports Server (NTRS)

The results of the Independent Orbiter Assessment (IOA) of the Failure Modes and Effects Analysis (FMEA) and Critical Items List (CIL) are presented. The IOA approach features a top-down analysis of the hardware to determine failure modes, criticality, and potential critical items. To preserve independence, this analysis was accomplished without reliance upon the results contained within the NASA FMEA/CIL documentation. This report documents the independent analysis results corresponding to the Orbiter Electrical Power Distribution and Control (EPD and C) hardware. The EPD and C hardware performs the functions of distributing, sensing, and controlling 28 volt DC power and of inverting, distributing, sensing, and controlling 117 volt 400 Hz AC power to all Orbiter subsystems from the three fuel cells in the Electrical Power Generation (EPG) subsystem. Volume 2 continues the presentation of IOA analysis worksheets and contains the potential critical items list.

Schmeckpeper, K. R.

1987-01-01

318

Assessment of Regional Ventilation Distribution: Comparison of Vibration Response Imaging (VRI) with Electrical Impedance Tomography (EIT)  

PubMed Central

Background Vibration response imaging (VRI) is a bedside technology to monitor ventilation by detecting lung sound vibrations. It is currently unknown whether VRI is able to accurately monitor the local distribution of ventilation within the lungs. We therefore compared VRI to electrical impedance tomography (EIT), an established technique used for the assessment of regional ventilation. Methodology/Principal Findings Simultaneous EIT and VRI measurements were performed in the healthy and injured lungs (ALI; induced by saline lavage) at different PEEP levels (0, 5, 10, 15 mbar) in nine piglets. Vibration energy amplitude (VEA) by VRI, and amplitudes of relative impedance changes (rel.?Z) by EIT, were evaluated in seven regions of interest (ROIs). To assess the distribution of tidal volume (VT) by VRI and EIT, absolute values were normalized to the VT obtained by simultaneous spirometry measurements. Redistribution of ventilation by ALI and PEEP was detected by VRI and EIT. The linear correlation between pooled VT by VEA and rel.?Z was R2?=?0.96. Bland-Altman analysis showed a bias of ?1.07±24.71 ml and limits of agreement of ?49.05 to +47.36 ml. Within the different ROIs, correlations of VT-distribution by EIT and VRI ranged between R2 values of 0.29 and 0.96. ALI and PEEP did not alter the agreement of VT between VRI and EIT. Conclusions/Significance Measurements of regional ventilation distribution by VRI are comparable to those obtained by EIT. PMID:24475160

Bentley, Alexander H.; Hartmann, Erik K.; Klein, Klaus U.; Bodenstein, Marc; Baumgardner, James E.; David, Matthias; Ullrich, Roman; Markstaller, Klaus

2014-01-01

319

Distribution of Drug Resistance Genotypes in Plasmodium falciparum in an Area of Limited Parasite Diversity in Saudi Arabia  

PubMed Central

Two hundred and three Plasmodium falciparum isolates from Jazan area, southwest Saudi Arabia, were typed for Pfcrt, Pfmdr1, dhps, and dhfr mutations associated with resistance to chloroquine, mefloquine, halofantrine, artemisinin, sulfadoxine-pyrimethamine, and the neutral polymorphic gene Pfg377. A large proportion (33%) of isolates harbored double mutant dhfr genotype (51I,59C,108N). However, only one isolate contained mutation dhps-437G. For Pfcrt, almost all examined isolates (163; 99%) harbored the mutant genotype (72C,73V,74I,75E,76T), whereas only 49 (31%) contained the mutant Pfmdr1 genotype (86Y,184F,1034S,1042N), 109 (66%) harbored the single mutant genotype (86N,184F,1034S,1042N), and no mutations were seen in codons 1034, 1042, and 1246. Nonetheless, three new single-nucleotide polymorphisms were detected at codons 182, 192, and 102. No differences were seen in distribution of drug resistance genes among Saudis and expatriates. There was a limited multiplicity (5%), mean number of clones (1.05), and two dominant multilocus genotypes among infected individuals in Jazan. A pattern consistent with limited cross-mating and recombination among local parasite was apparent. PMID:22556074

Bin Dajem, Saad M.; Al-Farsi, Hissa M.; Al-Hashami, Zainab S.; Al-Sheikh, Adel Ali H.; Al-Qahtani, Ahmed; Babiker, Hamza A.

2012-01-01

320

A critical assessment of in vitro tissue models for ADME and drug delivery.  

PubMed

Cultured cells are widely used in the evaluation of new drugs and drug delivery systems. Cells can be grown at different levels of complexity ranging from simple reductionist models to complex organotypic models. The models are based on primary, secondary or stem cell derived cell cultures. Generation of tissue mimics with cultured cells is a difficult task, because the tissues have well-defined morphology, complex protein expression patterns and multiple inter-linked functions. Development of organotypic cell culture models requires proper biomaterial matrix and cell culture protocols that are able to guide the cells to the correct phenotype. This review illustrates the critical features of the cell culture models and, then, selected models are discussed in more detail (epidermal, corneal epithelial, retinal pigment epithelium, and hepatocyte models). The cell models are critically evaluated paying attention to the level of characterization and reliability of in vivo translation. Properties of the cell models must be characterized in detail using multiple biological assays and broad sets of model drugs. Robust in vivo predictions can be achieved with well-characterized cell models that are used in combination with computational methods that will bridge the gap between in vitro cell experiments and physiological situation in vivo in the body. PMID:24993429

Vellonen, Kati-Sisko; Malinen, Melina; Mannermaa, Eliisa; Subrizi, Astrid; Toropainen, Elisa; Lou, Yan-Ru; Kidron, Heidi; Yliperttula, Marjo; Urtti, Arto

2014-09-28

321

X-ray crystallography: Assessment and validation of protein-small molecule complexes for drug discovery  

PubMed Central

Introduction Crystallography is the key initial component for structure-based and fragment-based drug design and can often generate leads that can be developed into high potency drugs. Therefore, huge sums of money are committed based on the outcome of crystallography experiments and their interpretation. Areas covered This review discusses how to evaluate the correctness of an X-ray structure, focusing on the validation of small molecule-protein complexes. Various types of inaccuracies found within the PDB are identified and the ramifications of these errors are discussed. The reader will gain an understanding of the key parameters that need to be inspected before a structure can be used in drug discovery efforts, as well as an appreciation of the difficulties of correctly interpreting electron density for small molecules. The reader will also be introduced to methods for validating small molecules within the context of a macromolecular structure. Expert opinion One of the reasons that ligand identification and positioning, within a macromolecular crystal structure, is so difficult is that the quality of small molecules widely varies in the PDB. For this reason, the PDB can not always be considered a reliable repository of structural information pertaining to small molecules, and this makes the derivation of general principles that govern small molecule-protein interactions more difficult. PMID:21779303

Cooper, David R.; Porebski, Przemyslaw J.; Chruszcz, Maksymilian; Minor, Wladek

2011-01-01

322

A unique drug distribution process for radium ra 223 dichloride injection and its implication for product quality, patient privacy, and delineation of professional responsibilities.  

PubMed

On May 15, 2013, Bayer Healthcare Pharmaceuticals announced that it had received marketing approval for the therapeutic radioactive medication radium Ra 223 dichloride injection (Xofigo; Ra 223). The product acquisition and distribution process for hospital-based nuclear pharmacies and nuclear medicine services is unlike any other. The product is distributed as a low-risk compounded sterile preparation through a single compounding nuclear pharmacy located in Denver, Colorado, pursuant to a prescription. This model for drug distribution and delivery to the user institution has implications for product quality, patient privacy, and delineation of professional responsibilities. PMID:25301826

Dansereau, Raymond N

2014-11-01

323

drug discovery drug discovery  

E-print Network

drug discovery at Purdue #12;drug discovery 2 #12;drug discovery 3 Introduction The drug discovery and innovative drug candidates to treat chronic and acute illnesses. Our researchers also continue to be invested in various approaches to drug discovery, which include understanding of drug targets for future drug

324

Trafficking of drug candidates relevant for sports drug testing: detection of non-approved therapeutics categorized as anabolic and gene doping agents in products distributed via the Internet.  

PubMed

Identifying the use of non-approved drugs by cheating athletes has been a great challenge for doping control laboratories. This is due to the additional complexities associated with identifying relatively unknown and uncharacterized compounds and their metabolites as opposed to known and well-studied therapeutics. In 2010, the prohibited drug candidates and gene doping substances AICAR and GW1516, together with the selective androgen receptor modulator (SARM) MK-2866 were obtained by the Cologne Doping Control Laboratory from Internet suppliers and their structure, quantity, and formulation elucidated. All three compounds proved authentic as determined by liquid chromatography-high resolution/high accuracy (tandem) mass spectrometry and comparison to reference material. While AICAR was provided as a colourless powder in 100 mg aliquots, GW1516 was obtained as an orange/yellow suspension in water/glycerol (150 mg/ml), and MK-2866 (25 mg/ml) was shipped dissolved in polyethylene glycol (PEG) 300. In all cases, the quantified amounts were considerably lower than indicated on the label. The substances were delivered via courier, with packaging identifying them as containing 'amino acids' and 'green tea extract', arguably to circumvent customs control. Although all of the substances were declared 'for research only', their potential misuse in illicit performance-enhancement cannot be excluded; moreover sports drug testing authorities should be aware of the facile availability of black market copies of these drug candidates. PMID:21538997

Thevis, Mario; Geyer, Hans; Thomas, Andreas; Schänzer, Wilhelm

2011-05-01

325

Multi-risk assessment of L'Aquila gas distribution network  

NASA Astrophysics Data System (ADS)

This study focuses on the assessment of seismic risk for gas distribution networks. The basic function of a gas system is to deliver gas from sources to costumers and it is essentially composed of pipelines, reduction stations, and demand nodes, which are connected to end users to which the lifeline delivers gas. Because most of the components are spatially distributed and buried, seismic hazard has to account for both spatial correlation of ground motion intensity measures and effects induced by permanent ground deformation such as liquefaction and landslide, which determine localized ground failure. Different performance measures are considered in the study for the network, in terms of connectivity and flow reduction. Part of the gas distribution network operating in L'Aquila (central Italy), operated by ENEL Rete Gas spa has been chosen as case study. The whole network is distributed via a 621 km pipeline network: 234 km of pipes operating at medium pressure and the remaining 387 km with gas flowing at low pressure; it also consists of Metering/Pressure reduction stations, Reduction Groups and demand nodes. The framework presented makes use of probabilistic seismic hazard analysis, both in terms of ground motion and permanent ground deformation, empirical relations to estimate pipeline response, fragility curves for the evaluation of reduction cabins vulnerability, performance indicators to characterize the functionality of the gas network. The analysis were performed through a computer code specific for risk assessment of distributed systems developed by the authors. Probabilistic hazard scenarios have been simulated for the region covering the case study considering the Paganica fault on which L'Aquila 2009 earthquake was originated as source. The strong motion has been evaluated using an European ground motion prediction equation and an associated spatial correlation model. Regarding geotechnical hazards the landslide potential of L'Aquila region, according to HAZUS procedure has been performed. System's vulnerability has been performed through fragility curves available in literature, the use of which was validated via the analysis of damages following the 2009 L'Aquila earthquake. In order to study the effects of different components on risk assessment, different combinations have been identified. In particular the importance of modelling spatial correlations of ground motion and geotechnical hazard on risk assessment evaluation has been investigated. Results indicate that the system loss may be underestimated when spatial correlation and ground failure effects are ignored.

Esposito, S.; Iervolino, I.; Silvestri, F.; d'Onofrio, A.; Santo, A.; Franchin, P.; Cavalieri, F.

2012-04-01

326

Study of interaction energies between the PAMAM dendrimer and nonsteroidal anti-inflammatory drug using a distributed computational strategy and experimental analysis by ESI-MS/MS.  

PubMed

The structure of a dendrimer exhibits a large number of internal and superficial cavities, which can be exploited, to capture and deliver small organic molecules, enabling their use in drug delivery. Structure-based modeling and quantum mechanical studies can be used to accurately understand the interactions between functionalized dendrimers and molecules of pharmaceutical and industrial interest. In this study, we implemented a Metropolis Monte Carlo algorithm to calculate the interaction energy of dendrimer-drug complexes, which can be used for in silico prediction of dendrimer-drug affinity. Initially, a large-scale sampling of different dendrimer-drug conformations was generated using Euler angles. Then, each conformation was distributed on different nodes of a GRID computational system, where its interaction energy was calculated by semiempirical quantum mechanical methods. These energy calculations were performed for four different nonsteroidal anti-inflammatory drugs, each showing different affinities for the PAMAM-G4 dendrimer. The affinities were also characterized experimentally by using Cooks' kinetic method to calculate PAMAM-drug dissociation constants. The quantitative structure-activity relationship between the interaction energies and dissociation constants showed statistical correlations with r(2) > 0.9. PMID:22324459

Avila-Salas, Fabián; Sandoval, Claudia; Caballero, Julio; Guiñez-Molinos, Sergio; Santos, Leonardo S; Cachau, Raúl E; González-Nilo, Fernando D

2012-02-23

327

Study of Interaction Energies between PAMAM Dendrimer and non-Steroidal Anti-Inflammatory Drug Using a Distributed Computational Strategy and Experimental Analysis by ESI-MS/MS  

PubMed Central

The structure of a dendrimer exhibits a large number of internal and superficial cavities, which can be exploited, to capture and deliver small organic molecules, enabling their use in drug delivery. Structure-based modeling and quantum mechanical studies can be used to accurately understand the interactions between functionalized dendrimers and molecules of pharmaceutical and industrial interest. In this study, we implemented a Metropolis Monte Carlo algorithm to calculate the interaction energy of dendrimer–drug complexes, which can be used for in silico prediction of dendrimer–drug affinity. Initially, a large-scale sampling of different dendrimer–drug conformations were generated using Euler angles. Then, each conformation was distributed on different nodes of a GRID computational system; where its interaction energy was calculate by semi-empirical quantum mechanical methods. These energy calculations were performed for four different non-steroidal anti-inflammatory drugs, each showing different affinities for PAMAM–G4 dendrimer. The affinities were also characterized experimentally by using Cooks’ kinetic method to calculate PAMAM–drug dissociation constants. The quantitative structure–activity relationship between the interaction energies and dissociation constants showed statistical correlations with r2 > 0.9. PMID:22324459

Avila-Salas, Fabián; Sandoval, Claudia; Caballero, Julio; Guiñez-Molinos, Sergio; Santos, Leonardo S.; Cachau, Raúl E.; González-Nilo, Fernando D.

