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1

Assessing drug distribution in tissues expressing P-glycoprotein through physiologically based pharmacokinetic modeling: model structure and parameters determination  

PubMed Central

Background The expression and activity of P-glycoproteins due to genetic or environmental factors may have a significant impact on drug disposition, drug effectiveness or drug toxicity. Hence, characterization of drug disposition over a wide range of conditions of these membrane transporters activities is required to better characterize drug pharmacokinetics and pharmacodynamics. This work aims to improve our understanding of the impact of P-gp activity modulation on tissue distribution of P-gp substrate. Methods A PBPK model was developed in order to examine activity and expression of P-gp transporters in mouse brain and heart. Drug distribution in these tissues was first represented by a well-stirred (WS) model and then refined by a mechanistic transport-based (MTB) model that includes P-gp mediated transport of the drug. To estimate transport-related parameters, we developed an original three-step procedure that allowed extrapolation of in vitro measurements of drug permeability to the in vivo situation. The model simulations were compared to a limited set of data in order to assess the model ability to reproduce the important information of drug distributions in the considered tissues. Results This PBPK model brings insights into the mechanism of drug distribution in non eliminating tissues expressing P-gp. The MTB model accounts for the main transport mechanisms involved in drug distribution in heart and brain. It points out to the protective role of P-gp at the blood-brain barrier and represents thus a noticeable improvement over the WS model. Conclusion Being built prior to in vivo data, this approach brings an interesting alternative to fitting procedures, and could be adapted to different drugs and transporters. The physiological based model is novel and unique and brought effective information on drug transporters.

Fenneteau, Frederique; Turgeon, Jacques; Couture, Lucie; Michaud, Veronique; Li, Jun; Nekka, Fahima

2009-01-01

2

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

2011-02-01

3

Florida: Drug Threat Assessment.  

National Technical Information Service (NTIS)

This report is a strategic assessment that addresses the status and outlook of the drug threat to Florida. Analytical judgment determined the threat posed by each drug type or category, taking into account the most current quantitative and qualitative inf...

2003-01-01

4

National Drug Threat Assessment, 2002.  

National Technical Information Service (NTIS)

In accordance with the provisions of the General Counterdrug Intelligence Plan, the National Drug Threat Assessment integrates foreign and domestic counterdrug intelligence and information on domestic drug consumption trends in a single report. This repor...

2001-01-01

5

DRUG DISTRIBUTION AND STENT RETENTION OF DRUG ELUTING STENTS  

Microsoft Academic Search

In this paper the examinations of drug eluting coronary stents are shown, such as the morphology of the coatings before expansion, drug distribution, the methodology and the value of stent retention. Surface qualities of drug coatings were examined with stereo- microscope, metallographic microscope and scanning electron microscope. Examinations with confocal microscope show drug distribution in the coatings. Stent retention is

E. Bognár; T. Balázs

6

OFFICE OF NEW DRUG QUALITY ASSESSMENT ...  

Center for Drug Evaluation (CDER)

Text Version... Originator: Office of New Drug Quality Assessment Effective Date: 2/21/2007; 11/3/2007 Page 1 OFFICE OF NEW DRUG QUALITY ASSESSMENT ... More results from www.fda.gov/downloads/aboutfda/centersoffices

7

Drug Threat Assessment: New Hampshire. Update.  

National Technical Information Service (NTIS)

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

2002-01-01

8

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.

Foster, S. D.

1991-01-01

9

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

10

Nutritional assessment of drug addicts  

Microsoft Academic Search

Objective: To discern if factors such as organic pathology, sex, duration and\\/or intensity of drug addiction, alcohol abuse, hepatitis B infection, anorexia with poor food and drink consumption, or disturbance of social and familial networks, are related to an impaired nutritional status in hospitalized drug addicts. Design: Cross-sectional prospective study. Setting: Detoxication unit and internal medicine unit of a university

Francisco J. Santolaria-Fernández; J. L. Gómez-Sirvent; C. Emilio González-Reimers; José N. Batista-López; José A. Jorge-Hernández; Fermín Rodríguez-Moreno; Antonio Martínez-Riera; Miguel T. Hernández-García

1995-01-01

11

National Drug Threat Assessment, 2010.  

National Technical Information Service (NTIS)

Overall, the availability of illicit drugs in the United States is increasing .1 In fact, in 2009 the prevalence of four of the five major drugsheroin, methamphetamine, marijuana, and MDMA (3,4-methylenedioxym ethamphetamine)was widespread and increasing ...

2010-01-01

12

Effect of route of administration and distribution on drug action  

Microsoft Academic Search

The extent and time course of drug action can be markedly affected by the route of drug administration into the patient as well as the pattern of drug distribution within the patient. Drugs which are rapidly cleared by hepatic processes will show a decreased extent of availability following oral administration due to metabolism of drug on its first pass through

Leslie Z. Benet

1978-01-01

13

Effects of Drug Transporters on Volume of Distribution  

Microsoft Academic Search

Recently, drug transporters have emerged as significant modifiers of a patient’s pharmacokinetics. In cases where the functioning\\u000a of drug transporters is altered, such as by drug-drug interactions, by genetic polymorphisms, or as evidenced in knockout\\u000a animals, the resulting change in volume of distribution can lead to a significant change in drug effect or likelihood of toxicity,\\u000a as well as a

Anita Grover; Leslie Z. Benet

2009-01-01

14

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

Code of Federal Regulations, 2010 CFR

...products distributed under the Food, Drug and Cosmetic Act. 1310.11 Section 1310.11 Food and Drugs DRUG ENFORCEMENT ADMINISTRATION, DEPARTMENT OF JUSTICE RECORDS AND REPORTS OF LISTED...products distributed under the Food, Drug and Cosmetic...

2010-04-01

15

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

Code of Federal Regulations, 2010 CFR

...products distributed under the Food, Drug and Cosmetic Act. 1310.11 Section 1310.11 Food and Drugs DRUG ENFORCEMENT ADMINISTRATION, DEPARTMENT OF JUSTICE RECORDS AND REPORTS OF LISTED...products distributed under the Food, Drug and Cosmetic...

2009-04-01

16

Causality Assessment of Cutaneous Adverse Drug Reactions  

PubMed Central

Background Cutaneous adverse drug reactions (ADRs) are the most common adverse reactions attributed to drugs. A systematic and effective approach to a patient with suspected drug eruption allows for prompt recognition, classification and treatment of cutaneous ADRs. A standardized and effective approach for objective causality assessment is necessary to make consistent and accurate identification of ADRs. Objective Although the Naranjo algorithm is the most widely used assessment tool, it contains many components which are not suitable for clinical assessment of ADRs in Korea. The purpose of this study is to compare correlations of the Naranjo algorithm and the Korean algorithm to evaluate usefulness of both algorithms in order to make a causal link between drugs and cutaneous ADRs. In addition, this study classifies the clinical types and causative agents of cutaneous ADRs. Methods The authors retrospectively reviewed the clinical types and laboratory findings of patients who were diagnosed with cutaneous ADRs in the dermatology clinic at Gil hospital. One hundred forty-one patients were enrolled in this evaluation. The causal relationship of ADRs was assessed by using the Naranjo algorithm and Korean algorithm (version 2.0). Results A cross-tabulation analysis was applied to the Naranjo algorithm and Korean algorithm (version 2.0). Simple correlation analysis and a Bland-Altman plot were used for statistical analysis. Correlation analysis confirmed that the two assessment algorithms were significantly correlated. Exanthematous eruptions (68.8%), Stevens- Johnson syndrome (10.6%), and urticaria (8.5%) were the most common types of cutaneoues ADRs. The most common causative agents were antibiotics/antimicrobials, antipyretics/non-steroidal anti-inflammatory drugs, and central nervous system depressants. Conclusion The Naranjo algorithm and Korean algorithm (version 2.0) were significantly correlated with each other, and thus reliable assessment methods to determine cutaneous ADRs.

Son, Young-Min; Lee, Jong-Rok

2011-01-01

17

Mechanisms of cellular distribution of psychotropic drugs. Significance for drug action and interactions  

Microsoft Academic Search

Distribution of a drug in the body is dependent on its permeation properties, the blood flow rates in various tissues, and on plasma and tissue uptake. The distribution of drugs in vivo is largely determined by uptake competitions between blood and tissues, as well as competitions among individual tissues. Basic lipophilic drugs are characterized by extensive accumulation in tissues, which

W?adys?awa A Daniel

2003-01-01

18

Drug policy in China: pharmaceutical distribution in rural areas.  

PubMed

In 1978, China decided to reform its economy and since then has gradually opened up to the world. The economy has grown rapidly at an average of 9.8% per year from 1978 to 1994. Medical expenditure, especially for drugs, has grown even more rapidly. The increase in medical expenditure can be attributed to changing disease patterns, a higher proportion of older people in the population and fee-for-service incentives for hospitals. Due to the changing economic system and higher cost of health care, the Chinese government has reformed its health care system, including its health and drug policy. The drug policy reform has led to more comprehensive policy elements, including registration, production, distribution, utilization and administration. As a part of drug policy reform, the drug distribution network has also been changed, from a centrally controlled supply system (push system) to a market-oriented demand system (pull system). Hospitals can now purchase drugs directly from drug companies, factories and retailers, leading to increased price competition. Patients have easier access to drugs as more drugs are available on the market. At the same time, this has also entailed negative effects. The old drug administrative system is not suitable for the new drug distribution network. It is easy for people to get drugs on the market and this can lead to overuse and misuse. Marketing factors have influenced drug distribution so strongly that there is a risk of fake or low quality drugs being distributed. The government has taken some measures to fight these negative effects. This paper describes the drug policy reform in China, particularly the distribution of drugs to health care facilities. PMID:10190640

Dong, H; Bogg, L; Rehnberg, C; Diwan, V

1999-03-01

19

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.

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

2010-01-01

20

Distribution of veterinary drug residues among muscles  

Technology Transfer Automated Retrieval System (TEKTRAN)

The U.S. Food and Drug Administration sets tolerances for veterinary drug residues in muscle, but does not specify which muscle should be sampled for analysis. The goal of this research was to determine if antibiotic residue levels are dependent on muscle type. In this study, penicillin G (Pen G) d...

21

[The effect of implementation of a unit dose drug distribution system on drug consumption].  

PubMed

As an important drug consumer in Dubrava University Hospital, Department of Cardiac Surgery has been chosen for testing a new model of drug distribution system known as unit dose drug distribution system. During the first 39 weeks in 1996--comparative period, drugs were delivered from the Pharmacy to the Department of Cardiac Surgery in traditional way, known as floor stock system. Next 65 weeks, until the end of 1997--pilot study period, drugs were delivered directly from the Pharmacy to the patients, using unit dose drug distribution system. Consumption of drugs was measured every week by statistical unit DDD/100 hospital days (Defined Daily Dose) according to Anatomic-Therapeutic-Chemistry (ATC) classification of drugs. For statistical measurements, beside common arithmetic means, geometric means were used which are less sensitive to extreme values of drug consumption. During comparative period drug consumption was chaotic with great oscillations around mean value, while in pilot study period that process was without great oscillations around lower mean value and did not exceed the limits of process. Drug consumption was completely under control, so it was a predictable process. In the pilot study period total drug consumption was 39% less, while consumption of drugs from group C was 30% less. During comparative period group C makes 34%, while in the pilot study period it makes 38% of the total drug consumption. This model of drug distribution in hospital leads to a rationalization of drug consumption and great savings. The pharmacist-physician interactive role began to emerge as a direct result of these changes in the drug distribution system. Hospital pharmacist has become a visible member of health care team who is responsible for Quality of all medication-related activities and thus has taken opportunity for clinical pharmacy practice. PMID:11040532

Vrca, V B; Bozikov, V; Crncec, M C; Sutli?, Z; Simi?, D; Becirevi?, M

22

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

23

Compliance Policy on Reporting Drug Sample Distribution ...  