2012-01-01

328

Distribution of blood derivatives by registered blood establishments that qualify as health care entities; Prescription Drug Marketing Act of 1987; Prescription Drug Amendments of 1992; delay of applicability date. Final rule; delay of applicability date.  

PubMed

The Food and Drug Administration (FDA) is further delaying, until December 1, 2008, the applicability date of a certain requirement of a final rule published in the Federal Register of December 3, 1999 (64 FR 67720) (the final rule). The final rule implements the Prescription Drug Marketing Act of 1987 (PDMA), as modified by the Prescription Drug Amendments of 1992 (PDA), and the Food and Drug Administration Modernization Act of 1997 (the Modernization Act). The provisions of the final rule became effective on December 4, 2000, except for certain provisions whose effective or applicability dates were delayed in five subsequent Federal Register notices, until December 1, 2006. The provision with the delayed applicability date would prohibit wholesale distribution of blood derivatives by registered blood establishments that meet the definition of a "health care entity." In the Federal Register of February 1, 2006 (71 FR 5200), FDA published a proposed rule specific to the distribution of blood derivatives by registered blood establishments that qualify as health care entities (the proposed rule). The proposed rule would amend certain limited provisions of the final rule to allow certain registered blood establishments that qualify as health care entities to distribute blood derivatives. In response to the proposed rule, FDA received substantive comments. As explained in the SUPPLEMENTARY INFORMATION section of this document, further delaying the applicability of Sec. 203.3(q) (21 CFR 203.3(q)) to the wholesale distribution of blood derivatives by health care entities is necessary to give the agency additional time to address comments on the proposed rule, consider whether regulatory changes are appropriate, and, if so, to initiate such changes. PMID:17099971

2006-11-13

329

Distribution and quantitative assessment of world crude oil reserves and resources  

USGS Publications Warehouse

World Demonstrated Reserves of crude oil are approximately 723 billion barrels of oil (BBO). Cumulative production is 445 BBO and annual production is 20 BBO. Demonstrated Reserves of crude-oil have declined over the past 10 years consistent with discoveries lagging production over the same period. The assessment of Undiscovered Resources shows a 90 percent probability that the amount discoverable lies between 321 and 1,417 BBO, 550 BBO being the most likely value. The most likely value for Ultimate recoverable resources is 1,718 BBO. The distribution of Ultimate Resources of crude oil will remain highly skewed toward the Middle East; no frontier areas that have potentials large enough to significantly affect present distribution are recognized. Rates of discovery have continued to decline over the past 20 years even though exploration activity has increased in recent years. Prudence dictates, therefore, that the low side of the assessment of Undiscovered Resources be responsibly considered and that alternate energy sources be a part of future planning. Extra-heavy oil and bitumen are assessed separately, with Reserves being figured as the annual productive capacity of installed facilities times 25 years. The annual production of extra-heavy oil is about 8 million barrels and of bitumen about 60 million barrels.

Masters, Charles D.; Root, David H.; Dietzman, William D.

1983-01-01

330

Distribution and quantitative assessment of world crude-oil reserves and resources  

SciTech Connect

World Demonstrated Reserves of crude oil are approximately 723 billion barrels of oil (BBO). Cumulative production is 445 BBO and annual production is 20 BBO. Demonstrated Reserves of crude oil have declined over the past 10 years consistent with discoveries lagging production over the same period. The assessment of Undiscovered Resources shows a 90% probability that the amount discoverable lies between 321 and 1417 BBO, 550 BBO being the most likely value. The most likely value for Ultimate recoverable resources is 1718 BBO. The distribution of Ultimate Resources of crude oil will remain highly skewed toward the Middle East; no frontier areas that have potentials large enough to significantly affect present distribution are recognized. Rates of discovery have continued to decline over the past 20 years even though exploration activity has increased in recent years. Prudence dictates, therefore, that the low side of the assessment of Undiscovered Resources be responsibly considered and that alternate energy sources be a part of future planning. Extra-heavy oil and bitumen are assessed separately, with Reserves being figured as the annual productive capacity of installed facilities times 25 years. The annual production of extra-heavy oil is about 8 million barrels and of bitumen about 60 million barrels.

Masters, C.D.; Root, D.H.; Dietzman, W.D.

1984-01-01

331

Raman and infrared techniques for fighting drug-related crime: a preliminary assessment  

Microsoft Academic Search

A proof-of-concept hand-held Raman spectrometer and a commercial portable system based on Attenuated Total Reflectance Fourier Transform Infrared spectroscopy (ATR-FTIR) were assessed for the rapid, \\

Silvia Valussi; Mark Underhill

2006-01-01

332

The NIfETy Method for Environmental Assessment of Neighborhood-level Indicators of Violence, Alcohol, and Other Drug Exposure  

PubMed Central

There are limited validated quantitative assessment methods to measure features of the built and social environment that might form the basis for environmental preventive interventions. This study describes a model approach for epidemiologic assessment of suspected environmental determinants of violence, alcohol and other drug (VAOD) exposure and fills this gap in current research. The investigation sought to test the feasibility of a systematic and longitudinal assessment of residential block characteristics related to physical and social disorder and indicators of VAOD exposure. Planometric data were used to establish a stratified random sample of street segments within defined neighborhoods of an urban metropolitan area. Field rater assessments of these neighborhood street segments were conducted using the Neighborhood Inventory for Environmental Typology (NIfETy). This report provides a detailed description of the NIfETy Method, including metric properties of the NIfETy Instrument and outcomes of training procedures and quality control measures. Also presented are block-level characteristics and estimates of observable signs of VAOD activity. This work is a first step toward developing future community-level environmental preventive interventions geared to reduce community VAOD exposure among youthful urban populations and may prove to be useful to other public health research groups as well. PMID:18931911

Furr-Holden, C. D. M.; Smart, M. J.; Pokorni, J. L.; Ialongo, N. S.; Leaf, P. J.; Holder, H. D.; Anthony, J. C.

2010-01-01

333

Investigation of uniform biomaterial-based microspheres with precisely controlled size and size distribution for development of advanced drug delivery systems  

NASA Astrophysics Data System (ADS)

Uniform microspheres (MS) of biocompatible polymers were investigated for use as advanced drug delivery vehicles. Novel methods of fabricating the precision particles (i.e., precision particle fabrication (PPF) techniques) of biomaterials were developed utilizing mechanical, hydrodynamic, and electric forces, where the drug release kinetics could be accurately controlled without uncertainties resulting from uncontrolled size distribution of the MS. Monodisperse MS of EC with two different polymer viscosities (4- and 45-cp) were fabricated by the PPF method. The drugs encapsulated in the EC MS tended to concentrate near the surface depending on their hydrophilicity. The 30- and 35-mum MS exhibited more even distribution of the drug than the larger ones and showed almost linear release during the first 24 h. To fabricate uniform MS of a hydrophilic polymer, an electric force was utilized to separate the uniformly generated drops. Both direct and indirect drop charging were incorporated, resulting in coulombic repulsion among the drops. Because no surfactant was involved, the method became nontoxic. For chitosan and starch, the dry MS were obtained by solvent evaporation at a high temperature (140 ˜ 160°C). However, due to their degradation at such high temperature, the gelatin solution drops were gelled at a low temperature (0 ˜ 4°C). Uniform gelatin MS (GMS) were crosslinked using glutaraldehyde solutions with different concentrations. An acidic drug was introduced to form polyion complex with GMS. As a result of glutaraldehyde concentration gradient in the MS, heterogeneous crosslinking seemed to exist. The amount of complexed drug near the surface decreased as the glutaraldehyde concentration increased. In situ study of the degradation profiles of the GMS with higher glutaraldehyde concentrations revealed faster erosion at the center than near the surface. Uniform chitosan MS (CMS) were employed for precisely controlled delivery of acidic drug, where colon-specific delivery could be realized without any additive polymers or toxic process. For strong acidic drug, the smaller the CMS, the more drugs could be contained until the colonic site hence the better candidate for colon-specific delivery. Weak acidic drug preferred the larger CMS due to the smaller amount of release at the gastric fluid.

Choy, Young Bin

334

The features of the landslide distribution and assessment of landslide susceptibility in Japan  

NASA Astrophysics Data System (ADS)

Many landslides occur in the place which the landslide generated in the past, or its surrounding area. The causes are considered to be formation of slipping surface, the moving mass which becomes vulnerable by deformation or destruction and geological structures in which a slipping surface is easily formed. Therefore, it is very important for prevention and mitigation of the landslide damages to create the landslide inventory map which is shown the place which the landslide generated in the past. National Research Institute for Earth Science and Disaster Prevention (NIED), Japan, have published the landslide inventory map "landslide distribution maps" for preventing and mitigating landslide disasters. The landslide distribution map have mapped the 380,000 or more landslide topographies in whole Japan by interpretation of aerial photographs. The individual landslide not less than 150 m wide is drawn in the landslide distribution map. The objects of this research are to clarify geological and geomorphological features of landslide distributions by analyzing the landslide distribution map and to make the landslide susceptibility map for the assessment of landslide in whole Japan. The landside distribution in whole Japan is not equal and there is a difference in the density. I propose the method of the wide area landslide assessment used by the features and distributions according to of geological setting. I calculate the landslide body ratio in each geological unit. The landslide body ratio is that the rate of the landslide body area in each geological unit and the whole area in each geological unit. The landslide body ratio can be considered that landslide susceptibility (occurrence probability of landslides) in each geological unit. As a result, an average of the landslide body ratio is about 5.2 % in whole Japan. The area consist of the accretionary complex based on volcanic rocks and plutonic rocks have comparatively high-risk landslide susceptibility, and the area of Neogene rocks and Paleogene rocks have the high-risk too. On the other hand, the area of plutonic rocks and Quaternary rocks have low-risk landslide susceptibility. The results show that the landslide susceptibility is greatly different according to geological unit. Landslide body ratio map

Doshida, S.

2013-12-01

335

Controversies in ASSAY and Drug Development Technologies: A Focus on Assessing Irreproducibility.  

PubMed

Has the impact of irreproducibility on the discovery and development of drugs, as with global warming, metaphorically speaking, crept up on us as we slept? Or is the problem more an issue of heightened awareness? We currently find ourselves in a time when the impact of irreproducibility can easily be amplified by the combinatorial effect of our increasing reliance on advanced technologies and unrealistic expectations of how scientific truths unfold. How and why we got here is a topic that has been written on extensively (1-3) and is probably as complex as any other problem, given the dependence of science today on so many external forces. Through a series of questions, we asked members of our editorial board their opinions on scientific irreproducibility. They chose to answer the same questions from different levels, indicating the depth of the problem and perhaps where they each believe change for the better needs to begin. My thanks to the participants. -Jim Inglese, PhD Editor-in-Chief Assay and Drug Development Technologies. PMID:25383720

Glickman, J Fraser; Lundbäck, Thomas; Napper, Andrew D; Niles, Walter D; Simeonov, Anton; Weaver, C David; Yin, Hongwei Holly; Zaman, Guido J R; Osada, Hiroyuki

2014-10-01

336

Metrological assessment of a portable analyzer for monitoring the particle size distribution of ultrafine particles.  

PubMed

Adverse health effects caused by worker exposure to ultrafine particles have been detected in recent years. The scientific community focuses on the assessment of ultrafine aerosols in different microenvironments in order to determine the related worker exposure/dose levels. To this end, particle size distribution measurements have to be taken along with total particle number concentrations. The latter are obtainable through hand-held monitors. A portable particle size distribution analyzer (Nanoscan SMPS 3910, TSI Inc.) was recently commercialized, but so far no metrological assessment has been performed to characterize its performance with respect to well-established laboratory-based instruments such as the scanning mobility particle sizer (SMPS) spectrometer. The present paper compares the aerosol monitoring capability of the Nanoscan SMPS to the laboratory SMPS in order to evaluate whether the Nanoscan SMPS is suitable for field experiments designed to characterize particle exposure in different microenvironments. Tests were performed both in a Marple calm air chamber, where fresh diesel particulate matter and atomized dioctyl phthalate particles were monitored, and in microenvironments, where outdoor, urban, indoor aged, and indoor fresh aerosols were measured. Results show that the Nanoscan SMPS is able to properly measure the particle size distribution for each type of aerosol investigated, but it overestimates the total particle number concentration in the case of fresh aerosols. In particular, the test performed in the Marple chamber showed total concentrations up to twice those measured by the laboratory SMPS-likely because of the inability of the Nanoscan SMPS unipolar charger to properly charge aerosols made up of aggregated particles. Based on these findings, when field test exposure studies are conducted, the Nanoscan SMPS should be used in tandem with a condensation particle counter in order to verify and correct the particle size distribution data. PMID:24817159

Stabile, Luca; Cauda, Emanuele; Marini, Sara; Buonanno, Giorgio

2014-08-01

337

Ecosystem classification for EU habitat distribution assessment in sandy coastal environments: an application in central Italy.  

PubMed

Many recent developments in coastal science have gone against the demands of European Union legislation. Coastal dune systems which cover small areas of the earth can host a high level of biodiversity. However, human pressure on coastal zones around the world has increased dramatically in the last 50 years. In addition to direct habitat loss, the rapid extinction of many species that are unique to these systems can be attributed to landscape deterioration through the lack of appropriate management. In this paper, we propose to use of an ecosystem classification technique that integrates potential natural vegetation distribution as a reference framework for coastal dune EU Habitats (92/43) distribution analysis and assessment. As an example, the present study analyses the EU Habitats distribution within a hierarchical ecosystem classification of the coastal dune systems of central Italy. In total, 24 land elements belonging to 8 land units, 5 land facets, 2 land systems and 2 land regions were identified for the coastal dunes of central Italy, based on diagnostic land attributes. In central Italy, coastal dune environments including all the beach area, mobile dunes and all the fixed-dune land elements contain or could potentially hold at least one EU habitat of interest. Almost all dune slack transitions present the potentiality for the spontaneous development of EU woodlands of interest. The precise information concerning these ecosystems distribution and ecological relationships that this method produces, makes it very effective in Natura 2000 European network assessment. This hierarchical ecosystem classification method facilitates the identification of areas to be surveyed and eventually bound, under the implementation of EU Habitat directive (92/43) including areas with highly disturbed coastal dune ecosystems. PMID:17624597

Carranza, Maria Laura; Acosta, Alicia T R; Stanisci, Angela; Pirone, Gianfranco; Ciaschetti, Giampiero

2008-05-01

338

Overdoses among friends: Drug users are willing to administer naloxone to others  

Microsoft Academic Search

The distribution of naloxone to heroin users is a suggested intervention to reduce overdose and death rates. However, the level of willingness of drug users to administer this medication to others is unclear. Drug users recruited from the community between January 2002 and January 2004 completed a structured interview that assessed topics including drug use, overdose history, and attitudes toward

Tara Lagu; Bradley J. Anderson; Michael Stein

2006-01-01

339

Development and evaluation of an ITS1 "Touchdown" PCR for assessment of drug efficacy against animal African trypanosomosis.  

PubMed

Animal African trypanosomoses (AAT) are caused by flagellated protozoa of the Trypanosoma genus and contribute to considerable losses in animal production in Africa, Latin America and South East Asia. Trypanosoma congolense is considered the economically most important species. Drug resistant T. congolense strains present a threat to the control of AAT and have triggered research into discovery of novel trypanocides. In vivo assessment of trypanocidal efficacy relies on monitoring of treated animals with microscopic parasite detection methods. Since these methods have poor sensitivity, follow-up for up to 100 days after treatment is recommended to increase the chance of detecting recurrent parasitaemia waves. Molecular techniques are more amendable to high throughput processing and are generally more sensitive than microscopic detection, thus bearing the potential of shortening the 100-day follow up period. The study presents a "Touchdown" PCR targeting the internal transcribed spacer 1 of the ribosomal DNA (ITS1 TD PCR) that enables detection and discrimination of different Trypanosoma taxa in a single run due to variations in PCR product sizes. The assay achieves analytical sensitivity of 10 parasites per ml of blood for detection of T. congolense savannah type and T. brucei, and 100 parasites per ml of blood for detection of T. vivax in infected mouse blood. The ITS1 TD PCR was evaluated on cattle experimentally infected with T. congolense during an investigational new veterinary trypanocide drug efficacy study. ITS1 TD PCR demonstrated comparable performance to microscopy in verifying trypanocide treatment success, in which parasite DNA became undetectable in cured animals within two days post-treatment. ITS1 TD PCR detected parasite recrudescence three days earlier than microscopy and had a higher positivity rate than microscopy (84.85% versus 57.58%) in 66 specimens of relapsing animals collected after treatments. Therefore, ITS1 TD PCR provides a useful tool in assessment of drug efficacy against T. congolense infection in cattle. As the assay bears the potential for detection of mixed infections, it may be applicable for drug efficacy studies and diagnostic discrimination of T. vivax and T. congolense against other pathogenic trypanosomes, including T. brucei, T. evansi and T. equiperdum. PMID:24685024

Tran, Thao; Napier, Grant; Rowan, Tim; Cordel, Claudia; Labuschagne, Michel; Delespaux, Vincent; Van Reet, Nick; Erasmus, Heidi; Joubert, Annesca; Büscher, Philippe

2014-05-28

340

Overdose prevention for injection drug users: Lessons learned from naloxone training and distribution programs in New York City  

Microsoft Academic Search

BACKGROUND: Fatal heroin overdose is a significant cause of mortality for injection drug users (IDUs). Many of these deaths are preventable because opiate overdoses can be quickly and safely reversed through the injection of Naloxone [brand name Narcan], a prescription drug used to revive persons who have overdosed on heroin or other opioids. Currently, in several cities in the United

Tinka Markham Piper; Sasha Rudenstine; Sharon Stancliff; Susan Sherman; Vijay Nandi; Allan Clear; Sandro Galea

2007-01-01

341

Assessment of the integration capability of system architectures from a complex and distributed software systems perspective  

NASA Astrophysics Data System (ADS)

Procurement and design of system architectures capable of network centric operations demand for an assessment scheme in order to compare different alternative realizations. In this contribution an assessment method for system architectures targeted at the C4ISR domain is presented. The method addresses the integration capability of software systems from a complex and distributed software system perspective focusing communication, interfaces and software. The aim is to evaluate the capability to integrate a system or its functions within a system-of-systems network. This method uses approaches from software architecture quality assessment and applies them on the system architecture level. It features a specific goal tree of several dimensions that are relevant for enterprise integration. These dimensions have to be weighed against each other and totalized using methods from the normative decision theory in order to reflect the intention of the particular enterprise integration effort. The indicators and measurements for many of the considered quality features rely on a model based view on systems, networks, and the enterprise. That means it is applicable to System-of-System specifications based on enterprise architectural frameworks relying on defined meta-models or domain ontologies for defining views and viewpoints. In the defense context we use the NATO Architecture Framework (NAF) to ground respective system models. The proposed assessment method allows evaluating and comparing competing system designs regarding their future integration potential. It is a contribution to the system-of-systems engineering methodology.

Leuchter, S.; Reinert, F.; Müller, W.

2014-06-01

342

Animal models of depression and neuroplasticity: assessing drug action in relation to behavior and neurogenesis.  

PubMed

Depression is among the most prevalent forms of mental illness and a major cause of morbidity worldwide. Diagnosis of depression is mainly based on symptomatic criteria, and the heterogeneity of the disease suggests that multiple different biological mechanisms may underlie its etiology. Animal models have been important for recent advances in experimental neuroscience, including modeling of human mood disorders, such as depression and anxiety. Over the past few decades, a number of stress and neurobiochemical models have been developed as primary efficacy measures in depression trials, which are paving the way for the discovery of novel therapeutic targets. Recent data indicates that stress-related mood disorders have influence on neuroplasticity and adult neurogenesis. In this chapter, several currently available animal models are presented as powerful tools for both mechanistic studies into the neurobiology of the antidepressant response and for drug discovery. PMID:22231809

Xu, Ying; Barish, Philip A; Pan, Jianchun; Ogle, William O; O'Donnell, James M

2012-01-01

343

Swelling kinetics of spray-dried chitosan acetate assessed by magnetic resonance imaging and their relation to drug release kinetics of chitosan matrix tablets  

Microsoft Academic Search

Magnetic resonance imaging (MRI) was used to assess in situ swelling behaviors of spray-dried chitosan acetate (CSA) in 0.1N HCl, pH 6.8 and pH 5.0 Tris–HCl buffers. The in vitro drug releases from CSA matrix tablets containing the model drugs, diclofenac sodium and theophylline were investigated in all media using USP-4 apparatus. The effect of chitosan molecular weight, especially in

Kampanart Huanbutta; Pornsak Sriamornsak; Sontaya Limmatvapirat; Manee Luangtana-anan; Yasuo Yoshihashi; Etsuo Yonemochi; Katsuhide Terada; Jurairat Nunthanid

2011-01-01

344

In vitro assessment of N -[2-(dimethylamino)ethyl]acridine-4-carboxamide, a DNA-intercalating antitumour drug with reduced sensitivity to multidrug resistance  

Microsoft Academic Search

The successful treatment of cancer requires the identification of new drugs with novel actions.N-[2-(Dimethylamino)ethyl]acridine-4-carboxamide dihydrochloride (DACA) is a topoisomerase II-targeted antitumour drug with curative activity against murine Lewis lung carcinoma. DACA was assessed for novel patterns of growth inhibition using normal and multidrug-resistant human cell lines. Cells were cultured in 96-well microtitre trays and tested against DACA and related topoisomerase-directed

Graeme J. Finlayl; Elaine Marshall; John H. L. Matthews; Kenneth D. Paull; Bruce C. Baguleyl

1993-01-01

345

Religiosity and HIV-related drug risk behavior: a multidimensional assessment of individuals from communities with high rates of drug use  

PubMed Central

We examined the relationship between religiosity and HIV-related drug risk behavior among individuals from communities with high rates of drug use who participated in the SHIELD (Self-Help in Eliminating Life Threatening Disease) study. This analysis examined the dimensions of religious ideation, religious participation and religious support separately to further understand the relationship with risk taking. Results indicate that greater religious participation appeared to be the dimension most closely associated with drug behaviors. Specifically, we found that those with greater religious participation are significantly less likely to report recent opiates or cocaine use; injection drug use; crack use; needle, cotton or cooker sharing. Future work to understand the nature of these associations will assist in the development of interventions in communities with high rates of drug use. PMID:22399161

Billioux, Veena G.; Sherman, Susan G.; Latkin, Carl A.

2012-01-01

346

Development of an in vitro cytochrome P450 cocktail inhibition assay for assessing the inhibition risk of drugs of abuse.  

PubMed

Drugs of abuse are not tested for cytochrome P450 (CYP) inhibition potential before distribution. Therefore, a cocktail assay should be developed for testing the inhibition potential for all relevant CYPs. The following CYP test substrates and selective inhibitors were incubated in pooled human liver microsomes: phenacetin (alpha-naphthoflavone for CYP1A2), coumarin (tranylcypromine, CYP2A6), bupropion (sertraline, CYP2B6), amodiaquine (trimethoprim, CYP2C8), diclofenac (sulfaphenazole, CYP2C9), omeprazole (fluconazole, CYP2C19), dextromethorphan (quinidine, CYP2D6), chlorzoxazone (clomethiazole, CYP2E1), testosterone (verapamil, CYP3A). Samples were analyzed after protein precipitation using a Thermo Fisher Q-Exactive LC-high-resolution-MS/MS. The IC50 values were calculated by plotting the concentration of the formed metabolite, relative to the control sample, over the logarithm of the inhibitor concentration. They were determined either for single substrate or the cocktail incubation. Unfortunately, the cocktail assay had to be split because of interferences during incubation caused by substrates or metabolites, but the mixture of both incubates could be analyzed in one analytical run. The IC50 values determined in the single substrate or both cocktail incubations were comparable among themselves and with published data. In conclusion, the new inhibition cocktail assay was reproducible and applicable for testing the inhibition potential of drugs of abuse as exemplified for 2,5-dimethoxy-4-iodo-amfetamine (DOI). PMID:25111188

Dinger, Julia; Meyer, Markus R; Maurer, Hans H

2014-10-01

347

Drug assessment based on detection of L-glutamate released from C6 glioma cells using an enzyme-luminescence method.  

PubMed

Monitoring of excitation activity of nerve cells is very useful for not only brain research but also assessment of the effects of various chemicals, including drugs and toxins. We previously reported a novel enzyme-luminescence method for real-time monitoring of l-glutamate release from C6 glioma cells with high levels of sensitivity ( approximately 10 nM) and temporal resolution (<1 s) using a luminescence plate reader. In the present study, we tested the applicability of this novel system for assessment of effects of drugs in vitro. Several drugs (e.g., veratridine and 4-aminopyridine) were administered to C6 glioma cells for inducing glutamate release. Moreover, antagonists of voltage-dependent Ca (2+) channels (e.g., nifedipine, flunarizine, and NiCl 2) and Na (+) channels (e.g., carbamazepine and lidocaine) were applied separately for evaluating the effects of these chemicals on glutamate release from the cells. The combined effect of carbamazepine and lidocaine was also investigated by using our method, and the combined effect was found to be more potent than that of single drug administration. These results indicated that the glutamate release from C6 cells was modulated by these drugs in a way similar to that found by using several conventional analytical techniques. We therefore conclude that the developed monitoring system for real-time detection of dynamic l-glutamate release from cells could be very useful for application to assessment of drugs acting on the nervous system. PMID:18399661

Zakir Hossain, S M; Shinohara, Hiroaki; Kitano, Hiromi

2008-05-15

348

Development of a high drug load tablet formulation based on assessment of powder manufacturability: moving towards quality by design.  