Center for Biologics Evaluation and Research (CBER)

Text Version... 13 14 15 16 I. INTRODUCTION 17 18 Section 6004 of the Patient Protection and Affordable Care Act requires that manufacturers and 19 authorized ... More results from www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation

24

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

Code of Federal Regulations, 2010 CFR

...of drugs distributed under the Food, Drug and Cosmetic Act. 1310.10 Section 1310.10 Food and Drugs DRUG ENFORCEMENT ADMINISTRATION, DEPARTMENT OF JUSTICE RECORDS AND REPORTS OF LISTED...of drugs distributed under the Food, Drug and Cosmetic...

2010-04-01

25

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

Code of Federal Regulations, 2010 CFR

...of drugs distributed under the Food, Drug and Cosmetic Act. 1310.10 Section 1310.10 Food and Drugs DRUG ENFORCEMENT ADMINISTRATION, DEPARTMENT OF JUSTICE RECORDS AND REPORTS OF LISTED...of drugs distributed under the Food, Drug and Cosmetic...

2009-04-01

26

Maraviroc: in vitro assessment of drug-drug interaction potential  

PubMed Central

AIMS To characterize the cytochrome P450 enzyme(s) responsible for the N-dealkylation of maraviroc in vitro, and predict the extent of clinical drug–drug interactions (DDIs). METHODS Human liver and recombinant CYP microsomes were used to identify the CYP enzyme responsible for maraviroc N-dealkylation. Studies comprised enzyme kinetics and evaluation of the effects of specific CYP inhibitors. In vitro data were then used as inputs for simulation of DDIs with ketoconazole, ritonavir, saquinavir and atazanvir, using the Simcyp™ population-based absorption, distribution, metabolism and elimination (ADME) simulator. Study designs for simulations mirrored those actually used in the clinic. RESULTS Maraviroc was metabolized to its N-dealkylated product via a single CYP enzyme characterized by a Km of 21 µM and Vmax of 0.45 pmol pmol?1 min?1 in human liver microsomes and was inhibited by ketoconazole (CYP3A4 inhibitor). In a panel of recombinant CYP enzymes, CYP3A4 was identified as the major CYP responsible for maraviroc metabolism. Using recombinant CYP3A4, N-dealkylation was characterized by a Km of 13 µM and a Vmax of 3 pmol pmol?1 CYP min?1. Simulations therefore focused on the effect of CYP3A4 inhibitors on maraviroc pharmacokinetics. The simulated median AUC ratios were in good agreement with observed clinical changes (within twofold in all cases), although, in general, there was a trend for overprediction in the magnitude of the DDI. CONCLUSION Maraviroc is a substrate for CYP3A4, and exposure will therefore be modulated by CYP3A4 inhibitors. Simcyp™ has successfully simulated the extent of clinical interactions with CYP3A4 inhibitors, further validating this software as a good predictor of CYP-based DDIs. WHAT IS ALREADY KNOWN ABOUT THE SUBJECTMaraviroc is known to undergo oxidative metabolism in vivo and is a substrate for cytochrome P450 (CYP).Simcyp™ has recently become more widely used for the prediction of CYP-mediated drug–drug interactions (DDIs) using in vitro metabolism data. WHAT THIS STUDY ADDS Maraviroc has been identified as a CYP3A4 substrate and the kinetic constants characterized.The predicted DDIs associated with maraviroc as a CYP3A4 substrate using Simcyp™ have been compared against the clinical data.This study demonstrates the value of a reliable Simcyp™ model for prediction of DDIs.

Hyland, Ruth; Dickins, Maurice; Collins, Claire; Jones, Hannah; Jones, Barry

2008-01-01

27

Drugs in Thailand: Assessing Police Attitudes  

Microsoft Academic Search

This article examines the attitudes of Thai police regarding illegal drugs in the following areas: (a) drug-crime connections, (b) drug enforcement, (c) drug-related corruption, and (d) the seriousness of the drug problem The authors explore the effects of 16 independent variables on officers' attitudes derived from personal background indicators, institutional support measures, and drug offense information variables. Using data collected

Sutham Cheurprakobkit; Pomchai Kuntee; Michael S. Vauhgn

1998-01-01

28

Drug product distribution systems and departmental operations.  

PubMed

Technologies affecting institutional pharmacy practice and the operation of pharmacy departments are reviewed, future developments are outlined, and implications of these developments for pharmacy education are proposed. Computer technology, especially as applied to areas such as artificial intelligence, online information databases, electronic bulletin boards, hospital information systems, and point-of-care systems, will have a strong impact on pharmacy practice and management in the 1990s. Other areas in which growth is likely to be active include bar-code technology, robotics, and automated drug dispensing. The applications of these technologies are described, with particular attention placed on the effects of increased automation on the drug-dispensing function. Technological advances may effect marked reductions in dispensing and medication errors; questions concerning the cost-effectiveness of these new systems remain to be answered. These advances also create new opportunities for clinical involvement by pharmacists; however, a fundamental understanding of computer systems is essential. Current practitioners can benefit from attending seminars, participating in users' groups, and keeping current with the computer literature. Many students now acquire the needed skills in computer laboratories and in the classroom. Technological advances will offer the opportunity for pharmacists to expand their clinical role. PMID:1772111

Hynniman, C E

1991-10-01

29

Drug utilization 90% – a simple method for assessing the quality of drug prescribing  

Microsoft Academic Search

Objectives: To describe a simple method for assessing the quality of drug prescribing. Methods: We tested the idea that the number of drugs accounting for 90% of drug use – drug utilization 90% (DU90%) – may serve as\\u000a an indicator of the quality of drug prescribing. We ranked the drugs by volume of defined daily doses (DDD) and determined\\u000a how

U. Bergman; C. Popa; Y. Tomson; B. Wettermark; T. R. Einarson; H. Åberg; F. Sjöqvist

1998-01-01

30

Use of In Vivo Animal Models to Assess Pharmacokinetic Drug-Drug Interactions  

Microsoft Academic Search

Animal models are used commonly in various stages of drug discovery and development to aid in the prospective assessment of\\u000a drug-drug interaction (DDI) potential and the understanding of the underlying mechanism for DDI of a drug candidate. In vivo assessments in an appropriate animal model can be very valuable, when used in combination with in vitro systems, to help verify

Cuyue Tang; Thomayant Prueksaritanont

2010-01-01

31

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

Code of Federal Regulations, 2013 CFR

...products distributed under the Food, Drug and Cosmetic Act. 1310.11 Section 1310.11 Food and Drugs DRUG ENFORCEMENT...RECORDS AND REPORTS OF LISTED CHEMICALS AND CERTAIN MACHINES § 1310...products distributed under the Food, Drug and Cosmetic...

2013-04-01

32

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

Code of Federal Regulations, 2013 CFR

...distributed under the Federal Food, Drug and Cosmetic Act. 1310.10 Section 1310.10 Food and Drugs DRUG ENFORCEMENT...RECORDS AND REPORTS OF LISTED CHEMICALS AND CERTAIN MACHINES § 1310...distributed under the Federal Food, Drug and Cosmetic...

2013-04-01

33

13 CFR 147.210 - To whom must I distribute my drug-free workplace statement?  

Code of Federal Regulations, 2013 CFR

...To whom must I distribute my drug-free workplace statement? 147.210 ...GOVERNMENTWIDE REQUIREMENTS FOR DRUG-FREE WORKPLACE (NONPROCUREMENT) Requirements...whom must I distribute my drug-free workplace statement? You must...

2013-01-01

34

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

Code of Federal Regulations, 2013 CFR

...To whom must I distribute my drug-free workplace statement? 1267.210...GOVERNMENTWIDE REQUIREMENTS FOR DRUG-FREE WORKPLACE (FINANCIAL ASSISTANCE...whom must I distribute my drug-free workplace statement? You must...

2013-01-01

35

22 CFR 312.210 - To whom must I distribute my drug-free workplace statement?  

Code of Federal Regulations, 2013 CFR

...To whom must I distribute my drug-free workplace statement? 312.210 ...GOVERNMENTWIDE REQUIREMENTS FOR DRUG-FREE WORKPLACE (FINANCIAL ASSISTANCE...To whom must I distribute my drug-free workplace statement? You must...

2013-04-01

36

29 CFR 1472.210 - To whom must I distribute my drug-free workplace statement?  

Code of Federal Regulations, 2013 CFR

...To whom must I distribute my drug-free workplace statement? 1472.210...GOVERNMENTWIDE REQUIREMENTS FOR DRUG-FREE WORKPLACE (FINANCIAL ASSISTANCE...whom must I distribute my drug-free workplace statement? You must...

2013-07-01

37

21 CFR 1405.210 - To whom must I distribute my drug-free workplace statement?  

Code of Federal Regulations, 2013 CFR

...To whom must I distribute my drug-free workplace statement? 1405.210...GOVERNMENTWIDE REQUIREMENTS FOR DRUG-FREE WORKPLACE (FINANCIAL ASSISTANCE...To whom must I distribute my drug-free workplace statement? You must...

2013-04-01

38

2 CFR 182.210 - To whom must I distribute my drug-free workplace statement?  

Code of Federal Regulations, 2013 CFR

...To whom must I distribute my drug-free workplace statement? 182.210 ...GOVERNMENTWIDE REQUIREMENTS FOR DRUG-FREE WORKPLACE (FINANCIAL ASSISTANCE...whom must I distribute my drug-free workplace statement? You must...

2013-01-01

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22 CFR 133.210 - To whom must I distribute my drug-free workplace statement?  

Code of Federal Regulations, 2013 CFR

...To whom must I distribute my drug-free workplace statement? 133.210 ...GOVERNMENTWIDE REQUIREMENTS FOR DRUG-FREE WORKPLACE (FINANCIAL ASSISTANCE...To whom must I distribute my drug-free workplace statement? You must...

2013-04-01

40

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

Code of Federal Regulations, 2013 CFR

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

2013-07-01

41

29 CFR 94.210 - To whom must I distribute my drug-free workplace statement?  

Code of Federal Regulations, 2013 CFR

...To whom must I distribute my drug-free workplace statement? 94.210 Section...GOVERNMENTWIDE REQUIREMENTS FOR DRUG-FREE WORKPLACE (FINANCIAL ASSISTANCE...To whom must I distribute my drug-free workplace statement? You must...

2013-07-01

42

34 CFR 84.210 - To whom must I distribute my drug-free workplace statement?  

Code of Federal Regulations, 2013 CFR

...To whom must I distribute my drug-free workplace statement? 84.210 Section...GOVERNMENTWIDE REQUIREMENTS FOR DRUG-FREE WORKPLACE (FINANCIAL ASSISTANCE...To whom must I distribute my drug-free workplace statement? You...

2013-07-01

43

15 CFR 29.210 - To whom must I distribute my drug-free workplace statement?  

Code of Federal Regulations, 2013 CFR

...To whom must I distribute my drug-free workplace statement? 29.210 Section...GOVERNMENTWIDE REQUIREMENTS FOR DRUG-FREE WORKPLACE (FINANCIAL ASSISTANCE...whom must I distribute my drug-free workplace statement? You must...

2013-01-01

44

2 CFR 1401.310 - To whom must I distribute my drug-free workplace statement?  

Code of Federal Regulations, 2013 CFR

...To whom must I distribute my drug-free workplace statement? 1401.310...INTERIOR REQUIREMENTS FOR DRUG-FREE WORKPLACE (FINANCIAL ASSISTANCE...whom must I distribute my drug-free workplace statement? You must...