PubMed

The development of a robust tablet formulation for a high dose active pharmaceutical ingredient (API) by the trial-and-error approach is challenging. To meet the growing needs of bringing drugs to market faster and with reduced costs, more targeted and efficient development practices are in demand. Here we show detailed understanding of mechanical properties of API and excipients are essential in achieving efficient development of a high API loading formulation. The loading of the experimental drug, AMG458, was 50 wt% plus accompanying 1:1 molar ratio organic acid of approximately 19%. We assessed manufacturability of powders based on their flow and compaction properties using a shear cell and a compaction simulator, respectively. We selected granulation process on the basis of poor flow properties of API and its blends with common direct compaction excipients. During the course of formulation development, we could quickly identify manufacturability deficiencies in the lead formulation. With detailed knowledge of the mechanical properties of excipients and formulated powders, we improved the lead formulation by overcoming manufacturability deficiencies using predictive and material sparing (<10 g) approaches. Larger batches were subsequently manufactured to confirm predictions. PMID:18428197

Sun, Changquan Calvin; Hou, Hao; Gao, Ping; Ma, Chandra; Medina, Cesar; Alvarez, Francisco J

2009-01-01

349

Direct Assessment of Drug Penetration into Tissue Using a Novel Application of Three-Dimensional Cell Culture  

Microsoft Academic Search

The failure of many anticancer drugs to control growth of solid cancers may stem in part from inadequate delivery to tumor regions distant from vasculature. Although the identification of new anticancer drug targets has led to the development of many new drug candidates, there is a lack of methodology for identifying drugs that adequately penetrate tumor tissue. We have developed

Alastair H. Kyle; Lynsey A. Huxham; Aaron S. J. Chiam; David H. Sim; Andrew I. Minchinton

2004-01-01

350

Risk assessment using the species sensitivity distribution method: data quality versus data quantity.  

PubMed

Species sensitivity distributions (SSDs) are cumulative distributions of measures of species sensitivity to a stressor or toxicant, and are used to estimate concentrations that will protect p% of a community (PCp ). There is conflict between the desire to use high-quality sensitivity data in SSDs, and to construct them with a large number of species forming a representative sample. Trade-offs between data quality and quantity were investigated using the effects of increasing salinity on the macroinvertebrate community from the Hunter River catchment, in eastern Australia. Five SSDs were constructed, representing five points along a continuum of data quality versus data quantity and representativeness. This continuum was achieved by the various inclusion/exclusion of censored data, nonmodeled data, and extrapolation from related species. Protective concentrations were estimated using the Burr type III distribution, Kaplan-Meier survival function, and two Bayesian statistical models. The dominant taxonomic group was the prime determinant of protective concentrations, with an increase in PC95 values resulting from a decrease in the proportion of Ephemeropteran species included in the SSD. In addition, decreases in data quantity in a SSD decreased community representativeness. The authors suggest, at least for salinity, that the inclusion of right censored data provides a more representative sample of species that reflects the natural biotic assemblage of an area to be protected, and will therefore improve risk assessment. PMID:23440771

Dowse, Renee; Tang, Doudou; Palmer, Carolyn G; Kefford, Ben J

2013-06-01

351

High frequency resonant waveguide grating imager for assessing drug-induced cardiotoxicity  

NASA Astrophysics Data System (ADS)

We report a high-frequency resonant waveguide grating imager for assessing compound-induced cardiotoxicity. The imager sweeps the wavelength range from 823 nm to 838 nm every 3 s to identify and monitor compound-induced shifts in resonance wavelength and then switch to the intensity-imaging mode to detect the beating rhythm and proarrhythmic effects of compounds on induced pluripotent stem cell-derived cardiomyocytes. This opens possibility to study cardiovascular biology and compound-induced cardiotoxicity.

Ferrie, Ann M.; Wu, Qi; Deichmann, Oberon D.; Fang, Ye

2014-05-01

352

The Use of Kinetic and Dynamic Data in Risk Assessment of Drugs  

Microsoft Academic Search

The risk assessment process for non-carcinogens must incorporate all available scientific information, including toxicokinetic and toxicodynamic data. The framework for exposure limit setting proposed by Renwick and the International Programme on Chemical Safety (IPCS) subdivides traditional 10X uncertainty factors (UFs) into separate partial-log default values based on kinetic and dynamic considerations and allows for incorporation of compound-specific data when available.

Duck H. Suh; Gloria A. Skowronski; Mohamed S. Abdel-Rahman

1999-01-01

353

Risk assessment of premature drug release during wet granulation of ordered mesoporous silica loaded with poorly soluble compounds itraconazole, fenofibrate, naproxen, and ibuprofen.  

PubMed

In this study, the potential of wet granulation of ordered mesoporous silica (OMS) material was evaluated to assess the risk of premature drug release during processing and to improve the bulk powder flow properties and compactibility for the development of an immediate release oral dosage form. The poorly water soluble model compounds, itraconazole, fenofibrate, naproxen, and ibuprofen were loaded into the model OMS, COK-12, and granulated using a polyvinylpyrrolidone (PVP) binder solution. Preliminary assessments were made with itraconazole loaded COK-12 to study the effects of the initial drug load, binder concentration, binder addition rate, and granulation temperature on premature drug release. Comparison to pure COK-12 revealed particle size enlargement and enhanced powder flow based on Carr Index and Hausner Ratio results. Following compression to 120 MPa, the compactibility of the granulated material also improved when compared to the untreated COK-12. In vitro release of itraconazole from the compressed granulated material was assessed with and without the disintegrant, croscarmellose sodium. Incorporation of 2.4 wt. croscarmellose sodium prior to compression successfully recovered the slight release loss following compression. To assess premature drug release, developments made with itraconazole loaded COK-12 were applied to loaded fenofibrate, naproxen, and ibuprofen. Results from modulated differential scanning calorimetry (MDSC) indicated that the risk of premature drug release during wet granulation was primarily compound dependent. These findings highlight challenges in preparation for a successful manufacturing process of OMS based formulations. PMID:22306694

Vialpando, Monica; Backhuijs, Floris; Martens, Johan A; Van den Mooter, Guy

2012-05-01

354

Assessment of topical non-steroidal anti-inflammatory drugs in animal models.  

PubMed

Four commercial gel preparations of topical anti-inflammatory agents have been assessed in six animal models commonly used to determine the biological activity of non-steroidal anti-inflammatory agents for systemic administration. Only UV-induced erythema of the skin, adjuvant induced arthritis and the measurement of vascular permeability proved suitable for differentiation of the potency of the four topical agents. Carrageenin-induced paw oedema, the cotton pellet test and the assessment of the pain threshold according to Randall and Selitto were of little value. The effects of the gel preparation of diclofenac (CAS 15307-86-5) diethylammonium (Voltaren Emulgel) were comparable to two preparations containing 1% and 5% active ingredient, respectively. Gel 4 showed low overall activity. The experiments demonstrated that some of the models used for the assessment of anti-inflammatory agent for systemic administration proved suitable for the testing of topical preparations and that percutaneous absorption was insufficient to elicit anti-inflammatory effect in the animals at sites remote from the site of application. PMID:2291749

Hiramatsu, Y; Akita, S; Salamin, P A; Maier, R

1990-10-01

355

21 CFR 205.4 - Wholesale drug distributor licensing requirement.  

...STATE LICENSING OF WHOLESALE PRESCRIPTION DRUG DISTRIBUTORS § 205.4 ...wholesale distributions of prescription drugs in interstate commerce must...wholesale distributions of prescription drugs in interstate...

2014-04-01

356

21 CFR 205.4 - Wholesale drug distributor licensing requirement.  

Code of Federal Regulations, 2010 CFR

...STATE LICENSING OF WHOLESALE PRESCRIPTION DRUG DISTRIBUTORS § 205.4 ...wholesale distributions of prescription drugs in interstate commerce must...wholesale distributions of prescription drugs in interstate...

2010-04-01

357

21 CFR 205.4 - Wholesale drug distributor licensing requirement.  

Code of Federal Regulations, 2011 CFR

...STATE LICENSING OF WHOLESALE PRESCRIPTION DRUG DISTRIBUTORS § 205.4 ...wholesale distributions of prescription drugs in interstate commerce must...wholesale distributions of prescription drugs in interstate...

2011-04-01

358

21 CFR 205.4 - Wholesale drug distributor licensing requirement.  

Code of Federal Regulations, 2012 CFR

...STATE LICENSING OF WHOLESALE PRESCRIPTION DRUG DISTRIBUTORS § 205.4 ...wholesale distributions of prescription drugs in interstate commerce must...wholesale distributions of prescription drugs in interstate...

2012-04-01

359

21 CFR 205.4 - Wholesale drug distributor licensing requirement.  

Code of Federal Regulations, 2013 CFR

...STATE LICENSING OF WHOLESALE PRESCRIPTION DRUG DISTRIBUTORS § 205.4 ...wholesale distributions of prescription drugs in interstate commerce must...wholesale distributions of prescription drugs in interstate...

2013-04-01

360

Drug pharmacokinetics and pharmacodynamics: Technological considerations  

SciTech Connect

Additionally, the use of PET to examine drug pharmacokinetics and pharmacadynamics and the relationship of these properties to the behavioral, therapeutic and toxic properties of drugs and substances of abuse is emerging as a powerful new scientific tool. The pharmacokinetic properties of a drug, which comprises all of the biological processes which determine the fraction of the drug available, can be measured using the labeled drug itself. For example, the labeled drug can be used to measure the absolute uptake, regional distribution and kinetics of a drug at its site of action in the body. Additionally the labeled drug and whole body its labeled metabolites and thus provide information an potential toxic effects as well as tissue half lives. On the other hand, different labeled tracers can be used to assess drug pharmacodynamics which include the biological Processes involved in the drug`s effects. For example, with appropriate radiotracers, the effects of a drug on metabolism, neurotransmitter activity, blood flew, enzyme activity or other processes can be probed.

Fowler, J.S.; Volkow, N.D.; Wolf, A.P.

1992-12-31

361

Swelling kinetics of spray-dried chitosan acetate assessed by magnetic resonance imaging and their relation to drug release kinetics of chitosan matrix tablets.  

PubMed

Magnetic resonance imaging (MRI) was used to assess in situ swelling behaviors of spray-dried chitosan acetate (CSA) in 0.1N HCl, pH 6.8 and pH 5.0 Tris-HCl buffers. The in vitro drug releases from CSA matrix tablets containing the model drugs, diclofenac sodium and theophylline were investigated in all media using USP-4 apparatus. The effect of chitosan molecular weight, especially in pH 6.8 Tris-HCl, was also studied. In 0.1N HCl, the drug release from the matrix tablets was the lowest in relation to the highest swelling of CSA. The swelling kinetics in Tris-HCl buffers are Fickian diffusion according to their best fit to Higuchi's model as well as the drug release kinetics in all the media. The high swelling rate (k(s)(')) was found to delay the drug release rate (k'). The linear relationship between the swelling and fractions of drug release in Tris-HCl buffers was observed, indicating an important role of the swelling on controlling the drug release mechanism. Additionally, CSA of 200 and 800 kDa chitosan did not swell in pH 6.8 Tris-HCl but disintegrated into fractions, and the drug release from the matrix tablets was the highest. PMID:21129484

Huanbutta, Kampanart; Sriamornsak, Pornsak; Limmatvapirat, Sontaya; Luangtana-anan, Manee; Yoshihashi, Yasuo; Yonemochi, Etsuo; Terada, Katsuhide; Nunthanid, Jurairat

2011-02-01

362

Affordable non-traditional source data mining for context assessment to improve distributed fusion system robustness  

NASA Astrophysics Data System (ADS)

This paper describes methods to affordably improve the robustness of distributed fusion systems by opportunistically leveraging non-traditional data sources. Adaptive methods help find relevant data, create models, and characterize the model quality. These methods also can measure the conformity of this non-traditional data with fusion system products including situation modeling and mission impact prediction. Non-traditional data can improve the quantity, quality, availability, timeliness, and diversity of the baseline fusion system sources and therefore can improve prediction and estimation accuracy and robustness at all levels of fusion. Techniques are described that automatically learn to characterize and search non-traditional contextual data to enable operators integrate the data with the high-level fusion systems and ontologies. These techniques apply the extension of the Data Fusion & Resource Management Dual Node Network (DNN) technical architecture at Level 4. The DNN architecture supports effectively assessment and management of the expanded portfolio of data sources, entities of interest, models, and algorithms including data pattern discovery and context conformity. Affordable model-driven and data-driven data mining methods to discover unknown models from non-traditional and `big data' sources are used to automatically learn entity behaviors and correlations with fusion products, [14 and 15]. This paper describes our context assessment software development, and the demonstration of context assessment of non-traditional data to compare to an intelligence surveillance and reconnaissance fusion product based upon an IED POIs workflow.

Bowman, Christopher; Haith, Gary; Steinberg, Alan; Morefield, Charles; Morefield, Michael

2013-05-01

363

The Geographical Information System (GIS) based water quality assessment of a drinking water distribution system in the Denizli City  

Microsoft Academic Search

Nowadays, continuous, healthy water supply and total water quality management have emerged as an important issue in engineering applications. In a wide ranging assessment, the quality of the drinking water is being monitored in the distribution system, until it is supplied to the end user. It includes regular sampling and testing performed for assessing compliance with guideline values. The major

Abdullah Cem Koc; Fehiman Ciner; Selcuk Toprak; Huseyin Selcuk; Burcu Aktan

2010-01-01

364

Pharmaceutical characterization and thermodynamic stability assessment of a colloidal iron drug product: iron sucrose.  

PubMed

The study objective was to evaluate the thermodynamic stability of iron sucrose complexes as determined by molecular weight (m.w.) changes. The first part of the study focused on the effect of thermal stress, pH, electrolyte or excipient dilution on the stability of a colloidal iron drug product. Part two focused on the physical and chemical evaluation of the colloidal nature of iron sucrose using a series of characterization experiments: ultracentrifugation, dialysis, particle size, zeta potential, and osmotic pressure analysis. A validated Taguchi-optimized high performance gel permeation chromatography method was used for m.w. determinations. Results indicate m.w. of the iron sucrose complex remained unchanged after excipient dilution, ultracentrifugation, dialysis, and electrolyte dilution. Electrolyte dilution studies indicated the lyophilic nature of the iron sucrose colloid with a particle size of 10nm and zeta potential of 0 mV. The complex deformed at low pH and reformed back at the formulation pH. The complex is stable under mild-to-moderate temperature <50°C but aggregates following prolonged exposure to high temperatures >70°C. In conclusion, the resistance of the complex to breakdown by electrolytic conditions, excipient dilution, ultracentrifugation and the reversible complexation after alteration of formulation pH suggest iron sucrose is a lyophilic colloid in nature and lyophilic colloidals are thermodynamically stable. PMID:24440404

Shah, Rakhi B; Yang, Yongsheng; Khan, Mansoor A; Raw, Andre; Yu, Lawrence X; Faustino, Patrick J

2014-04-10

365

Distribution of Spoligotyping Defined Genotypic Lineages among Drug-Resistant Mycobacterium tuberculosis Complex Clinical Isolates in Ankara, Turkey  

Microsoft Academic Search

BackgroundInvestigation of genetic heterogeneity and spoligotype-defined lineages of drug-resistant Mycobacterium tuberculosis clinical isolates collected during a three-year period in two university hospitals and National Tuberculosis Reference and Research Laboratory in Ankara, Turkey.Methods and FindingsA total of 95 drug-resistant M. tuberculosis isolates collected from three different centers were included in this study. Susceptibility testing of the isolates to four major antituberculous

Ozgul Kisa; Gulnur Tarhan; Selami Gunal; Ali Albay; Riza Durmaz; Zeynep Saribas; Thierry Zozio; Alpaslan Alp; Ismail Ceyhan; Ahmet Tombak; Nalin Rastogi

2012-01-01

366

Uncertainty assessment of spatially distributed nitrate reduction potential in groundwater using multiple geological realizations  

NASA Astrophysics Data System (ADS)

Spatially distributed nitrate reduction potential in groundwater was estimated for the clay till dominated Norsminde fjord catchment in Denmark using the distributed hydrological model MIKE SHE. The nitrate transport was simulated using particle tracking and nitrate was assumed to be instantaneously reduced at the redox interface. Spatially distributed depths of the redox interface were estimated based on the spatial patterns in groundwater recharge and sediment redox capacity. Uncertainty of the estimated nitrate reduction due to geological uncertainty was assessed using multiple geological realizations. The geological realizations were generated using the geostatistical software TProGS and either conditioned based on borehole data only or soft conditioned based on both borehole data and geophysical data. Finally an upscaling of the predicted nitrate reduction was done in order to evaluate the change in uncertainty with increasing scale. The study showed that the uncertainty (one standard deviation) of the estimated nitrate reduction potential (in percentage of nitrate input) on the original 100 m model scale was 25% if only using borehole data and 19% if combining the borehole data with geophysical data. The uncertainty on the model predictions decreased with increasing aggregation scale. The decrease in uncertainty was most apparent the first 500 m, where after the uncertainty started to level off. This scale corresponded well to the mean length of the sand units within the clay till. It is concluded that using geophysical data in combination with borehole data in generation of geological realizations can help decrease uncertainty on the estimated nitrate reduction and that the predictive capability of distributed models is constrained by the spatial resolution of key data such as geology.

Hansen, A. L.; Gunderman, D.; He, X.; Refsgaard, J. C.

2014-11-01

367

Adaptivity Assessment of Regional Semi-Parametric VTEC Modeling to Different Data Distributions  

NASA Astrophysics Data System (ADS)

Semi-parametric modelling of Vertical Total Electron Content (VTEC) combines parametric and non-parametric models into a single regression model for estimating the parameters and functions from Global Positioning System (GPS) observations. The parametric part is related to the Differential Code Biases (DCBs), which are fixed unknown parameters of the geometry-free linear combination (or the so called ionospheric observable). On the other hand, the non-parametric component is referred to the spatio-temporal distribution of VTEC which is estimated by applying the method of Multivariate Adaptive Regression B-Splines (BMARS). BMARS algorithm builds an adaptive model by using tensor product of univariate B-splines that are derived from the data. The algorithm searches for best fitting B-spline basis functions in a scale by scale strategy, where it starts adding large scale B-splines to the model and adaptively decreases the scale for including smaller scale features through a modified Gram-Schmidt ortho-normalization process. Then, the algorithm is extended to include the receiver DCBs where the estimates of the receiver DCBs and the spatio-temporal VTEC distribution can be obtained together in an adaptive semi-parametric model. In this work, the adaptivity of regional semi-parametric modelling of VTEC based on BMARS is assessed in different ground-station and data distribution scenarios. To evaluate the level of adaptivity the resulting DCBs and VTEC maps from different scenarios are compared not only with each other but also with CODE distributed GIMs and DCB estimates .

Durmaz, Murat; Onur Karsl?o?lu, Mahmut

2014-05-01

368

Kernel lot distribution assessment ( KeLDA ): a study on the distribution of GMO in large soybean shipments  

Microsoft Academic Search

The reliability of analytical testing is strongly affected by sampling uncertainty. Sampling is always a source of error and the aim of “good” sampling practice is to minimize this error. Generally the distribution of genetically modified (GM) material within lots is assumed to be random in order to use binomial distribution to make inferences. This assumption was never verified in

Claudia Paoletti; Andreas Heissenberger; Marco Mazzara; Sara Larcher; Emanuele Grazioli; Philippe Corbisier; Norbert Hess; Gilbert Berben; Peter S. Lübeck; Marc De Loose; Gillian Moran; Christine Henry; Carlo Brera; Imma Folch; Jaroslava Ovesna; Guy Van den Eede

2006-01-01

369

Lymphatic filariasis in Papua New Guinea: distribution at district level and impact of mass drug administration, 1980 to 2011  

PubMed Central

Background Lymphatic filariasis (LF) caused by Wuchereria bancrofti is present at high prevalence in some parts of Papua New Guinea. However, there has been no rigorous data-based representative assessment of nationwide prevalence of LF. The LF programme has been daunted by the scope of the problem, and progress on mass drug administration (MDA) has been slow and lacking in resources. Methods A systematic literature review identified LF surveys in Papua New Guinea between 1980 and 2011. Results were extracted by location, time period and test used (blood slide, immunochromatographic test (ICT) or Og4C3 ELISA) and combined by district. Three criteria schemes based on the Global Programme to Eliminate Lymphatic Filariasis guidelines, with modifications, were developed to classify and prioritize districts by prevalence level. Results of repeated surveys in the same sites were used to investigate the impact of MDA on LF prevalence over the time period. Results There were 312 distinct survey sites identified in 80 of the 89 districts over the 31-year period. The overall LF prevalence in the sites tested was estimated at 18.5 to 27.5% by blood slide for microfilariae (Mf), 10.1% to 12.9% by ICT and 45.4% to 48.8% by Og4C3. Biases in site selection towards areas with LF, and change in type of assay used, affected the prevalence estimates, but overall decline in prevalence over the time period was observed. Depending on the criteria used, 34 to 36 districts (population 2.7 to 2.9 million) were classed as high endemic (?5% prevalence), 15 to 25 districts (1.7 to 1.9 million) as low endemic (<5%) and 20 to 31 (1.3 to 2.2 million) as non-endemic. Nine districts (0.7 million) had no information. The strong impact of MDA, especially on microfilaria (Mf) prevalence, was noted in sites with repeat surveys. Conclusions This analytical review of past surveys of LF in Papua New Guinea enables better estimation of the national burden, identifies gaps in knowledge, quantifies and locates the population at risk, and can be used to predict the likely impact of MDA and/or vector control. Better targeting of districts by level of prevalence will strengthen the control programme, facilitate monitoring of the disease trend and increase the likelihood of reaching the target of LF elimination by 2020. PMID:23311302

2013-01-01

370

Human kidney proximal tubule-on-a-chip for drug transport and nephrotoxicity assessment.  

PubMed

Kidney toxicity is one of the most frequent adverse events reported during drug development. The lack of accurate predictive cell culture models and the unreliability of animal studies have created a need for better approaches to recapitulate kidney function in vitro. Here, we describe a microfluidic device lined by living human kidney epithelial cells exposed to fluidic flow that mimics key functions of the human kidney proximal tubule. Primary kidney epithelial cells isolated from human proximal tubule are cultured on the upper surface of an extracellular matrix-coated, porous, polyester membrane that splits the main channel of the device into two adjacent channels, thereby creating an apical 'luminal' channel and a basal 'interstitial' space. Exposure of the epithelial monolayer to an apical fluid shear stress (0.2 dyne cm(-2)) that mimics that found in living kidney tubules results in enhanced epithelial cell polarization and primary cilia formation compared to traditional Transwell culture systems. The cells also exhibited significantly greater albumin transport, glucose reabsorption, and brush border alkaline phosphatase activity. Importantly, cisplatin toxicity and Pgp efflux transporter activity measured on-chip more closely mimic the in vivo responses than results obtained with cells maintained under conventional culture conditions. While past studies have analyzed kidney tubular cells cultured under flow conditions in vitro, this is the first report of a toxicity study using primary human kidney proximal tubular epithelial cells in a microfluidic 'organ-on-a-chip' microdevice. The in vivo-like pathophysiology observed in this system suggests that it might serve as a useful tool for evaluating human-relevant renal toxicity in preclinical safety studies. PMID:23644926

Jang, Kyung-Jin; Mehr, Ali Poyan; Hamilton, Geraldine A; McPartlin, Lori A; Chung, Seyoon; Suh, Kahp-Yang; Ingber, Donald E

2013-09-01

371

Nutrients distribution and trophic status assessment in the northern Beibu Gulf, China  

NASA Astrophysics Data System (ADS)

Using historical and 2010 field data, the distribution of nutrients in the northern Beibu Gulf of China is described. There was a decreasing trend in the concentration of nutrients from the north coast to offshore waters of the northern Beibu Gulf, reflecting the influence of inputs from land-based sources. High concentrations of dissolved inorganic nitrogen (DIN) and phosphate (PO4-P) occurred mainly at Fangchenggang Bay, Qinzhou Bay, and Lianzhou Bay. Four different methods were used to assess eutrophication. The trophic status of the Beibu Gulf was characterized using the single factor, Eutrophication index (EI), Trophic index (TRIX) and Assessment of Estuarine Trophic Status (ASSETS) methods. Based on nutrient concentrations, 73.9% of DIN and 26.7% of PO4-P samples exceeded the fourth grade Seawater Quality Standard of China. Eutrophication index values varied widely, but higher levels of eutrophication were generally found in bays and estuaries. TRIX values ranged from 2.61 to 7.27, with an average of 4.98, indicating a mesotrophic and moderately productive system. A positive correlation between TRIX and harmful algal species richness and abundance was observed. The ASSETS model evaluates eutrophication status based on a Pressure-State-Response approach, including three main indices: influencing factors, overall eutrophic condition, and future outlook. The Beibu Gulf was graded as moderate using ASSETS. The single factor and Chinese nutrient index methods were considered inadequate for the assessment of trophic status. TRIX can be used as an indicator of trophic state and ASSETS showed good potential to assess eutrophication. The results of TRIX and ASSETS depend on threshold values. To establish these values, further research is required within the northern Beibu Gulf.