2013-01-01

45

32 CFR 26.210 - To whom must I distribute my drug-free workplace statement?  

Code of Federal Regulations, 2013 CFR

...To whom must I distribute my drug-free workplace statement? 26.210 Section...GOVERNMENTWIDE REQUIREMENTS FOR DRUG-FREE WORKPLACE (FINANCIAL ASSISTANCE...whom must I distribute my drug-free workplace statement? You must...

2013-07-01

46

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

Code of Federal Regulations, 2013 CFR

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

2013-07-01

47

22 CFR 1509.210 - To whom must I distribute my drug-free workplace statement?  

Code of Federal Regulations, 2013 CFR

...To whom must I distribute my drug-free workplace statement? 1509.210...GOVERNMENTWIDE REQUIREMENTS FOR DRUG-FREE WORKPLACE (FINANCIAL ASSISTANCE...To whom must I distribute my drug-free workplace statement? You must...

2013-04-01

48

22 CFR 1008.210 - To whom must I distribute my drug-free workplace statement?  

Code of Federal Regulations, 2013 CFR

...To whom must I distribute my drug-free workplace statement? 1008.210...GOVERNMENTWIDE REQUIREMENTS FOR DRUG-FREE WORKPLACE (FINANCIAL ASSISTANCE...To whom must I distribute my drug-free workplace statement? You must...

2013-04-01

49

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

Code of Federal Regulations, 2013 CFR

21 Food and Drugs 4 2013-04-01...50 Section 203.50 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED...GENERAL PRESCRIPTION DRUG MARKETING Wholesale Distribution...

2013-04-01

50

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

Code of Federal Regulations, 2010 CFR

...wholesale distribution of prescription drugs. 203.50 Section 203.50 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED...GENERAL PRESCRIPTION DRUG MARKETING Wholesale...

2009-04-01

51

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

Code of Federal Regulations, 2010 CFR

...wholesale distribution of prescription drugs. 203.50 Section 203.50 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED...GENERAL PRESCRIPTION DRUG MARKETING Wholesale...

2010-04-01

52

Pharmacological Mechanism-Based Drug Safety Assessment and Prediction  

Microsoft Academic Search

Advances in cheminformatics, bioinformatics, and pharmacology in the context of biological systems are now at a point that these tools can be applied to mechanism-based drug safety assessment and prediction. The development of such predictive tools at the US Food and Drug Administration (FDA) will complement ongoing efforts in drug safety that are focused on spontaneous adverse event reporting and

D R Abernethy; J Woodcock; L J Lesko; Abernethy

2011-01-01

53

Assessing Website Pharmacy Drug Quality: Safer Than You Think?  

PubMed Central

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

Bate, Roger; Hess, Kimberly

2010-01-01

54

National Drug Threat Assessment, 2005. Executive Summary.  

National Technical Information Service (NTIS)

The trafficking and abuse of illicit drugs and diverted pharmaceuticals pose a serious threat to the United States because of the adverse effects of drug abuse on the lives of millions of Americans and the substantial resources consumed in combating illic...

2005-01-01

55

Assessing Neurotoxicity of Drugs of Abuse.  

National Technical Information Service (NTIS)

The monograph is the result of a technical review meeting that was held May 20-21, 1991. The National Institute on Drug Abuse (NIDA) supports neurotoxicity research as part of its mandate to explore the consequences of drug abuse. During the course of the...

L. Erinoff

1993-01-01

56

California Southern District Drug Threat Assessment.  

National Technical Information Service (NTIS)

The California-Mexico border continues to be one of the most active drug smuggling corridors in the Southwest. Although only 7 percent of the length of the Southwest Border, the California portion accounted for about 18 percent of the drugs seized there i...

2000-01-01

57

Modelling Dermal Drug Distribution After Topical Application in Human  

Microsoft Academic Search

Purpose  To model and interpret drug distribution in the dermis and underlying tissues after topical application which is relevant\\u000a to the treatment of local conditions.\\u000a \\u000a \\u000a \\u000a \\u000a Methods  We created a new physiological pharmacokinetic model to describe the effect of blood flow, blood protein binding and dermal\\u000a binding on the rate and depth of penetration of topical drugs into the underlying skin. We used

Yuri G. Anissimov; Michael Stephen Roberts

58

Fourier transform Raman microscopic study of drug distribution in a transdermal drug delivery device  

Microsoft Academic Search

The mapping facility of a Fourier transform Raman microscope was used to construct a profile of oestradiol distribution in a transdermal drug delivery device (Hormone Replacement Therapy patch). Mapping was performed across a region of the patch which contained crystallised material for characterisation. The spectra acquired using the microscope facility were compared with those obtained of pure oestradiol and of

Clare L. Armstrong; Howell G. M. Edwards; Dennis W. Farwell; Adrian C. Williams

1996-01-01

59

Distribution and licensing of drug discovery tools--NIH perspectives.  

PubMed

Now, more than ever, drug discovery conducted at industrial or academic facilities requires rapid access to state-of-the-art research tools. Unreasonable restrictions or delays in the distribution or use of such tools can stifle new discoveries, thus limiting the development of future biomedical products. In grants and its own research programs the National Institutes of Health (NIH) is implementing its new policy to facilitate the exchanges of these tools for research discoveries and product development. PMID:12546842

Ferguson, Steven M; Kim, J P

2002-11-01

60

Distribution and licensing of drug discovery tools - NIH perspectives  

PubMed Central

Now, more than ever, drug discovery conducted at industrial or academic facilities requires rapid access to state-of-the-art research tools. Unreasonable restrictions or delays in the distribution or use of such tools can stifle new discoveries, thus limiting the development of future biomedical products. In grants and its own research programs the National Institutes of Health (NIH) is implementing its new policy to facilitate the exchanges of these tools for research discoveries and product development.

Kim, J. P.

2009-01-01

61

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

ERIC Educational Resources Information Center

|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, we examined whether craving and cognitions assessed during drug detoxification treatment were associated with…

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

2013-01-01

62

Absorption, distribution, metabolism and excretion pharmacogenomics of drugs of abuse.  

PubMed

Pharmacologic and toxic effects of xenobiotics, such as drugs of abuse, depend on the genotype and phenotype of an individual, and conversely on the isoenzymes involved in their metabolism and transport. The current knowledge of such isoenzymes of frequently abused therapeutics such as opioids (oxycodone, hydrocodone, methadone, fentanyl, buprenorphine, tramadol, heroin, morphine and codeine), anesthetics (?-hydroxybutyric acid, propofol, ketamine and phencyclidine) and cognitive enhancers (methylphenidate and modafinil), and some important plant-derived hallucinogens (lysergide, salvinorin A, psilocybin and psilocin), as well as of nicotine in humans are summarized in this article. The isoenzymes (e.g., cytochrome P450, glucuronyltransferases, esterases and reductases) involved in the metabolism of drugs and some pharmacokinetic data are discussed. The relevance of such data is discussed for predicting possible interactions with other xenobiotics, understanding pharmacokinetic behavior and pharmacogenomic variations, assessing toxic risks, developing suitable toxicological analysis procedures, and finally for interpretating drug testing results. PMID:21332315

Meyer, Markus R; Maurer, Hans H

2011-02-01

63

Assessment of drugs in schizophrenia. Asessment of drug-induced extrapyramidal reactions and of drugs given for their control.  

PubMed Central

I have tried to bring out some of the important methodological problems found in examining the effectiveness of drugs used in the control of druginduced parkinsonism by referring mainly to studies in which I have taken part. I hope I have shown that the whole topic is far less well understood than is often assumed. The main points may be summarized as follows: there is doubt as to whether many of the drugs used in controlling drug-induced parkinsonism are really effective; the results of many studies are conflicting; many studies contain serious flaws in design; methods for assessing extrapyramidal signs are not well developed; we are ignorant of the way in which drug-induced extrapyramidal signs change spontaneously. There is a clear need for further research in this area to improve techniques of assessment, to provide basic information on drug-induced syndromes, and to rigorously examine the efficacy of the drugs used in controlling them.

Mindham, R H

1976-01-01

64

Environmental risk assessment of pharmaceutical drug substances—conceptual considerations  

Microsoft Academic Search

Drugs, i.e. active ingredients of human medicinal products, may be introduced into the environment after use in patients by sewage effluent pathways and consequently are detected at low concentrations in sewage effluents and in surface waters. Legal requirements in a number of geographical regions (Europe, US, and intended in Canada) demand environmental risk assessments (ERA) for new drug substances. Existing

Reinhard Länge; Daniel Dietrich

2002-01-01

65

Assessing the Effects of Drug Use on Antisocial Behavior  

Microsoft Academic Search

Nonmedical drug taking and antisocial be havior are both complex, dynamic processes; consequently, the impact of these behaviors on each other is difficult to assess. Among the multiple factors to be considered are the pharmacological properties of the drug, the psychological characteristics of the individual, the social environment, and the various categories of antisocial behavior. Many methodological problems are inherent

Jared R. Tinklenberg

1975-01-01

66

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

2010-10-27

67

Sonophoresis for Rapid Assessment of Interstitial Fluid and Drug Delivery.  

National Technical Information Service (NTIS)

The general objective of the proposed studies was to develop sonophoresis as a platform technology for assessing interstitial fluid from the skin and perform transdermal drug delivery. In this method, a short application of low-frequency ultrasound is use...

S. Mitragotri

2007-01-01

68

78 FR 59308 - Antimicrobial Animal Drug Sales and Distribution Annual Summary Report Data Tables  

Federal Register 2010, 2011, 2012, 2013

...Docket No. FDA-2012-N-0447] Antimicrobial Animal Drug Sales and Distribution Annual Summary Report...collected from sponsors of antimicrobial new animal drugs in accordance with the new animal drug records and reporting provisions of...

2013-09-26

69

Assessing the effects of drugs on choice performance  

Microsoft Academic Search

Interest in how teaching interventions and drugs jointly affect performance has produced a demand for assessment methods that\\u000a are sensitive to both types of variables. An adequate assessment procedure needs to provide quantitative measures of the influence\\u000a of these variables on critical aspects of performance. Two critical aspects of performance that might be adversely affected\\u000a by drugs are motivation to

R. Don Tustin

1995-01-01

70

Ultrasound-Enhanced Drug Transport and Distribution in the Brain  

PubMed Central

Drug delivery in the brain is limited by slow drug diffusion in the brain tissue. This study tested the hypothesis that ultrasound can safely enhance the permeation of drugs in the brain. In vitro exposure to ultrasound at various frequencies (85 kHz, 174 kHz, and 1 MHz) enhanced the permeation of tritium-labeled molecules with molecular weight up to 70 kDa across porcine brain tissue. A maximum enhancement of 24-fold was observed at 85 kHz and 1,200 J/cm2. In vivo exposure to 1-MHz ultrasound further demonstrated the ability of ultrasound to facilitate molecule distribution in the brain of a non-human primate. Finally, ultrasound under conditions similar to those used in vivo was shown to cause no damage to plasmid DNA, siRNA, adeno-associated virus, and fetal rat cortical neurons over a range of conditions. Altogether, these studies demonstrate that ultrasound can increase drug permeation in the brain in vitro and in vivo under conditions that did not cause detectable damage.

Liu, Ying; Paliwal, Sumit; Bankiewicz, Krystof S.; Bringas, John R.; Heart, Gill

2010-01-01

71

Assessing drug target association using semantic linked data.  