Lai, Junxiang; Jiang, Fajun; Ke, Ke; Xu, Mingben; Lei, Fu; Chen, Bo

2014-09-01

372

Assessment of the aerosol distribution over Indian subcontinent in CMIP5 models  

NASA Astrophysics Data System (ADS)

This paper examines the aerosol distribution over Indian subcontinent as represented in 21 models from Coupled Model Inter-comparison Project Phase 5 (CMIP5) simulations, wherein model simulated aerosol optical depth (AOD) is compared with Moderate Resolution Imaging Spectro-radiometer (MODIS) satellite observations. The objective of the study is to provide an assessment of the capability of various global models, participating in CMIP5 project, in capturing the realistic spatial and temporal distribution of aerosol species over the Indian subcontinent. Results from our analysis show that majority of the CMIP5 models (excepting HADGEM2-ES, HADGEM2-CC) seriously underestimates the spatio-temporal variability of aerosol species over the Indian subcontinent, in particular over Indo-Gangetic Plains (IGP). Since IGP region is dominated by anthropogenic activities, high population density, and wind driven transport of dust and other aerosol species, MODIS observations reveal high AOD values over this region. Though the representation of black carbon (BC) loading in many models is fairly good, the dust loading is observed to be significantly low in majority of the models. The presence of pronounced dust activity over northern India and dust being one of the major constituent of aerosol species, the biases in dust loading has a great impact on the AOD of that region. We found that considerable biases in simulating the 850 hPa wind field (which plays important role in transport of dust from adjacent deserts) would be the possible reason for poor representation of dust AOD and in turn total AOD over Indian region in CMIP5 models. In addition, aerosol radiative forcing (ARF) underestimated/overestimated in most of the models. However, spatial distribution of ARF in multi-model ensemble mean is comparable reasonably well with observations with bias in magnitudes. This analysis emphasizes the fundamental need to improve the representation of aerosol species in current state of the art climate models. As reported in Intergovernmental Panel on Climate Change (IPCC) fourth assessment report (AR4), the level of scientific understanding (LOSU) of climatic impact of aerosols is medium-low. For better understanding of short and long term implications of changing concentrations of aerosol species on climate, it is imperative to have a realistic representation of aerosol distribution over regions with high aerosol loading.

Sanap, S. D.; Ayantika, D. C.; Pandithurai, G.; Niranjan, K.

2014-04-01

373

Assessment of herbicide transport and distribution in subsurface environments of an orange field.  

PubMed

The demand for assessing both the variability of risk areas and the intensity of pollutant load rates on pesticide transferring to waters in China has been increasingly vigorous in recent decades. Therefore, to explore the transport of linuron with rainfall and irrigation in canopy-soil systems, an integrated pesticide transport modeling system has been selected and verified for simulating the three-phase linuron environmental fate in an orange field of the Three Gorges Reservoir (TGR) area. Results demonstrate that spatio-temporal distributions of linuron in surface soil primarily depend on its properties, rainfall, irrigation, and its applications; the peak levels of linuron in subsurface and deep soil are closely related to the cumulative and delayed effects. The findings may be used for policy supporting of soil-water-crop-pesticide management in an agricultural field of the TGR area. PMID:25306788

Wu, Lei; Ma, Xiao-Yi; Liu, Xia

2014-08-01

374

Assessing the occurrence and distribution of pyrethroids in water and suspended sediments  

USGS Publications Warehouse

The distribution of pyrethroid insecticides in the environment was assessed by separately measuring concentrations in the dissolved and suspended sediment phases of surface water samples. Filtered water was extracted by HLB solid-phase extraction cartridges, while the sediment on the filter was sonicated and cleaned up using carbon and aluminum cartridges. Detection limits for the 13 pyrethroids analyzed by gas chromatography-tandem mass spectrometry were 0.5 to 1 ng L-1 for water and 2 to 6 ng g for the suspended sediments. Seven pyrethroids were detected in six water samples collected from either urban or agricultural creeks, with bifenthrin detected the most frequently and at the highest concentrations. In spiked water samples and field samples, the majority of the pyrethroids were associated with the suspended sediments.

Hladik, M.L.; Kuivila, K.M.

2009-01-01

375

Assessing T Cell Clonal Size Distribution: A Non-Parametric Approach  

PubMed Central

Clonal structure of the human peripheral T-cell repertoire is shaped by a number of homeostatic mechanisms, including antigen presentation, cytokine and cell regulation. Its accurate tuning leads to a remarkable ability to combat pathogens in all their variety, while systemic failures may lead to severe consequences like autoimmune diseases. Here we develop and make use of a non-parametric statistical approach to assess T cell clonal size distributions from recent next generation sequencing data. For 41 healthy individuals and a patient with ankylosing spondylitis, who undergone treatment, we invariably find power law scaling over several decades and for the first time calculate quantitatively meaningful values of decay exponent. It has proved to be much the same among healthy donors, significantly different for an autoimmune patient before the therapy, and converging towards a typical value afterwards. We discuss implications of the findings for theoretical understanding and mathematical modeling of adaptive immunity. PMID:25275470

Bolkhovskaya, Olesya V.; Zorin, Daniil Yu.; Ivanchenko, Mikhail V.

2014-01-01

376

Assessment of the aerosols distribution in the Bucharest metropolitan area in relation with health effects  

NASA Astrophysics Data System (ADS)

MODIS Terra/Aqua time-series satellite images and in- situ monitoring of particle matter PM2.5 and PM10 have been used in an effort to qualitatively assess distribution of aerosols in the greater Bucharest area during 2010-2011 period. It was found that PM2.5 and PM10 aerosols exhibit their highest concentration mostly in the central part mainly due to road traffic as well as in the industrialized parts outside of city's centre. An epidemiological study examining the relationships between adverse health outcomes and exposure to air pollutants in metropolitan agglomeration of Bucharest used ambient air pollution measurements like as PM10 and PM2.5 levels as a proxy for personal exposure levels. The measurements of environmental concentrations of particulate matter air pollutants have been correlated with health effects on respiratory health status of school children in urban/periurban areas of Bucharest.

Zoran, M. A.; Dida, M. R.

2013-06-01

377

The geographic distribution patterns of HIV-, HCV- and co-infections among drug users in a national methadone maintenance treatment program in Southwest China  

PubMed Central

Background HIV-, HCV- and HIV/HCV co-infections among drug users have become a rapidly emerging global public health problem. In order to constrain the dual epidemics of HIV/AIDS and drug use, China has adopted a methadone maintenance treatment program (MMTP) since 2004. Studies of the geographic heterogeneity of HIV and HCV infections at a local scale are sparse, which has critical implications for future MMTP implementation and health policies covering both HIV and HCV prevention among drug users in China. This study aimed to characterize geographic patterns of HIV and HCV prevalence at the township level among drug users in a Yi Autonomous Prefecture, Southwest of China. Methods Data on demographic and clinical characteristics of all clients in the 11 MMTP clinics of the Yi Autonomous Prefecture from March 2004 to December 2012 were collected. A GIS-based geographic analysis involving geographic autocorrelation analysis and geographic scan statistics were employed to identify the geographic distribution pattern of HIV-, HCV- and co-infections among drug users. Results A total of 6690 MMTP clients was analyzed. The prevalence of HIV-, HCV- and co-infections were 25.2%, 30.8%, and 10.9% respectively. There were significant global and local geographic autocorrelations for HIV-, HCV-, and co-infection. The Moran’s I was 0.3015, 0.3449, and 0.3155, respectively (P?distribution pattern of each infection group was different. Conclusion HIV-, HCV-, and co-infections among drug users in the Yi Autonomous Prefecture all exhibited substantial geographic heterogeneity at the township level. The geographic distribution patterns of the three groups were different. These findings imply that it may be necessary to inform or invent site-specific intervention strategies to better devote currently limited resource to combat these two viruses. PMID:24612875

2014-01-01

378

Protectiveness of species sensitivity distribution hazard concentrations for acute toxicity used in endangered species risk assessment.  

PubMed

A primary objective of threatened and endangered species conservation is to ensure that chemical contaminants and other stressors do not adversely affect listed species. Assessments of the ecological risks of chemical exposures to listed species often rely on the use of surrogate species, safety factors, and species sensitivity distributions (SSDs) of chemical toxicity; however, the protectiveness of these approaches can be uncertain. We comprehensively evaluated the protectiveness of SSD first and fifth percentile hazard concentrations (HC1, HC5) relative to the application of safety factors using 68 SSDs generated from 1,482 acute (lethal concentration of 50%, or LC50) toxicity records for 291 species, including 24 endangered species (20 fish, four mussels). The SSD HC5s and HCls were lower than 97 and 99.5% of all endangered species mean acute LC50s, respectively. The HC5s were significantly less than the concentrations derived from applying safety factors of 5 and 10 to rainbow trout (Oncorhynchus mykiss) toxicity data, and the HCls were generally lower than the concentrations derived from a safety factor of 100 applied to rainbow trout toxicity values. Comparison of relative sensitivity (SSD percentiles) of broad taxonomic groups showed that crustaceans were generally the most sensitive taxa and taxa sensitivity was related to chemical mechanism of action. Comparison of relative sensitivity of narrow fish taxonomic groups showed that standard test fish species were generally less sensitive than salmonids and listed fish. We recommend the use of SSDs as a distribution-based risk assessment approach that is generally protective of listed species. PMID:18699704

Raimondo, Sandy; Vivian, Deborah N; Delos, Charles; Barron, Mace G

2008-12-01

379

Towards a regional distributed hydrological modelling for flash-flood risk assessment  

NASA Astrophysics Data System (ADS)

Flash floods result from the combination of meteorological and hydrological conditions. Recognition of the coupled meteorological / hydrological nature of flash floods is now evident in interpretative studies and in the development of predictive models. There is a real need for research to improve the understanding of the major atmospheric and hydrologic factors leading to extreme flood events, especially those affecting small to medium ungauged basins. The paper presents a regional distributed hydrological modeling approach aiming at providing useful information for flash-flood understanding and risk assessment, especially in small ungauged basins. The analysis of the September 2002 event in the south-east of France has shown that these small ungauged catchments are the most vulnerable to flask floods, with a large number of casualties (Ruin et al., 2008). The model discretization is based on the concept of hydro-landscapes proposed by Dehotin and Braud (2008). In a first approach, only sub-catchments and the soil units derived from an existing soil data base were used to delineate the hydro-landscapes. In order to study the feasibility of the regional approach, a first model, implemented within the LIQUID numerical modelling platform (Viallet et al., 2006) was set up in the Cévennes - Vivarais region. It is based on the 1D Richards equation for the simulation of infiltration and water redistribution within the hydro-landscapes (including the representation of the vertical soil heterogeneity). The ponding was routed to the closest river reach using a simple flux formulation and the routing through the river performed using the kinematic wave approximation of the St-Venant equation. The model was forced with 5 minutes radar images with a 1km2 resolution and used without any calibration phase. A verification of the results was conducted at the regional scale, based on distributed post-flood estimation of maximum peak discharge from the September 2002 event and showed promising results (Manus et al., 2009). The modelling approach was used for sensitivity study on two catchments of about 100 km2 in order to assess the impact of the spatial variability, spatial and temporal aggregation of rainfall on the hydrological response. The sensitivity to the soil description was also conducted. The results show that, in terms of peak discharges, both factors are equally sensitive, when the soils are not fully saturated. The impact of boundary conditions was also important and the permeability of the bedrock should be studied in more details. The use of high resolution radar rainfall estimates proved to be of great importance for the correct simulation of small catchments peak discharge. The hydrological response in terms of processes (infiltration excess, saturation excess) was also analysed on some small catchments, based on model results. The impact of the soil vertical heterogeneity and soil depths was highlighted (Manus et al., 2009). The sensitivity to initial conditions was tackled through the addition of an evapotranspiration module to the existing model based on Varado et al. (2006). The results of such a study are interesting in terms of field experiment planning as they allow to assess functioning hypothesis and highlight sensitive factors. The results are currently used to set up field experiments in the framework of the HyMex project. In terms of warning and risk assessment, the idea is to extend the approach to larger catchments and determine the most sensitive areas for a given rainfall amount. References Dehotin, J. and Braud, I., 2008. Which spatial discretization for distributed hydrological models? Proposition of a methodology and illustration for medium to large scale catchments, Hydrology and Earth System Sciences, 12, 769-796 Manus, C., Anquetin, S., Braud, I., Vandervaere, J.P., Viallet, P., Creutin, J.D. and Gaume, E., 2009. A modelling approach to assess the hydrological response of small Mediterranean catchments to the variability of soil characteristics in a context of extreme events. Hydrology and Earth Sy

Braud, I.; Manus, C.; Anquetin, S.; Viallet, P.

2009-09-01

380

Distributed Drug Discovery, Part 2: Global Rehearsal of Alkylating Agents for the Synthesis of Resin-Bound Unnatural Amino Acids and Virtual D3 Catalog Construction  

PubMed Central

Distributed Drug Discovery (D3) proposes solving large drug discovery problems by breaking them into smaller units for processing at multiple sites. A key component of the synthetic and computational stages of D3 is the global rehearsal of prospective reagents and their subsequent use in the creation of virtual catalogs of molecules accessible by simple, inexpensive combinatorial chemistry. The first section of this article documents the feasibility of the synthetic component of Distributed Drug Discovery. Twenty-four alkylating agents were rehearsed in the United States, Poland, Russia, and Spain, for their utility in the synthesis of resin-bound unnatural amino acids 1, key intermediates in many combinatorial chemistry procedures. This global reagent rehearsal, coupled to virtual library generation, increases the likelihood that any member of that virtual library can be made. It facilitates the realistic integration of worldwide virtual D3 catalog computational analysis with synthesis. The second part of this article describes the creation of the first virtual D3 catalog. It reports the enumeration of 24?416 acylated unnatural amino acids 5, assembled from lists of either rehearsed or well-precedented alkylating and acylating reagents, and describes how the resulting catalog can be freely accessed, searched, and downloaded by the scientific community. PMID:19105725

2008-01-01

381

Assessing the Causal Effect of Organ Transplantation on the Distribution of Residual Lifetime  

PubMed Central

Summary Because the number of patients waiting for organ transplants exceeds the number of organs available, a better understanding of how transplantation affects the distribution of residual lifetime is needed to improve organ allocation. However, there has been little work to assess the survival benefit of transplantation from a causal perspective. Previous methods developed to estimate the causal effects of treatment in the presence of time-varying confounders have assumed that treatment assignment was independent across patients, which is not true for organ transplantation. We develop a version of G-estimation that accounts for the fact that treatment assignment is not independent across individuals to estimate the parameters of a structural nested failure time model. We derive the asymptotic properties of our estimator and confirm through simulation studies that our method leads to valid inference of the effect of transplantation on the distribution of residual lifetime. We demonstrate our method on the survival benefit of lung transplantation using data from the United Network for Organ Sharing. PMID:24128090

Vock, David M.; Tsiatis, Anastasios A.; Davidian, Marie; Laber, Eric B.; Tsuang, Wayne M.; Copeland, C. Ashley Finlen; Palmer, Scott M.

2013-01-01

382

Distribution, sources and health risk assessment of mercury in kindergarten dust  

NASA Astrophysics Data System (ADS)

Mercury (Hg) contamination in urban area is a hot issue in environmental research. In this study, the distribution, sources and health risk of Hg in dust from 69 kindergartens in Wuhan, China, were investigated. In comparison with most other cities, the concentrations of total mercury (THg) and methylmercury (MeHg) were significantly elevated, ranging from 0.15 to 10.59 mg kg-1 and from 0.64 to 3.88 ?g kg-1, respectively. Among the five different urban areas, the educational area had the highest concentrations of THg and MeHg. The GIS mapping was used to identify the hot-spot areas and assess the potential pollution sources of Hg. The emissions of coal-power plants and coking plants were the main sources of THg in the dust, whereas the contributions of municipal solid waste (MSW) landfills and iron and steel smelting related industries were not significant. However, the emission of MSW landfills was considered to be an important source of MeHg in the studied area. The result of health risk assessment indicated that there was a high adverse health effect of the kindergarten dust in terms of Hg contamination on the children living in the educational area (Hazard index (HI) = 6.89).

Sun, Guangyi; Li, Zhonggen; Bi, Xiangyang; Chen, Yupeng; Lu, Shuangfang; Yuan, Xin

2013-07-01

383

Assessment of function and clinical utility of alcohol and other drug web sites: An observational, qualitative study  

PubMed Central

Background The increasing popularity and use of the internet makes it an attractive option for providing health information and treatment, including alcohol/other drug use. There is limited research examining how people identify and access information about alcohol or other drug (AOD) use online, or how they assess the usefulness of the information presented. This study examined the strategies that individuals used to identify and navigate a range of AOD websites, along with the attitudes concerning presentation and content. Methods Members of the general community in Brisbane and Roma (Queensland, Australia) were invited to participate in a 30-minute search of the internet for sites related to AOD use, followed by a focus group discussion. Fifty one subjects participated in the study across nine focus groups. Results Participants spent a maximum of 6.5 minutes on any one website, and less if the user was under 25 years of age. Time spent was as little as 2 minutes if the website was not the first accessed. Participants recommended that AOD-related websites should have an engaging home or index page, which quickly and accurately portrayed the site's objectives, and provided clear site navigation options. Website content should clearly match the title and description of the site that is used by internet search engines. Participants supported the development of a portal for AOD websites, suggesting that it would greatly facilitate access and navigation. Treatment programs delivered online were initially viewed with caution. This appeared to be due to limited understanding of what constituted online treatment, including its potential efficacy. Conclusions A range of recommendations arise from this study regarding the design and development of websites, particularly those related to AOD use. These include prudent use of text and information on any one webpage, the use of graphics and colours, and clear, uncluttered navigation options. Implications for future website development are discussed. PMID:21545748

2011-01-01

384

New concept for HPTLC peak purity assessment and identification of drugs in multi-component mixtures.  

PubMed

Simple methods for HPTLC peak purity assessment and identification of the HPTLC peaks were presented. The spectrodensitograms - selected at different time intervals across the elution time of the HPTLC peak - were extracted and digital algorithms for manipulating the data were carried out in the wavelength domain. Three different methods were developed for testing the HPTLC peak purity using the mathematically transformed data of the spectrodensitograms. These included the method of relative absorption, the method of logA versus the wavelength plots and the derivative (first, second, third and fourth) method. The identification of the HPTLC peaks was based on the use of the derivative profile of the spectrodensitogram and the derivative ratios as fingerprints for the compounds. The wavelengths of absorbance and derivative (first, second, third and fourth) optima of the extracted spectrodensitograms were allocated. The data were compared with those obtained using the corresponding reference standard. The validity of the proposed methods was performed by chromatography of a mixture containing mebendazole and methylparaben as a model versus the winCATS(®) spectral correlation method as a reference method. The study indicated that the proposed concept is a reliable non-confusing valuable tool for testing the purity and identity of the HPTLC peaks as the results are easily and rigorously interpreted. PMID:22265550

Hewala, Ismail I; Bedair, Mona M; Shousha, Sherif M

2012-01-15

385

Drug pharmacokinetics and pharmacodynamics: Technological considerations  

SciTech Connect

Additionally, the use of PET to examine drug pharmacokinetics and pharmacadynamics and the relationship of these properties to the behavioral, therapeutic and toxic properties of drugs and substances of abuse is emerging as a powerful new scientific tool. The pharmacokinetic properties of a drug, which comprises all of the biological processes which determine the fraction of the drug available, can be measured using the labeled drug itself. For example, the labeled drug can be used to measure the absolute uptake, regional distribution and kinetics of a drug at its site of action in the body. Additionally the labeled drug and whole body its labeled metabolites and thus provide information an potential toxic effects as well as tissue half lives. On the other hand, different labeled tracers can be used to assess drug pharmacodynamics which include the biological Processes involved in the drug's effects. For example, with appropriate radiotracers, the effects of a drug on metabolism, neurotransmitter activity, blood flew, enzyme activity or other processes can be probed.

Fowler, J.S.; Volkow, N.D.; Wolf, A.P.

1992-01-01

386

Distribution  

Microsoft Academic Search

e're closer than you think: Portland's geographic location and Oregon's transportation infra - structure offer unmatched con - nectivity and time savings to international and domestic markets. Our economic development practices combine project-ready property with efficient, high-capacity infrastructure to create today's logistics advantages. Connecting people, places and products is the core of Portland's distribution and logistics industry sec - tor.

F. Gregory; B. Boyd; R. Bridges; D. Mitchell; J. Halsell; S. Fancher; D. King; R. Fore; E. Mango; D. Berlinrut; M. Leinbach; M. Maier; M. Wetmore; H. Herring; J. Guidi; M. Coolidge; J. Heald; T. Knox; D. Bartine; R. Bailey; H. Delgado; P. Conant; J. Madura; R. Thomas; F. Merceret; G. Allen; E. Bensman; R. Dittemore; N. Feldman; C. Boykin; H. Tileston; F. Brody; L. Hagerman; S. Pearson; L. Uccellini; W. Vaughan; J. Golden; D. Johnson; J. McQueen; B. Roberts; L. Freeman; G. Jasper; B. Hagemeyer; A. McCool; X. W. Proenza; S. Glover

2006-01-01

387

Closantel plasma and milk disposition in dairy goats: assessment of drug residues in cheese and ricotta.  

PubMed

Closantel (CLS) is currently used in programs for the strategic control of gastrointestinal nematodes. CLS is extralabel used in different dairy goat production systems. From available data in dairy cows, it can be concluded that residues of CLS persist in milk. The current work evaluated the concentration profiles of CLS in plasma and milk from lactating orally treated dairy goats to assess the residues pattern in dairy products such as cheese and ricotta. Six (6) female Saanen dairy goats were treated orally with CLS administered at 10 mg/kg. Blood and milk samples were collected between 0 and 36 days post-treatment. The whole milk production was collected at 1, 4, 7, and 10 days post-treatment to produce soft cheese and ricotta. CLS concentrations in plasma, milk, cheese, whey, and ricotta were determined by HPLC. The concentrations of CLS measured in plasma were higher than those measured in milk at all sampling times. However, the calculated withdrawal time for CLS in milk was between 39 and 43 days postadministration to dairy goats. CLS residual concentrations in cheese (between 0.93 and 1.8 ?g/g) were higher than those measured in the milk used for its production. CLS concentrations in ricotta were sixfold higher than those in the milk and 20-fold higher than those in the whey used for its production. The persistent and high residual concentrations of CLS in the milk and in the cheese and ricotta should be seriously considered before issuing any recommendation on the extralabel use of CLS in dairy goat farms. PMID:24903569

Iezzi, S; Lifschitz, A; Sallovitz, J; Nejamkin, P; Lloberas, M; Manazza, J; Lanusse, C; Imperiale, F

2014-12-01

388

A Distributed Adverse Drug Reaction Detection System Using Intelligent Agents with Fuzzy Recognition-Primed Decision Model  

E-print Network

about 100,000 deaths in the U.S. due to medical errors, of which about 7,000 were attributed to various, USA 4 Veterans Affairs Medical Center, Detroit, Michigan, USA #12;2 Abstract Discovering unknown model; Medical decision-making. #12;3 1. Introduction 1.1 Adverse Drug Reactions Every day numerous

389

A Network-Based Classification Model for Deriving Novel Drug-Disease Associations and Assessing Their Molecular Actions  

PubMed Central

The growing number and variety of genetic network datasets increases the feasibility of understanding how drugs and diseases are associated at the molecular level. Properly selected features of the network representations of existing drug-disease associations can be used to infer novel indications of existing drugs. To find new drug-disease associations, we generated an integrative genetic network using combinations of interactions, including protein-protein interactions and gene regulatory network datasets. Within this network, network adjacencies of drug-drug and disease-disease were quantified using a scored path between target sets of them. Furthermore, the common topological module of drugs or diseases was extracted, and thereby the distance between topological drug-module and disease (or disease-module and drug) was quantified. These quantified scores were used as features for the prediction of novel drug-disease associations. Our classifiers using Random Forest, Multilayer Perceptron and C4.5 showed a high specificity and sensitivity (AUC score of 0.855, 0.828 and 0.797 respectively) in predicting novel drug indications, and displayed a better performance than other methods with limited drug and disease properties. Our predictions and current clinical trials overlap significantly across the different phases of drug development. We also identified and visualized the topological modules of predicted drug indications for certain types of cancers, and for Alzheimer’s disease. Within the network, those modules show potential pathways that illustrate the mechanisms of new drug indications, including propranolol as a potential anticancer agent and telmisartan as treatment for Alzheimer’s disease. PMID:25356910

Oh, Min; Ahn, Jaegyoon; Yoon, Youngmi

2014-01-01

390

What Matters Most? Assessing the Influence of Demographic Characteristics, College-Specific Risk Factors, and Poly-Drug Use on Nonmedical Prescription Drug Use  

ERIC Educational Resources Information Center

Objective: Although prior recent research has revealed a significant relationship between the nonmedical use of prescription drugs, demographic characteristics, college-specific risk factors, and other substance use among college students, there remains a need to conduct a comparative analysis on the differential impact these factors may have on…

Lanier, Christina; Farley, Erin J.

2011-01-01

391

Laser Doppler and transcutaneous oximetry: modern investigations to assess drug efficacy in chronic venous insufficiency.  