PubMed

The rapidly increasing amount of public data in chemistry and biology provides new opportunities for large-scale data mining for drug discovery. Systematic integration of these heterogeneous sets and provision of algorithms to data mine the integrated sets would permit investigation of complex mechanisms of action of drugs. In this work we integrated and annotated data from public datasets relating to drugs, chemical compounds, protein targets, diseases, side effects and pathways, building a semantic linked network consisting of over 290,000 nodes and 720,000 edges. We developed a statistical model to assess the association of drug target pairs based on their relation with other linked objects. Validation experiments demonstrate the model can correctly identify known direct drug target pairs with high precision. Indirect drug target pairs (for example drugs which change gene expression level) are also identified but not as strongly as direct pairs. We further calculated the association scores for 157 drugs from 10 disease areas against 1683 human targets, and measured their similarity using a [Formula: see text] score matrix. The similarity network indicates that drugs from the same disease area tend to cluster together in ways that are not captured by structural similarity, with several potential new drug pairings being identified. This work thus provides a novel, validated alternative to existing drug target prediction algorithms. The web service is freely available at: http://chem2bio2rdf.org/slap. PMID:22859915

Chen, Bin; Ding, Ying; Wild, David J

2012-07-05

72

Assessing Drug Abuse Within and Across Communities: Community Epidemiology Surveillance Networks on Drug Abuse. Second Edition.  

National Technical Information Service (NTIS)

Drug abuse has devastating consequences on individual abusers, their families, their communities, and our Nation. The phenomenon is dynamic, constantly changing, and complex. Like other diseases, it is important to identify and assess the nature and exten...

2006-01-01

73

Heterogeneous distribution of Plasmodium falciparum drug resistance haplotypes in subsets of the host population  

Microsoft Academic Search

BACKGROUND: The emergence of drug resistance is a major problem in malaria control. For mathematical modelling of the transmission and spread of drug resistance the determinant parameters need to be identified and measured. The underlying hypothesis is that mutations associated with drug resistance incur fitness costs to the parasite in absence of drug pressure. The distribution of drug resistance haplotypes

Sonja Schoepflin; Jutta Marfurt; Mary Goroti; Moses Baisor; Ivo Mueller; Ingrid Felger

2008-01-01

74

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

75

Comparison of Fusion Imaging Using a Combined SPECT/CT System and Intra-arterial CT: Assessment of Drug Distribution by an Implantable Port System in Patients Undergoing Hepatic Arterial Infusion Chemotherapy  

SciTech Connect

Hepatic arterial infusion (HAI) chemotherapy is effective for treating primary and metastatic carcinoma of the liver. We compared the perfusion patterns of HAI chemotherapy on intra-arterial port-catheter computed tomography (iapc-CT) and fused images obtained with a combined single-photon emission computed tomography/computed tomography (SPECT/CT) system. We studied 28 patients with primary or metastatic carcinoma of the liver who bore an implantable HAI port system. All underwent abdominal SPECT using Tc-99m-MAA (185 Mbq); the injection rate was 1 mL/min, identical to the chemotherapy infusion rate, and 0.5 mL/sec for iapc-CT. Delivery was through an implantable port. We compared the intrahepatic perfusion (IHP) and extrahepatic perfusion (EHP) patterns of HAI chemotherapy on iapc-CT images and fused images obtained with a combined SPECT/CT system. In 23 of 28 patients (82%), IHP patterns on iapc-CT images and fused images were identical. In 5 of the 28 patients (18%), IHP on fusion images was different from IHP on iapc-CT images. EHP was seen on fused images in 12 of the 28 patients (43%) and on iapc-CT images in 8 patients (29%). In 17 patients (61%), upper gastrointestinal endoscopy revealed gastroduodenal mucosal lesions. EHP was revealed on fused images in 10 of these patients; 9 of them manifested gastroduodenal toxicity at the time of subsequent HAI chemotherapy. Fusion imaging using the combined SPECT/CT system reflects the actual distribution of the infused anticancer agent. This information is valuable not only for monitoring adequate drug distribution but also for avoiding potential extrahepatic complications.

Ikeda, Osamu, E-mail: osamu-3643ik@do9.enjoy.ne.jp; Kusunoki, Shinichiroh; Nakaura, Takeshi; Shiraishi, Shinya; Kawanaka, Kouichi; Tomiguchi, Seiji; Yamashita, Yasuyuki [Kumamoto University Graduate School of Medical and Pharmaceutical Sciences, Department of Diagnostic Radiology (Japan); Takamori, Hiroshi; Chikamoto, Akira; Kanemitsu, Keiichiro [Kumamoto University Graduate School of Medical and Pharmaceutical Sciences, Gastroenterological Surgery (Japan)

2006-06-15

76

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

2013-03-21

77

An algorithm for evaluating potential tissue drug distribution in toxicology studies from readily available pharmacokinetic parameters.  

PubMed

Having an understanding of drug tissue accumulation can be informative in the assessment of target organ toxicities; however, obtaining tissue drug levels from toxicology studies by bioanalytical methods is labor-intensive and infrequently performed. Additionally, there are no described methods for predicting tissue drug distribution for the experimental conditions in toxicology studies, which typically include non-steady-state conditions and very high exposures that may saturate several processes. The aim was the development of an algorithm to provide semiquantitative and quantitative estimates of tissue-to-plasma concentration ratios (Kp ) for several tissues from readily available parameters of pharmacokinetics (PK) such as volume of distribution (Vd ) and clearance of each drug, without performing tissue measurement in vivo. The computational approach is specific for the oral route of administration and non-steady-state conditions and was applied for a dataset of 29 Genentech small molecules such as neutral compounds as well as weak and strong organic bases. The maximum success rate in predicting Kp values within 2.5-fold error of observed Kp values was 82% at low doses (<100 mg/kg) in preclinical species. Prediction accuracy was relatively lower with saturation at high doses (?100 mg/kg); however, an approach to perform low-to-high dose extrapolations of Kp values was presented and applied successfully in most cases. An approach for the interspecies scaling was also applied successfully. Finally, the proposed algorithm was used in a case study and successfully predicted differential tissue distribution of two small-molecule MET kinase inhibitors, which had different toxicity profiles in mice. This newly developed algorithm can be used to predict the partition coefficients Kp for small molecules in toxicology studies, which can be leveraged to optimize the PK drivers of tissue distribution in an attempt to decrease drug tissue level, and improve safety margins. © 2013 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 102:3816-3829, 2013. PMID:23878104

Poulin, Patrick; Dambach, Donna M; Hartley, Dylan H; Ford, Kevin; Theil, Frank-Peter; Harstad, Eric; Halladay, Jason; Choo, Edna; Boggs, Jason; Liederer, Bianca M; Dean, Brian; Diaz, Dolores

2013-07-22

78

The Results of the Roadside Drug Testing Assessment Project  

Microsoft Academic Search

The 21-mo Roadside Testing Assessment (ROSITA) project started in January 1999 and included a literature survey of drugs and\\u000a medicines that have detrimental impacts on road users’ performance, an inventory of the available roadside drug-testing equipment\\u000a for urine, oral fluid, and sweat, an evaluation of the operational, user, and legal requirements for roadside testing equipment\\u000a in the different European Union

Alain G. Verstraete

79

Predictive computational toxicology to support drug safety assessment.  

PubMed

Use of predictive technologies is an important aspect of many efforts in today's research, development, and regulatory landscapes. Computational methods as predictive tools for supporting drug safety assessments is of widespread interest as the field of in silico assessments rapidly changes with emerging technologies and the large amount of existing data available for modeling. There are challenges associated with application of in silico analyses for drug toxicity predictions and need for strategies and harmonization to enable an acceptable in silico evaluation for prediction of specific toxicity assay outcomes. This chapter will provide an overview focused on computational tools using structure-activity relationships and will highlight initiatives for use of computational assessments and realistic applications for predictive modeling in evaluating potential toxicities of drug-related molecules. PMID:23086849

Valerio, Luis G

2013-01-01

80

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.

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

2012-01-01

81

Assessing the impact of distributed generation on distribution network costs  

Microsoft Academic Search

The support of electricity generation from renewable energy sources (RES) and combined heat and power (CHP) has led to increasing penetration levels of distributed generation (DG). Nevertheless, Large-scale connection of DG faces numerous regulatory, economic, social and technological challenges. Distribution networks were not originally designed to accommodate generation. Hence, distribution system operators (DSOs) face great uncertainties about the impacts of

Rafael Cossent; Tomas Gomez; Luis Olmos; Carlos Mateo; Pablo Frias

2009-01-01

82

The brain slice method for studying drug distribution in the CNS  

PubMed Central

The high-throughput brain slice method is a precise and robust technique for estimating the overall uptake of drugs into brain tissue through determination of the unbound volume of distribution in the brain (Vu,brain; ml·g brain-1). Vu,brain describes the relationship between the total drug concentration in the brain and the concentration of unbound drug in the brain interstitial fluid, regardless of blood–brain barrier function. The brain slice method is more physiologically based than the brain homogenate method with respect to the assessment of drug distribution in the brain because the cell-cell interactions, pH gradients and active transport systems are all conserved. The method provides information that is directly relevant to issues such as nonspecific binding to brain tissue, lysosomal trapping, and active uptake into the cells. For these reasons, the brain slice method is recommended for estimation of target-site pharmacokinetics in the early drug discovery process and fundamental pharmacological studies. This article provides a detailed protocol for the rat and mouse brain slice methods, with the aim of enabling simple, cost-effective profiling of compounds with diverse physicochemical properties. The procedure for assessing the viability of the brain slices after the 5 h incubation period is also described. The results are interpreted for a set of compounds covering a wide range of physicochemical properties and various pharmacological targets. Application of the method for evaluating the unbound intracellular-to-extracellular concentration ratio (Kp,uu,cell) and the unbound brain-to-plasma concentration ratio (Kp,uu,brain) is discussed.

2013-01-01

83

Drug-likeness analysis of traditional Chinese medicines: 1. property distributions of drug-like compounds, non-drug-like compounds and natural compounds from traditional Chinese medicines  

PubMed Central

Background In this work, we analyzed and compared the distribution profiles of a wide variety of molecular properties for three compound classes: drug-like compounds in MDL Drug Data Report (MDDR), non-drug-like compounds in Available Chemical Directory (ACD), and natural compounds in Traditional Chinese Medicine Compound Database (TCMCD). Results The comparison of the property distributions suggests that, when all compounds in MDDR, ACD and TCMCD with molecular weight lower than 600 were used, MDDR and ACD are substantially different while TCMCD is much more similar to MDDR than ACD. However, when the three subsets of ACD, MDDR and TCMCD with similar molecular weight distributions were examined, the distribution profiles of the representative physicochemical properties for MDDR and ACD do not differ significantly anymore, suggesting that after the dependence of molecular weight is removed drug-like and non-drug-like molecules cannot be effectively distinguished by simple property-based filters; however, the distribution profiles of several physicochemical properties for TCMCD are obviously different from those for MDDR and ACD. Then, the performance of each molecular property on predicting drug-likeness was evaluated. No single molecular property shows good performance to discriminate between drug-like and non-drug-like molecules. Compared with the other descriptors, fractional negative accessible surface area (FASA-) performs the best. Finally, a PCA-based scheme was used to visually characterize the spatial distributions of the three classes of compounds with similar molecular weight distributions. Conclusion If FASA- was used as a drug-likeness filter, more than 80% molecules in TCMCD were predicted to be drug-like. Moreover, the principal component plots show that natural compounds in TCMCD have different and even more diverse distributions than either drug-like compounds in MDDR or non-drug-like compounds in ACD.