PubMed

During chronic venous insufficiency (CVI), microcirculatory changes, e.g. a decrease in transcutaneous oxygen pressure (tcpO2) and an increase in transcutaneous carbon dioxide pressure (tcpCO2), are implicated in the pathophysiology of trophic disorders leading ultimately to venous ulcers. Daflon 500 mg1, a micronized purified flavonoid fraction, has been shown to improve venous tone, capillary permeability and resistance, and lymphagogue activity at a daily dose of 2 tablets. To assess the effects of Daflon 500 mg on microcirculatory parameters by means of laser Doppler fluxmetry and transcutaneous oxiketry, a 3-month, double-blind, randomized, parallel-group study was carried out in 104 patients divided into 3 groups according to the daily dose: 1 tablet (group 1, n = 34), 2 tablets (group 2, n = 33), on 4 tablets (group 3, n = 37). All patients (mean age 43.7 +/- 13.1 years; 100 females, 4 males) included in the study were affected by mild CVI. They were followed for 90 days with visits at 1 month (day 28) and 3 months (day 90). At inclusion, there were no significant differences between groups as regards biometric data, mean tcpO2 (group 1, 62.7 +/- 4.5 mm Hg; group 2, 64.0 +/- 3.3 mm Hg; group 3, 64.1 +/- 3.5 mm Hg), mean tcpCO2 (group 1, 40.7 +/- 2.5 mm Hg; group 2, 39.3 +/- 2.9 mm Hg; group 3, 40.0 +/- 2.5 mm Hg) and laser Doppler parameters. Fourteen patients withdrew from the study (group 1, n = 4; group 2, n = 3; group 3, n = 7): 9 for reasons not related to treatment, 3 for adverse events, 2 because they were lost to follow-up. From day 0 to day 90, mean tcpO2 significantly increased (p < 0.001) in each group (group 1, 3.0 +/- 2.1 mm Hg; group 2, 2.9 +/- 2.1 mm Hg; group 3, 2.5 +/- 1.6 mm Hg), mean tcpCO2 significantly decreased (p < 0.001) in each group (group 1, 2.6 +/- 2.0 mm Hg; group 2, 1.7 +/- 1.9 mm Hg; group 3, 2.2 +/- 1.5 mm Hg). No significant differences were observed between groups. Laser Doppler parameters remained unchanged from day 0 to day 90 in the 3 groups. Symptoms (discomfort, pain, heaviness, burning sensation) and signs (oedema) of CVI as well as perimetric measurements of calf and supramalleolar area were significantly improved in the 3 groups. In conclusion, during this 3-month study, Daflon 500 mg improved oximetric measurements and did not alter laser Doppler parameters. These data suggest that Daflon 500 mg, at the early stages of CVI, acts favourably on the microcirculatory disturbances also involved in the pathophysiology of more severe stages of CVI. PMID:8748889

Belcaro, G; Cesarone, M R; de Sanctis, M T; Incandela, L; Laurora, G; Février, B; Wargon, C; De Gregoris, P

1995-01-01

392

Feedback-controlled bolus plus infusion (FC-B/I) method for quantitative drug assessment in living brain with PET  

PubMed Central

We have developed a feedback-controlled bolus plus infusion (FC-B/I) method for monitoring the interaction between positron emission tomography (PET) ligands and their specific target molecules with PET. The usefulness of the FC-B/I method was evaluated by the direct interaction between [11C]raclopride, a dopamine D2 receptor (D2R) ligand, and cold raclopride (10 and 100??g/kg) in the brains of conscious monkeys. The present results demonstrated that the FC-B/I method could achieve the equilibrium state of [11C]raclopride in the striatum of monkey brain, and also that the cold raclopride-induced reduction of [11C]raclopride binding to D2R was observed in a dose-dependent manner. Good correlations of distribution volume ratio of the striatum to cerebellum between the conventional bolus plus infusion (B/I) method and the FC-B/I method as well as between the conventional bolus injection method and the FC-B/I method were observed. These results indicated that the system could be a useful tool for the evaluation of interaction between drug candidates and their target molecules like enzymes, receptors, and transporters by using of their specific PET ligands. PMID:22968323

Ohba, Hiroyuki; Harada, Norihiro; Nishiyama, Shingo; Kakiuchi, Takeharu; Kimura, Yuichi; Tsukada, Hideo

2013-01-01

393

Assessing potential impacts associated with contamination events in water distribution systems : a sensitivity analysis.  

SciTech Connect

An understanding of the nature of the adverse effects that could be associated with contamination events in water distribution systems is necessary for carrying out vulnerability analyses and designing contamination warning systems. This study examines the adverse effects of contamination events using models for 12 actual water systems that serve populations ranging from about 104 to over 106 persons. The measure of adverse effects that we use is the number of people who are exposed to a contaminant above some dose level due to ingestion of contaminated tap water. For this study the number of such people defines the impact associated with an event. We consider a wide range of dose levels in order to accommodate a wide range of potential contaminants. For a particular contaminant, dose level can be related to a health effects level. For example, a dose level could correspond to the median lethal dose, i.e., the dose that would be fatal to 50% of the exposed population. Highly toxic contaminants may be associated with a particular response at a very low dose level, whereas contaminants with low toxicity may only be associated with the same response at a much higher dose level. This report focuses on the sensitivity of impacts to five factors that either define the nature of a contamination event or involve assumptions that are used in assessing exposure to the contaminant: (1) duration of contaminant injection, (2) time of contaminant injection, (3) quantity or mass of contaminant injected, (4) population distribution in the water distribution system, and (5) the ingestion pattern of the potentially exposed population. For each of these factors, the sensitivities of impacts to injection location and contaminant toxicity are also examined. For all the factors considered, sensitivity tends to increase with dose level (i.e., decreasing toxicity) of the contaminant, with considerable inter-network variability. With the exception of the population distribution (factor 4 above), sensitivity to the various factors tends to be highest at lower impact levels (e.g., impacts below the 80th percentile). Conversely, for the population distribution factor, sensitivity is lowest at the lower impact levels. For injection duration, impacts generally are higher for longer duration injections. Definite patterns are present in the sensitivity of impacts to injection time, but these vary substantially across the networks. As would be expected, impacts are larger for larger mass injections, but the sensitivity can vary dramatically depending on dose level and the network. Estimated impacts can be sensitive to assumptions about how population is distributed in a network, particularly at high impact levels and high dose levels, again with considerable variability across networks. Finally, impacts can be sensitive to assumptions about ingestion patterns in the potentially exposed population, with sensitivities varying across networks and tending to be highest for high dose levels. When considered in combination with the other factors (but not including the ingestion model used), impacts at low dose levels (levels at which the effects of highly toxic contaminants can be significant) are most sensitive to injection duration. Similarly, when considered in combination, impacts at higher dose levels (levels required for significant effects from contaminants with low toxicity) are most sensitive to injection mass. At low dose levels, for a likely range in injection masses, impacts are not particularly sensitive to injection mass. The influence of the various factors on the location of high percentile injection locations can be as important or more important than their influence on the magnitudes of impacts. In addition, the choice of contaminant has a major influence on which nodes are high impact injection locations. The sharing (overlap) of the same high-percentile injection nodes for different values of a factor can vary substantially by contaminant and impact level (percentile of impact). Overlap tends to decrease with decreasing toxicity of the con

Davis, M. J.; Janke, R.; Taxon, T. N. (Decision and Information Sciences); ( EVS); (EPA)

2010-11-01

394

Distribution of Spoligotyping Defined Genotypic Lineages among Drug-Resistant Mycobacterium tuberculosis Complex Clinical Isolates in Ankara, Turkey  

PubMed Central

Background Investigation of genetic heterogeneity and spoligotype-defined lineages of drug-resistant Mycobacterium tuberculosis clinical isolates collected during a three-year period in two university hospitals and National Tuberculosis Reference and Research Laboratory in Ankara, Turkey. Methods and Findings A total of 95 drug-resistant M. tuberculosis isolates collected from three different centers were included in this study. Susceptibility testing of the isolates to four major antituberculous drugs was performed using proportion method on Löwenstein–Jensen medium and BACTEC 460-TB system. All clinical isolates were typed by using spoligotyping and IS6110-restriction fragment length polymorphism (RFLP) methods. Seventy-three of the 95 (76.8%) drug resistant M. tuberculosis isolates were isoniazid-resistant, 45 (47.4%) were rifampicin-resistant, 32 (33.7%) were streptomycin-resistant and 31 (32.6%) were ethambutol-resistant. The proportion of multidrug-resistant isolates (MDR) was 42.1%. By using spoligotyping, 35 distinct patterns were observed; 75 clinical isolates were grouped in 15 clusters (clustering rate of 79%) and 20 isolates displayed unique patterns. Five of these 20 unique patterns corresponded to orphan patterns in the SITVIT2 database, while 4 shared types containing 8 isolates were newly created. The most prevalent M. tuberculosis lineages were: Haarlem (23/95, 24.2%), ill-defined T superfamily (22/95, 23.2%), the Turkey family (19/95, 20%; previously designated as LAM7-TUR), Beijing (6/95, 6.3%), and Latin-America & Mediterranean (LAM, 5/95 or 5.3%), followed by Manu (3/95, 3.2%) and S (1/95, 1%) lineages. Four of the six Beijing family isolates (66.7%) were MDR. A combination of IS6110-RFLP and spoligotyping reduced the clustering rate from 79% to 11.5% among the drug resistant isolates. Conclusions The results obtained showed that ill-defined T, Haarlem, the Turkey family (previously designated as LAM7-TUR family with high phylogeographical specifity for Turkey), Beijing and LAM were predominant lineages observed in almost 80% of the drug-Resistant M. tuberculosis complex clinical isolates in Ankara, Turkey. PMID:22279583

Kisa, Ozgul; Tarhan, Gulnur; Gunal, Selami; Albay, Ali; Durmaz, Riza; Saribas, Zeynep; Zozio, Thierry; Alp, Alpaslan; Ceyhan, Ismail; Tombak, Ahmet; Rastogi, Nalin

2012-01-01

395

A Comprehensive Assessment of Lymphatic Filariasis in Sri Lanka Six Years after Cessation of Mass Drug Administration  

PubMed Central

Background The Sri Lankan Anti-Filariasis Campaign conducted 5 rounds of mass drug administration (MDA) with diethycarbamazine plus albendazole between 2002 and 2006. We now report results of a comprehensive surveillance program that assessed the lymphatic filariasis (LF) situation in Sri Lanka 6 years after cessation of MDA. Methodology and Principal Findings Transmission assessment surveys (TAS) were performed per WHO guidelines in primary school children in 11 evaluation units (EUs) in all 8 formerly endemic districts. All EUs easily satisfied WHO criteria for stopping MDA. Comprehensive surveillance was performed in 19 Public Health Inspector (PHI) areas (subdistrict health administrative units). The surveillance package included cross-sectional community surveys for microfilaremia (Mf) and circulating filarial antigenemia (CFA), school surveys for CFA and anti-filarial antibodies, and collection of Culex mosquitoes with gravid traps for detection of filarial DNA (molecular xenomonitoring, MX). Provisional target rates for interruption of LF transmission were community CFA <2%, antibody in school children <2%, and filarial DNA in mosquitoes <0.25%. Community Mf and CFA prevalence rates ranged from 0–0.9% and 0–3.4%, respectively. Infection rates were significantly higher in males and lower in people who denied prior treatment. Antibody rates in school children exceeded 2% in 10 study sites; the area that had the highest community and school CFA rates also had the highest school antibody rate (6.9%). Filarial DNA rates in mosquitoes exceeded 0.25% in 10 PHI areas. Conclusions Comprehensive surveillance is feasible for some national filariasis elimination programs. Low-level persistence of LF was present in all study sites; several sites failed to meet provisional endpoint criteria for LF elimination, and follow-up testing will be needed in these areas. TAS was not sensitive for detecting low-level persistence of filariasis in Sri Lanka. We recommend use of antibody and MX testing as tools to complement TAS for post-MDA surveillance. PMID:25393404

Rao, Ramakrishna U.; Nagodavithana, Kumara C.; Samarasekera, Sandhya D.; Wijegunawardana, Asha D.; Premakumara, Welmillage D. Y.; Perera, Samudrika N.; Settinayake, Sunil; Miller, J. Phillip; Weil, Gary J.

2014-01-01

396

Microspectroscopic FT-IR mapping system as a tool to assess blend homogeneity of drug-excipient mixtures.  

PubMed

In order to prepare a controlled-release tablet by direct compression, a Fourier transform infrared (FT-IR) microspectroscopic mapping system was utilized to assess the blend homogeneity of a pharmaceutical powder blend. The model powder blend was a two-component mixture consisting of captopril as a model drug and micronized ethylcellulose (EC) as a direct-compressible model excipient, which was mixed in a laboratory mill. The two-component mixture was mixed in two different weight proportions (captopril:EC, 1:1 or 10:1). By varying the mixing time, different blend mixtures sampled were determined by a reflectance FT-IR microspectroscopic mapping system to collect successively the IR spectra from the actual analysis area. The results revealed that the blend homogeneity increased gradually with increased mixing times, but the powder began to demix or segregate as mixing continued beyond the time when homogeneity was reached. In addition, the statistical results indicated that the sample mixture proportion had an effect on the uniformity of the powder blend. This study demonstrates that microspectroscopic FT-IR mapping technique can be easily used to determine the blend homogeneity in a powder blend mixture. PMID:15450999

Lee, Ting-Huei; Lin, Shan-Yang

2004-10-01

397

Assessment of neurological effects of drugs on oculomotor and visual function in the primate. Annual report, September 1981-August 1982  

SciTech Connect

A number of cholinergic agents are deemed useful as prophylactics or antidotes to organophosphate poisoning, yet have their own toxic effects. Dosages of these agents which are known to not grossly disrupt behavior may nonetheless degrade performance of sophisticated tasks required of the personnel of a modern mechanized army. The contract uses on animal model (primate) to assess the effects of cholinergic drugs on the performance of visual search and tracking tasks which mimic skills generally used in the field. The eye movements of cynomolgous monkeys (Macaca fascicularis) were recorded with the magnetic search coil technique while they searched for camouflaged visual targets. To date the research has defined the normal patterns of eye movements of monkeys engaged in visual search and there are preliminary results describing the effects of physostigmine and pralidoxime. Only at the highest dose did physostigimine consistently degrade eye movements and impair visual search. The deficit was a subtle one and was primarily an oculomotor effect rather than a motivational, visual, or cognitive impairment. Pralidoxime also had no consistent effect at any but the highest dose. Behavioral testing was erratic at this dose but visual search was successful when attempted at all by the monkey, suggesting a motivational rather than specifically oculomotor impairment.

Keating, E.G.

1982-12-10

398