2012-01-01

84

Drug enforcement's doubleedged sword: An assessment of asset forfeiture programs  

Microsoft Academic Search

This paper presents the first ethnographic examination of asset forfeiture during the drug war era. The study is based on 12 months of covert participant observation, in which one of the authors assumed the role of confidential informant in undercover narcotics operations in a southern state. Contemporary methods of narcotics policing are assessed at two vital points: case selection and

J. Mitchell Miller; Lance H. Selva

1994-01-01

85

Assess Epithelial Permeability of Drugs from Pharmaceutical Formulations  

Microsoft Academic Search

The following chapter gives an overview of instrumented approaches to investigate the interactions of orally or pulmonary administered formulations with epithelial cell cultures in vitro. The first section is focused on the combined assessment of drug release\\/dissolution and subsequent absorp- tion\\/permeation for solid oral dosage forms. Experimental approaches to mimic the complex physiologically surroundings in the gastrointestinal tract are pre-

Stephan A. Motz; Michael Bur; Ulrich F. Schaefer; Claus-Michael Lehr

86

Mental Health, Alcohol and Drug Abuse Needs Assessment Report.  

National Technical Information Service (NTIS)

A mental health, alcohol, and drug abuse (MHADA) needs assessment study was conducted from July 1979 through May 1980 in southern New Jersey. Study goals were to determine the prevalence of MHADA problems among the service area's population, to evaluate t...

1980-01-01

87

Assessing the Influence of Need to Inject and Drug Withdrawal on Drug Injectors' Perceptions of HIV Risk Behavior  

Microsoft Academic Search

This article aims to assess the influence of the need to inject and drug withdrawal on drug injectors' perceptions of human immunodeficiency virus (HIV) risk behavior inside and outside prison. Complementary qualitative research methods were used with 24 drug injectors in England. It was found that when sterile injecting equipment was unavailable the need to inject and drug withdrawal were

Rhidian A. Hughes

2001-01-01

88

Evaluating the roles of autophagy and lysosomal trafficking defects in intracellular distribution-based drug-drug interactions involving lysosomes.  

PubMed

Many currently approved drugs possess weakly basic properties that make them substrates for extensive sequestration in acidic intracellular compartments such as lysosomes through an ion trapping-type mechanism. Lysosomotropic drugs often have unique pharmacokinetic properties that stem from the extensive entrapment in lysosomes, including an extremely large volume of distribution and a long half-life. Accordingly, pharmacokinetic drug-drug interactions can occur when one drug modifies lysosomal volume such that the degree of lysosomal sequestration of secondarily administered drugs is significantly altered. In this work, we have investigated potential mechanisms for drug-induced alterations in lysosomal volume that give rise to drug-drug interactions involving lysosomes. We show that eight hydrophobic amines, previously characterized as perpetrators in this type of drug-drug interaction, cause a significant expansion in lysosomal volume that was correlated with both the induction of autophagy and with decreases in the efficiency of lysosomal egress. We also show that well-known chemical inducers of autophagy caused an increase in apparent lysosomal volume and an increase in secondarily administered lysosomotropic drugs without negatively impacting vesicle-mediated lysosomal egress. These results could help rationalize how the induction of autophagy could cause variability in the pharmacokinetic properties of lysosomotropic drugs. © 2013 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 102:4173-4180, 2013. PMID:23970383

Logan, Randall; Kong, Alex; Krise, Jeffrey P

2013-08-22

89

41 CFR 105-74.210 - To whom must I distribute my drug-free workplace statement?  

Code of Federal Regulations, 2013 CFR

...To whom must I distribute my drug-free workplace statement? 105-74.210...74-GOVERNMENTWIDE REQUIREMENTS FOR DRUG-FREE WORKPLACE (FINANCIAL ASSISTANCE...whom must I distribute my drug-free workplace statement? You must...

2013-01-01

90

Biopsy assessment of drug efficacy in the gastrointestinal tract  

PubMed Central

When using biopsy pathology in clinical pharmacology to assess drug efficacy in the gastrointestinal tract, a number of questions must be answered: Is the biopsy necessary or more effective than macroscopic views by endoscopy? Can we extract maximal information from the specimen? Are there surrogate serum or other markers that give an overall measure of disease and/or improvement? Indeed, clinicopathological correlation is of paramount importance. If biopsy is to be used, it is important to utilize appropriate scoring systems. Many grading systems use continuous spectra, which are ordinal categorical variables and therefore a grading system of assigned ‘numbers’ which cannot be used in processes that require continuous variables such as linear regression. The use of grading vs a ‘true’ score with real numbers must be carefully considered, the site and number of biopsies must be precisely chosen and interobserver reproducibility of results evaluated before undertaking drug trials. Immunocytochemistry and in situ hybridization, however, can provide quantifiable molecular information related to mechanisms of drug action. The biopsy is of significant value as it is a true in vivo assessment if the above caveats are taken into account. However, further work is needed to determine sound histological criteria to assess the efficacy of drugs for use in gastrointestinal disease.

Walker, Marjorie M

2003-01-01

91

Critical Assessment of Implantable Drug Delivery Devices in Glaucoma Management  

PubMed Central

Glaucoma is a group of heterogeneous disorders involving progressive optic neuropathy that can culminate into visual impairment and irreversible blindness. Effective therapeutic interventions must address underlying vulnerability of retinal ganglion cells (RGCs) to degeneration in conjunction with correcting other associated risk factors (such as elevated intraocular pressure). However, realization of therapeutic outcomes is heavily dependent on suitable delivery system that can overcome myriads of anatomical and physiological barriers to intraocular drug delivery. Development of clinically viable sustained release systems in glaucoma is a widely recognized unmet need. In this regard, implantable delivery systems may relieve the burden of chronic drug administration while potentially ensuring high intraocular drug bioavailability. Presently there are no FDA-approved implantable drug delivery devices for glaucoma even though there are several ongoing clinical studies. The paper critically assessed the prospects of polymeric implantable delivery systems in glaucoma while identifying factors that can dictate (a) patient tolerability and acceptance, (b) drug stability and drug release profiles, (c) therapeutic efficacy, and (d) toxicity and biocompatibility. The information gathered could be useful in future research and development efforts on implantable delivery systems in glaucoma.

Manickavasagam, Dharani; Oyewumi, Moses O.

2013-01-01

92

7 CFR 1230.74 - Prohibited use of distributed assessments.  

Code of Federal Regulations, 2012 CFR

7 Agriculture 10 2012-01-01...false Prohibited use of distributed assessments...Section 1230.74 Agriculture Regulations of...DEPARTMENT OF AGRICULTURE PORK PROMOTION...74 Prohibited use of distributed...

2012-01-01

93

Risk Assessment of Mechanism-Based Inactivation in Drug-Drug Interactions  

PubMed Central

Drug-drug interactions (DDIs) that occur via mechanism-based inactivation of cytochrome P450 are of serious concern. Although several predictive models have been published, early risk assessment of MBIs is still challenging. For reversible inhibitors, the DDI risk categorization using [I]/Ki ([I], the inhibitor concentration; Ki, the inhibition constant) is widely used in drug discovery and development. Although a simple and reliable methodology such as [I]/Ki categorization for reversible inhibitors would be useful for mechanism-based inhibitors (MBIs), comprehensive analysis of an analogous measure reflecting in vitro potency for inactivation has not been reported. The aim of this study was to evaluate whether the term ?/kdeg (?, first-order inactivation rate at a given MBI concentration; kdeg, enzyme degradation rate constant) would be useful in the prediction of the in vivo DDI risk of MBIs. Twenty-one MBIs with both in vivo area under the curve (AUC) change of marker substrates and in vitro inactivation parameters were identified in the literature and analyzed. The results of this analysis show that in vivo DDIs with >2-fold change of object drug AUC can be identified with the cutoff value of ?/kdeg = 1, where unbound steady-state Cmax is used for inhibitor concentration. However, the use of total Cmax led to great overprediction of DDI risk. The risk assessment using ?/kdeg coupled with unbound Cmax can be useful for the DDI risk evaluation of MBIs in drug discovery and development.

Fujioka, Yasushi; Kunze, Kent L.

2012-01-01

94

Herb-drug interactions: Review and assessment of report reliability  

PubMed Central

Aims The aim of this systematic review was to assess the published clinical evidence on interactions between herbal and conventional drugs. Methods Four electronic databases were searched for case reports, case series or clinical trials of such interactions. The data were extracted and validated using a scoring system for interaction probability. Results One hundred and eight cases of suspected interactions were found. 68.5% were classified as ‘unable to be evaluated’, 13% as ‘well-documented’ and 18.5% as ‘possible’ interactions. Warfarin was the most common drug (18 cases) and St John's wort the most common herb (54 cases) involved. Conclusion Herb–drug interactions undoubtedly do occur and may put individuals at risk. However our present knowledge is incomplete and more research is urgently needed.

Fugh-Berman, Adriane; Ernst, E

2001-01-01

95

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

96

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

97

77 FR 59156 - Antimicrobial Animal Drug Sales and Distribution Reporting; Extension of Comment Period  

Federal Register 2010, 2011, 2012, 2013

...Docket No. FDA-2012-N-0447] Antimicrobial Animal Drug Sales and Distribution...to records and reports for approved antimicrobial new animal drugs. The Agency is taking...and information about the extent of antimicrobial drug use in food-producing...

2012-09-26

98

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

Federal Register 2010, 2011, 2012, 2013

...Agency's implementation of the drug sample transparency reporting provisions...Compliance Policy on Reporting Drug Sample Distribution Information...the submission of certain drug sample information to FDA not later...notifies covered entities that FDA plans to use its Electronic...

2012-04-03

99

Social Marketing of Anti-Drug Messages: Keeping the Parental Distribution Channel Open  

Microsoft Academic Search

Social marketing campaigns targeting parents of young people encourage parents to act as a social marketing distribution channel, providing messages about drug use to their children. For parents to be effective distribution channels they must be seen as a credible source of information on drug issues. Eight focus groups were conducted with male and female groups (18-24 years old) in

Fiona Perman; Nadine Henley

2002-01-01

100

Ultrasound-Enhanced Drug Transport and Distribution in the Brain  

Microsoft Academic Search

Drug delivery in the brain is limited by slow drug diffusion in the brain tissue. This study tested the hypothesis that ultrasound\\u000a can safely enhance the permeation of drugs in the brain. In vitro exposure to ultrasound at various frequencies (85 kHz, 174 kHz, and 1 MHz) enhanced the permeation of tritium-labeled molecules\\u000a with molecular weight up to 70 kDa across porcine brain tissue.

Ying Liu; Sumit Paliwal; Krystof S. Bankiewicz; John R. Bringas; Gill Heart; Samir Mitragotri; Mark R. Prausnitz

2010-01-01

101

Control of antibiotic use by a unit-dose drug distribution system  

Microsoft Academic Search

The aim of the study was to test a new model of drug distribution known as unit-dose drug distribution including the effects\\u000a of implementing this system on total drug consumption, especially in curbing antimicrobial use.\\u000a \\u000a The study was carried out in the Department of Surgery at the University Clinical Center in Nis, Serbia. During the first\\u000a six months of the

Karin Vasic; Zorica Jovic; Gordana Pesic

2007-01-01

102

Physics and instrumentation for imaging in-vivo drug distribution  

Microsoft Academic Search

Several imaging methods are currently available to measure drugs noninvasively. Of these, two techniques are today central to such measurements: nuclear imaging and magnetic resonance imaging\\/spectroscopy (MRI and MRS). While other methods, such as optical techniques, are rapidly gaining in interest, they have not yet attained the degree of development that makes them effective in measuring drugs in living systems,

Manbir Singh; Victor Waluch

2000-01-01

103

Mental models in risk assessment: informing people about drugs.  

PubMed

One way to communicate about the risks of drugs is through the use of package inserts. The problems associated with this medium of informing patients have been investigated by several researchers who found that people require information about drugs they are using, including extensive risk information, and that they are willing to take this information into account in their usage of drugs. But empirical results also show that people easily misinterpret the information given. A conceptual framework is proposed that might be used for better understanding the cognitive processes involved in such a type of risk assessment and communication. It is based on the idea that people develop, through experience, a mental model of how a drug works, which effects it might produce, that contraindications have to be considered, etc. This mental model is "run" when a specific package insert has been read and a specific question arises such as, for example, whether certain symptoms can be explained as normal or whether they require special attention and action. We argue that the mental model approach offers a useful perspective for examining how people understand package inserts, and consequently for improving their content and design. The approach promises to be equally useful for other aspects of risk analysis that are dependent upon human judgment and decision making, e.g., threat diagnosis and human reliability analysis. PMID:3375502

Jungermann, H; Schütz, H; Thüring, M

1988-03-01

104

Drug safety assessment in clinical trials: methodological challenges and opportunities  

PubMed Central

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.

2012-01-01

105

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

2013-02-21

106

Novel approach to in vitro drug susceptibility assessment of clinical strains of Leishmania spp.  

PubMed

Resistance to antimonial drugs has been documented in Leishmania isolates transmitted in South America, Europe, and Asia. The frequency and distribution of resistance to these and other antileishmanial drugs are unknown. Technical constraints have limited the assessment of drug susceptibility of clinical strains of Leishmania. Susceptibility of experimentally selected lines and 130 clinical strains of Leishmania panamensis, L. braziliensis, and L. guyanensis to meglumine antimoniate and miltefosine was determined on the basis of parasite burden and percentage of infected U-937 human macrophages. Reductions of infection at single predefined concentrations of meglumine antimoniate and miltefosine and 50% effective doses (ED(50)s) were measured and correlated. The effects of 34°C and 37°C incubation temperatures and different parasite-to-host cell ratios on drug susceptibility were evaluated at 5, 10, and 20 parasites/cell. Reduction of the intracellular burden of Leishmania amastigotes in U-937 cells exposed to the predefined concentrations of meglumine antimoniate or miltefosine discriminated sensitive and experimentally derived resistant Leishmania populations and was significantly correlated with ED(50) values of clinical strains (for meglumine antimoniate, ? = -0.926 and P < 0.001; for miltefosine, ? = -0.906 and P < 0.001). Incubation at 37°C significantly inhibited parasite growth compared to that at 34°C in the absence of antileishmanial drugs and resulted in a significantly lower ED(50) in the presence of drugs. Susceptibility assessment was not altered by the parasite-to-cell ratio over the range evaluated. In conclusion, measurement of the reduction of parasite burden at a single predetermined drug concentration under standardized conditions provides an efficient and reliable strategy for susceptibility evaluation and monitoring of clinical strains of Leishmania. PMID:22518860

Fernández, Olga; Diaz-Toro, Yira; Valderrama, Liliana; Ovalle, Clemencia; Valderrama, Mabel; Castillo, Harry; Perez, Mauricio; Saravia, Nancy Gore

2012-04-18

107

Use of Medication Guides to Distribute Drug Risk Information ...  

Center for Drug Evaluation (CDER)

Text Version... Warranty $130-220 Annually Lexmark *Administrative cost applied to cover the expense incurred during acquisition, delivery, and storage of ... More results from www.fda.gov/downloads/drugs/drugsafety

108

Dependable distributed embedded system assessment platform design  

Microsoft Academic Search

Dependable distributed embedded systems (DDES) are being deployed widely in automobile industry over the world. These systems always post rigorous requirement for timing accuracy and reliability. Both hardware and software architecture have important effect on the system dependability. Adding or substitute for more reliable hardware could increase the system reliability moreover achieves faster system response. Apparently this would increase the

Huang Qiang; Liang XiaoFeng; Zhu YingYing

2007-01-01

109

The Development of a Test to Assess Drug Using Behavior.  

ERIC Educational Resources Information Center

|The objective of the study was to develop a test which could measure both the qualitative and quantitative aspects of drug-using behavior, including such factors as attitudes toward drugs, experience with drugs, and knowledge about drugs. The Drug Use Scale was developed containing 134 items and dealing with five classes of drugs: marijuana,…

Althoff, Michael E.

110

Data Mining On Distributed Assessment System  

Microsoft Academic Search

A final year project where a data mining module and an on-line assessment system were developed. The data mining module was developed based on a decision tree algorithm. The Decision algorithm has been used widely and successfully in many areas of data mining and knowledge discovery. Examples are the location of protein coding in human DNA (1), data analysis and

T. T. GOH; E. E. KWAN

2000-01-01

111

Assessment of distributed arterial network models  

Microsoft Academic Search

The aim of this study is to evaluate the relative importance of elastic non-linearities, viscoelasticity and resistance vessel\\u000a modelling on arterial pressure and flow wave contours computed with distributed arterial network models. The computational\\u000a results of a non-linear (time-domain) and a linear (frequency-domain) mode were compared using the same geometrical configuration\\u000a and identical upstream and downstream boundary conditions and mechanical

P. Segers; N. Stergiopulos; P. Verdonck; R. Verhoeven

1997-01-01

112

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

Code of Federal Regulations, 2013 CFR

...procedures for the control of distribution of PET drug products shipped from the PET drug production facility to ensure that the method of shipping chosen will not adversely affect the identity, purity, or quality of the PET drug product. (b)...

2013-04-01

113

Microsphere size, precipitation kinetics and drug distribution control drug release from biodegradable polyanhydride microspheres  

Microsoft Academic Search

A thorough understanding of the factors affecting drug release mechanisms from surface-erodible polymer devices is critical to the design of optimal delivery systems. Poly(sebacic anhydride) (PSA) microspheres were loaded with three model drug compounds (rhodamine B, p-nitroaniline and piroxicam) with a range of polarities (water solubilities). The drug release profiles from monodisperse particles of three different sizes were compared to

Cory Berkland; Matt J. Kipper; Balaji Narasimhan; Daniel W. Pack

2004-01-01

114

Membrane vesicle ABC transporter assays for drug safety assessment.  

PubMed

The use of plasma membrane vesicles that overexpress the bile salt export pump (BSEP) or multidrug resistance-associated protein 2, 3, or 4 (MRP2-4) with an in vitro vacuum filtration system offers a rapid and reliable means for screening drug candidates for their effects on transporter function in hepatocytes and thus their potential for causing drug-induced liver injury (DILI). Comparison of transporter activity in the presence and absence of ATP allows for determination of a specific assay window for each transporter. This window is used to determine the degree to which each test compound inhibits transporter activity. This assay battery is helpful for prioritizing and rank-ordering compounds within a chemical series with respect to each other and in the context of known inhibitors of transporter activity and/or liver injury. This model can be used to influence the drug development process at an early stage and provide rapid feedback regarding the selection of compounds for advancement to in vivo safety evaluations. A detailed protocol for the high-throughput assessment of ABC transporter function is provided, including specific recommendations for curve-fitting to help ensure consistent results. PMID:23169270

van Staden, Carlo J; Morgan, Ryan E; Ramachandran, Bharath; Chen, Yuan; Lee, Paul H; Hamadeh, Hisham K

2012-11-01

115

Developability assessment of clinical drug products with maximum absorbable doses.  

PubMed

Maximum absorbable dose refers to the maximum amount of an orally administered drug that can be absorbed in the gastrointestinal tract. Maximum absorbable dose, or D(abs), has proved to be an important parameter for quantifying the absorption potential of drug candidates. The purpose of this work is to validate the use of D(abs) in a developability assessment context, and to establish appropriate protocol and interpretation criteria for this application. Three methods for calculating D(abs) were compared by assessing how well the methods predicted the absorption limit for a set of real clinical candidates. D(abs) was calculated for these clinical candidates by means of a simple equation and two computer simulation programs, GastroPlus and an program developed at Eli Lilly and Company. Results from single dose escalation studies in Phase I clinical trials were analyzed to identify the maximum absorbable doses for these compounds. Compared to the clinical results, the equation and both simulation programs provide conservative estimates of D(abs), but in general D(abs) from the computer simulations are more accurate, which may find obvious advantage for the simulations in developability assessment. Computer simulations also revealed the complex behavior associated with absorption saturation and suggested in most cases that the D(abs) limit is not likely to be achieved in a typical clinical dose range. On the basis of the validation findings, an approach is proposed for assessing absorption potential, and best practices are discussed for the use of D(abs) estimates to inform clinical formulation development strategies. PMID:22349050

Ding, Xuan; Rose, John P; Van Gelder, Jan

2012-02-13

116

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.

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

2013-01-01

117

Integration of distributed computing into the drug discovery process.  

PubMed

Grid computing offers an opportunity to gain massive computing power at low costs. We give a short introduction into the drug discovery process and exemplify the use of grid computing for image processing, docking and 3D pharmacophore descriptor calculations. The principle of a grid and its architecture are briefly explained. More emphasis is laid on the issues related to a company-wide grid installation and embedding the grid into the research process. The future of grid computing in drug discovery is discussed in the expert opinion section. Most needed, besides reliable algorithms to predict compound properties, is embedding the grid seamlessly into the discovery process. User friendly access to powerful algorithms without any restrictions, that is, by a limited number of licenses, has to be the goal of grid computing in drug discovery. PMID:22647131

von Korff, Modest; Rufener, Christian; Stritt, Manuel; Freyss, Joel; Bär, Roman; Sander, Thomas

2010-11-19

118

Nurse Resource Service Distribution Assessment (NRSDA) Model Systems Documentation.  

National Technical Information Service (NTIS)

The components of the Online Model System (OMS) of the Nurse Resource Service Distribution Assessment (NSRDA) Model are described. The OMS consists of four COBOL computer programs and a subsystem stored at the National Institutes of Health Department of C...

1978-01-01

119

Drug policy in China: pharmaceutical distribution in rural areas  

Microsoft Academic Search

In 1978, China decided to reform its economy and since then has gradually opened up to the world. The economy has grown rapidly at an average of 9.8% per year from 1978 to 1994. Medical expenditure, especially for drugs, has grown even more rapidly. The increase in medical expenditure can be attributed to changing disease patterns, a higher proportion of

Hengjin Dong; Lennart Bogg; Clas Rehnberg; Vinod Diwan

1999-01-01

120

Connecting Patients With Specialty Products: Part 2: The future of specialty drug distribution.  

PubMed

Previously, this series described distribution channels through which specialty drugs move to patients. This installment discusses changes and challenges that lie ahead, especially at the dispensing end. PMID:23091429

McCain, Jack

2012-01-01

121

Imaging Mass Spectrometry for Visualization of Drug and Endogenous Metabolite Distribution: Toward In Situ Pharmacometabolomes  

Microsoft Academic Search

It is important to determine how a candidate drug is distributed and metabolized within the body in early phase of drug discovery.\\u000a Recently, matrix-assisted laser desorption\\/ionization (MALDI) imaging mass spectrometry (IMS; also referred to as mass spectrometry\\u000a imaging) has attracted great interest for monitoring drug delivery and metabolism. Since this emerging technique enables simultaneous\\u000a imaging of many types of metabolite

Yuki Sugiura; Mitsutoshi Setou

2010-01-01

122

Assessment of distributed photovoltaic electric-power systems. Final report  

Microsoft Academic Search

The purpose of this study was to develop a methodology for assessing 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. The investigations focused upon five specific utilities. Three were actual planned future systems for Northeast Utilities Service Company, Alabama Power Company, and

R. W. Neal; P. F. DeDuck; R. N. Marshall

1982-01-01

123

Assessment of distributed photovoltaic electric-power systems. Summary report  

Microsoft Academic Search

The purpose of this study was to develop a methodology for assessing 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. The investigations focused upon five specific utilities. Three were actual planned future systems for Northeast Utilities Service Company, Alabama Power Company, and

R. W. Neal; P. F. DeDuck; R. N. Marshall

1982-01-01

124

Drug Distribution: A Guided-Inquiry Laboratory Experiment in Coupled Homogeneous and Heterogeneous Equilibria  

Microsoft Academic Search

A simple and inexpensive experiment for the study of simultaneous homogeneous and heterogeneous equilibria is described using a common antihistamine drug, diphenhydramine. This experiment gives students an opportunity to study the distribution of a drug in a two-phase system by measuring the concentrations of two chemical species and predicting the others by considering charge balance, mass balance, and equilibrium constant

John Hein; Michael Jeannot

2001-01-01

125

Cost of drugs wasted in the multiple-dose drug distribution system in long-term-care facilities.  

PubMed

The potential cost of discarding unused drugs packaged in multiple-dose containers for patients in long-term-care facilities (LTCFs) was studied. Data were collected during 1982-83 for patients in 12 LTCFs in the state of Washington that used modified unit dose drug distribution systems. When drugs were supplied in multiple-dose containers--by the Veterans Administration, a health maintenance organization, or another pharmacy--for patients in the LTCFs, the pharmacy providing services to the LTCFs routinely repackaged these drugs for unit dose distribution to these patients. The number of drug doses per month administered to all patients in each LTCF was recorded. The numbers of patients with multiple-dose prescriptions and the numbers of those whose medications were changed or discontinued were recorded, and the dollar value of the unused drugs, which would have been wasted if these patients' medications had been dispensed in multiple-dose containers, was calculated based on average wholesale prices. Based on approximately 100 patients per month for whom one or more medications were supplied in multiple-dose containers, annual average wholesale costs of drugs that would have been wasted were $56.50 per patient in 1982 and $67.57 per patient in 1983. Based on the 1983 average number of drug doses per patient in the 12 LTCFs and the pharmacy's cost of $0.02 per dose for unit-of-use packaging, the average cost of unit-of-use packaging per patient was $50.37.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:3934962

Farmer, R G; White, C P; Plein, J B; Plein, E M

1985-11-01

126

Gender differences in risk and treatment uptake in drug using offenders assessed in custody suite settings  

Microsoft Academic Search

The aim of the study was to assess gender differences in risk profile among drug users in police custody in Birmingham and to examine levels of drug treatment engagement by gender. This article presents findings from an assessment of 1082 Arrest Referral Risk Matrices used by Drug Arrest Referral Workers in police custody between 2005 and 2006. Risk is measured

David Best; Debbie Walker; Angela Foster; Stephanie Ellis-Gray; Edward Day

2008-01-01

127

Reduced-Reference Video Quality Assessment using Distributed Source Coding  

Microsoft Academic Search

In this paper we propose a reduced-reference quality assessment algorithm which computes an ap- proximation of the structural similarity (SSIM) metric exploiting coding tools provided by the distributed source coding theory. The algorithm has been tested to evaluate the quality of decoded video bitstreams after transmission over error-prone networks. We evaluate the accuracy of the proposed quality assessment algorithm by

M. Tagliasacchi; G. Valenzise; M. Naccari; S. Tubaro

2008-01-01

128

Quantitative assessment of time dependent drug-use trends by the analysis of drugs and related metabolites in raw sewage  

Microsoft Academic Search

Background: Accurate and timely information on the scale and dynamics of drug consumption is important for assessing the needs of law enforcement and public health services in a community. Aims: This paper presents a detailed examination of a comprehensive sewage-sampling campaign for the purposes of increasing an understanding of the dynamics of drug-flows in sewage streams, and developing new methodology

Malcolm J. Reid; Katherine H. Langford; Jørg Mørland; Kevin V. Thomas

129

Compartmental Pharmacokinetics and Tissue Drug Distribution of the Pradimicin Derivative BMS 181184 in Rabbits  

PubMed Central

The pharmacokinetics of the antifungal pradimicin derivative BMS 181184 in plasma of normal, catheterized rabbits were characterized after single and multiple daily intravenous administrations of dosages of 10, 25, 50, or 150 mg/kg of body weight, and drug levels in tissues were assessed after multiple dosing. Concentrations of BMS 181184 were determined by a validated high-performance liquid chromatography method, and plasma data were modeled into a two-compartment open model. Across the investigated dosage range, BMS 181184 demonstrated nonlinear, dose-dependent kinetics with enhanced clearance, reciprocal shortening of elimination half-life, and an apparently expanding volume of distribution with increasing dosage. After single-dose administration, the mean peak plasma BMS 181184 concentration (Cmax) ranged from 120 ?g/ml at 10 mg/kg to 648 ?g/ml at 150 mg/kg; the area under the concentration-time curve from 0 to 24 h (AUC0–24) ranged from 726 to 2,130 ?g · h/ml, the volume of distribution ranged from 0.397 to 0.799 liter/kg, and the terminal half-life ranged from 4.99 to 2.31 h, respectively (P < 0.005 to P < 0.001). No drug accumulation in plasma occurred after multiple daily dosing at 10, 25, or 50 mg/kg over 15 days, although mean elimination half-lives were slightly longer. Multiple daily dosing at 150 mg/kg was associated with enhanced total clearance and a significant decrease in AUC0–24 below the values obtained at 50 mg/kg (P < 0.01) and after single-dose administration of the same dosage (P < 0.05). Assessment of tissue BMS 181184 concentrations after multiple dosing over 16 days revealed substantial uptake in the lungs, liver, and spleen and, most notably, dose-dependent accumulation of the drug within the kidneys. These findings are indicative of dose- and time-dependent elimination of BMS 181184 from plasma and renal accumulation of the compound after multiple dosing.

Groll, Andreas H.; Sein, Tin; Petraitis, Vidas; Petraitiene, Ruta; Callender, Diana; Gonzalez, Corina E.; Giri, Neelam; Bacher, John; Piscitelli, Stephen; Walsh, Thomas J.

1998-01-01

130

The value of assessing cognitive function in drug development  

PubMed Central

This paper reviews the value and utility of measuring cognitive function in the development of new medicines by reference to the most widely used automated system in clinical research. Evidence is presented from phase 1 to 3 of the nature and quality of the information that can be obtained by applying the Cognitive Drug Research computerized assessment system to ongoing clinical trials. Valuable evidence can be obtained even in the first trial in which a novel compound is administered to man. One application of such testing is to ensure that novel compounds are relatively free from cognition-impairing properties, particularly in relation to competitor products. Another is to ensure that unwanted interactions with alcohol and other medications do not occur, or, if they do, to put them in context. In many patient populations, cognitive dysfunction occurs as a result of the disease process, and newer medicines which can treat the symptoms of the disease without further impairing function can often reveal benefits as the disease-induced cognitive dysfunction is reduced. Another major application is to identify benefits for compounds designed to enhance cognitive function. Such effects can be sought in typical phase 1 trials, or a scopolamine model of the core deficits of Alzheimer's disease can be used to screen potential antidernentia drugs. Ultimately, of course, such effects can be demonstrated using properly validated and highly sensitive automated procedures in the target populations. The data presented demonstrate that the concept of independently assessing a variety of cognitive functions is crucial in helping differentiate drugs, types of dementia, and different illnesses. Such information offers a unique insight into how the alterations to various cognitive functions will manifest themselves in everyday behavior. This reveals a major limitation of scales that yield a single score, because such limited information does not permit anything but a quantitative interpretation; and the concept of “more” cognitive function or “less” is manifestly inappropriate for something as complex and diverse as the interplay between cognitive function and human behavior. Finally, the next generations of cognitive testing are described. Testing via the telephone has just been introduced and will have dramatic effects on the logistics of conducting cognitive testing in large patient trials. Testing via the Internet is not far off either, and will come fully into play as the proportion of homes connected to the Internet increases in Europe and North America. There are no sound reasons for not wishing to include cognitive function testing in the development protocol of any novel medicine.

Wesnes, Keith A.

2000-01-01

131

The distribution of controlled drugs on banknotes via counting machines  

Microsoft Academic Search

Bundles of paper, similar to sterling banknotes, were counted in banks in England and Wales. Subsequent analysis showed that the counting process, both by machine and by hand, transferred nanogram amounts of cocaine to the paper. Crystalline material, similar to cocaine hydrochloride, could be observed on the surface of the paper following counting. The geographical distribution of contamination broadly followed

James F Carter; Richard Sleeman; Joanna Parry

2003-01-01

132

Assessment and evaluation of drug information services Assessment and evaluation of drug information services Assessment and evaluation of drug information services Assessment and evaluation of drug information services Assessment and evaluation of drug information services provided in a South Indian teaching hospital provided in a South Indian teaching hospital provided in a South Indian teaching hospital provided in a South Indian teaching hospital provided in a South Indian teaching hospital  

Microsoft Academic Search

Objective: To evaluate the various drug information queries received, and to assess the qual- ity of services provided by the drug information center of the pharmacy practice department. Materials and Methods: The drug information queries received during ward rounds, by telephone, direct access, intranet etc. were documented in the drug information request and documentation forms prepared by the department. These

Beena George; Padma G. M. Rao

133

Imaging mass spectrometry: challenges in visualization of drug distribution in solid tumors.  

PubMed

Mass spectrometry imaging (MSI) is an emerging technique that allows molecular visualization of the distribution of drugs and metabolites in a two-dimensional space directly in biological tissues. Imaging drug distribution inside a tumor is an important tool to support strategies to improve penetration of anticancer drugs and consequently the outcome of chemotherapy. MSI has some advantages in comparison to other imaging techniques, that is, whole body autoradiography, positron emission tomography or microscopy imaging. It is a label-free technique with better specificity and provides the possibility to combine histological data with MS ones and to visualize simultaneously the distribution of biomarkers in relation to tumor heterogeneity. We overview here publications on MSI applied to studies of the distribution of anticancer agents in tumor tissue. In addition, we focused our attention on technical limitations and future perspectives pertaining to this technique. PMID:23810822

Morosi, Lavinia; Zucchetti, Massimo; D'Incalci, Maurizio; Davoli, Enrico

2013-06-28

134

PS2-42: Assessment of Drug Induced Liver Injury Using an Automated Causality Assessment Tool  

PubMed Central

Background/Aims Drugs are a common cause of acute liver failure. However, confirming the diagnosis of drug-induced liver injury (DILI) is challenging due to its low incidence, lack of diagnostic markers and idiosyncratic nature. Our aim was to develop an automated scoring algorithm to identify potential DILI cases based on the Roussel Uclaf Causality Assessment Method (RUCAM) and test it in healthcare data. Methods RUCAM includes seven criteria of causality assessment. Operational scoring definitions were developed for each of the criteria in collaboration with DILI experts and programmed into an automated algorithm. The automated algorithm was then tested on a retrospective cohort of patients at Kaiser Permanente Southern California. Study participants were 18 years old with twelve months of continuous membership plus drug benefit prior to exposure to one of 14 drugs commonly associated with DILI. Eligible patients filled at least one of the study drugs between January 1, 2003 and August 31, 2011. Patients were scored and cases were categorized into one of five categories ranging from ‘Highly Probable’ to ‘Excluded’. Rates of DILI events per 10,000 exposures were calculated and frequency counts of possible scores for each of the seven criteria were analyzed. Results We identified 14,925 potential DILI events following 3,321,835 study drug exposures. Four antibiotics accounted for 89.4% of events. The average (SD) patient age was 60 (16) years and 54.5% of potential DILI events occurred in females. Cholestatic injury (65.0%) was the most common type followed by hepatocellular 29.4%, and mixed 5.6%. DILI events were categorized as probable or highly probable in 15.5% of cases, 59.6% were identified as possible, and 24.9% were unlikely or excluded. The overall rate of probable or highly probable DILI events was 6.9 per 10,000 exposures. The scores for most criteria spanned the entire range of possible scores and there were no obvious floor or ceiling effects. However, Criteria 5 (other non-drug causes of liver injury) showed poor discrimination of possible scores. Conclusions An electronic causality assessment algorithm was developed and successfully tested on healthcare data. Further validation is needed comparing these results with the ‘gold standard’ medical record review by DILI experts.

Cheetham, T. Craig; Shin, Janet; Murray, Rich; Niu, Fang; Reisinger, Steph; Azadian, Robert; Powell, Gregory

2013-01-01

135

Cationic amphiphilic drugs cause a marked expansion of apparent lysosomal volume: Implications for an intracellular distribution-based drug interaction  

PubMed Central

How a drug distributes within highly compartmentalized mammalian cells can affect both the activity and pharmacokinetic behavior. Many commercially available drugs are considered to be lysosomotropic, meaning they are extensively sequestered in lysosomes by an ion trapping-type mechanism. Lysosomotropic drugs typically have a very large apparent volume of distribution and a prolonged half-life in vivo, despite minimal association with adipose tissue. In this report we tested the prediction that the accumulation of one drug (perpetrator) in lysosomes could influence the accumulation of a secondarily administered one (victim), resulting in an intracellular distribution-based drug interaction. To test this hypothesis cells were exposed to nine different hydrophobic amine-containing drugs, which included imipramine, chlorpromazine and amiodarone, at a 10 µM concentration for 24 to 48 hours. After exposure to the perpetrators the cellular accumulation of LysoTracker Red (LTR), a model lysosomotropic probe, was evaluated both quantitatively and microscopically. We found that all of the tested perpetrators caused a significant increase in the cellular accumulation of LTR. Exposure of cells to imipramine caused an increase in the cellular accumulation of other lysosomotropic probes and drugs including LyosTracker Green, daunorubicin, propranolol and methylamine; however, imipramine did not alter the cellular accumulation of non-lysosomotropic amine-containing molecules including MitoTracker Red and sulforhodamine 101. In studies using ionophores to abolish intracellular pH gradients we were able to resolve ion trapping-based cellular accumulation from residual pH-gradient independent accumulation. Results from these evaluations in conjunction with lysosomal pH measurements enabled us to estimate the relative aqueous volume of lysosomes of cells before and after imipramine treatment. Our results suggest that imipramine exposure caused a 4-fold expansion in the lysosomal volume, which provides the basis for the observed drug interaction. The imipramine-induced lysosomal volume expansion was shown to be both time- and temperature-dependent and reversed by exposing cells to hydroxypropyl-?-cyclodextrin, which reduced lysosomal cholesterol burden. This suggests that the expansion of lysosomal volume occurs secondary to perpetrator-induced elevations in lysosomal cholesterol content. In support of this claim, the cellular accumulation of LTR was shown to be higher in cells isolated from patients with Niemann-Pick Type C disease, which are known to hyper-accumulate cholesterol in lysosomes.

Funk, Ryan S.; Krise, Jeffrey P.

2012-01-01

136

Cationic amphiphilic drugs cause a marked expansion of apparent lysosomal volume: implications for an intracellular distribution-based drug interaction.  

PubMed

How a drug distributes within highly compartmentalized mammalian cells can affect both the activity and pharmacokinetic behavior. Many commercially available drugs are considered to be lysosomotropic, meaning they are extensively sequestered in lysosomes by an ion trapping-type mechanism. Lysosomotropic drugs typically have a very large apparent volume of distribution and a prolonged half-life in vivo, despite minimal association with adipose tissue. In this report we tested the prediction that the accumulation of one drug (perpetrator) in lysosomes could influence the accumulation of a secondarily administered one (victim), resulting in an intracellular distribution-based drug interaction. To test this hypothesis cells were exposed to nine different hydrophobic amine-containing drugs, which included imipramine, chlorpromazine and amiodarone, at a 10 ?M concentration for 24 to 48 h. After exposure to the perpetrators the cellular accumulation of LysoTracker Red (LTR), a model lysosomotropic probe, was evaluated both quantitatively and microscopically. We found that all of the tested perpetrators caused a significant increase in the cellular accumulation of LTR. Exposure of cells to imipramine caused an increase in the cellular accumulation of other lysosomotropic probes and drugs including LyosTracker Green, daunorubicin, propranolol and methylamine; however, imipramine did not alter the cellular accumulation of non-lysosomotropic amine-containing molecules including MitoTracker Red and sulforhodamine 101. In studies using ionophores to abolish intracellular pH gradients we were able to resolve ion trapping-based cellular accumulation from residual pH-gradient independent accumulation. Results from these evaluations in conjunction with lysosomal pH measurements enabled us to estimate the relative aqueous volume of lysosomes of cells before and after imipramine treatment. Our results suggest that imipramine exposure caused a 4-fold expansion in the lysosomal volume, which provides the basis for the observed drug interaction. The imipramine-induced lysosomal volume expansion was shown to be both time- and temperature-dependent and reversed by exposing cells to hydroxypropyl-?-cyclodextrin, which reduced lysosomal cholesterol burden. This suggests that the expansion of lysosomal volume occurs secondary to perpetrator-induced elevations in lysosomal cholesterol content. In support of this claim, the cellular accumulation of LTR was shown to be higher in cells isolated from patients with Niemann-Pick type C disease, which are known to hyperaccumulate cholesterol in lysosomes. PMID:22449202

Funk, Ryan S; Krise, Jeffrey P

2012-04-06

137

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

138

Completing the logarithmic scoring rule for assessing probability distributions  

NASA Astrophysics Data System (ADS)

We propose and motivate an expanded version of the logarithmic score for forecasting distributions, termed the Total Log score. It incorporates the usual logarithmic score, which is recognised as incomplete and has been mistakenly associated with the likelihood principle. The expectation of the Total Log score equals the Negentropy plus the Negextropy of the distribution. We examine both discrete and continuous forms of the scoring rule, and we discuss issues of scaling for scoring assessments. The analysis suggests the dual tracking of the quadratic score along with the usual log score when assessing the qualities of probability distributions. An application to the sequential scoring of forecast distributions for the daily rate of stock returns displays the usefulness of the proposal.

Lad, Frank; Sanfilippo, Giuseppe; Agrò, Gianna

2012-10-01

139

Assessment of distributed photovoltaic electric-power systems  

NASA Astrophysics Data System (ADS)

A methodology for assessing the potential impacts of distributed photovoltaic (PV) systems on electric utility systems, including subtransmission and distribution networks, and the application of that methodology to several illustrative examples are discussed. The investigations focused upon five 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. Presented are the methods that were developed for the study, the approach used to define preferred PV systems that could minimize the cost of energy, quantitative results for the case studies, and conclusions based on these results.

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

1982-10-01

140

Quantitative Assessment of the Transport of Elastic and Rigid Vesicle Components and a Model Drug from these Vesicle Formulations into Human Skin In Vivo  

Microsoft Academic Search

The aim of this study was to quantitatively assess the distribution profiles of elastic and rigid vesicle material in human skin in vivo. Furthermore, the distribution profiles of the model drug ketorolac applied in these vesicle formulations was investigated. A deuterium-labelled phospholipid was incorporated into these vesicles to serve as a marker for the vesicle material. The vesicles were loaded

P. Loan Honeywell-Nguyen; Gert S. Gooris; Joke A. Bouwstra

2004-01-01

141

The distribution of controlled drugs on banknotes via counting machines.  

PubMed

Bundles of paper, similar to sterling banknotes, were counted in banks in England and Wales. Subsequent analysis showed that the counting process, both by machine and by hand, transferred nanogram amounts of cocaine to the paper. Crystalline material, similar to cocaine hydrochloride, could be observed on the surface of the paper following counting. The geographical distribution of contamination broadly followed Government statistics for cocaine usage within the UK. Diacetylmorphine, Delta(9)-tetrahydrocannabinol (THC) and 3,4-methylenedioxymethylamphetamine (MDMA) were not detected during this study. PMID:12711189

Carter, James F; Sleeman, Richard; Parry, Joanna

2003-03-27

142

High concentrations of drug in target tissues following local controlled release are utilized for both drug distribution and biologic effect: An example with epicardial inotropic drug delivery.  

PubMed

Local drug delivery preferentially loads target tissues with a concentration gradient from the surface or point of release that tapers down to more distant sites. Drug that diffuses down this gradient must be in unbound form, but such drug can only elicit a biologic effect through receptor interactions. Drug excess loads tissues, increasing gradients and driving penetration, but with limited added biological response. We examined the hypothesis that local application reduces dramatically systemic circulating drug levels but leads to significantly higher tissue drug concentration than might be needed with systemic infusion in a rat model of local epicardial inotropic therapy. Epinephrine was infused systemically or released locally to the anterior wall of the heart using a novel polymeric platform that provides steady, sustained release over a range of precise doses. Epinephrine tissue concentration, upregulation of cAMP, and global left ventricular response were measured at equivalent doses and at doses equally effective in raising indices of contractility. The contractile stimulation by epinephrine was linked to drug tissue levels and commensurate cAMP upregulation for IV systemic infusion, but not with local epicardial delivery. Though cAMP was a powerful predictor of contractility with local application, tissue epinephrine levels were high and variable - only a small fraction of the deposited epinephrine was utilized in second messenger signaling and biologic effect. The remainder of deposited drug was likely used in diffusive transport and distribution. Systemic side effects were far more profound with IV infusion which, though it increased contractility, also induced tachycardia and loss of systemic vascular resistance, which were not seen with local application. Local epicardial inotropic delivery illustrates then a paradigm of how target tissues differentially handle and utilize drug compared to systemic infusion. PMID:23872515

Maslov, Mikhail Y; Edelman, Elazer R; Wei, Abraham E; Pezone, Matthew J; Lovich, Mark A

2013-07-18

143

The significance of microscopic mass spectrometry with high resolution in the visualisation of drug distribution.  

PubMed

The visualisation and quantitative analysis of the native drug distribution in a pre-clinical or clinical setting are desirable for evaluating drug effects and optimising drug design. Here, using matrix-assisted laser desorption ionisation imaging mass spectrometry (MALDI-IMS) with enhanced resolution and sensitivity, we compared the distribution of a paclitaxel (PTX)-incorporating micelle (NK105) with that of PTX alone after injection into tumour-bearing mice. We demonstrated optically and quantitatively that NK105 delivered more PTX to the tumour, including the centre of the tumour, while delivering less PTX to normal neural tissue, compared with injection with PTX alone. NK105 treatment yielded a greater antitumour effect and less neural toxicity in mice than did PTX treatment. The use of high-resolution MALDI-IMS may be an innovative approach for pharmacological evaluation and drug design support. PMID:24157937

Yasunaga, Masahiro; Furuta, Masaru; Ogata, Koretsugu; Koga, Yoshikatsu; Yamamoto, Yoshiyuki; Takigahira, Misato; Matsumura, Yasuhiro

2013-10-25

144

A multi-centre rapid assessment of injecting drug use in India  

Microsoft Academic Search

In 1998, a series of five rapid situation assessments (RSA) of injecting drug use were undertaken by The Society for Service to Urban Poverty (SHARAN) covering the major Metropolitan cities of Mumbai, Chennai, Calcutta, Delhi and Imphal. The RSA determined the extent and patterns of injecting drug use (IDU), the available responses, current and planned interventions, and drug users’ perceptions

Jimmy Dorabjee; Luke Samson

2000-01-01

145

Drug Distribution: A Guided-Inquiry Laboratory Experiment in Coupled Homogeneous and Heterogeneous Equilibria  

NASA Astrophysics Data System (ADS)

A simple and inexpensive experiment for the study of simultaneous homogeneous and heterogeneous equilibria is described using a common antihistamine drug, diphenhydramine. This experiment gives students an opportunity to study the distribution of a drug in a two-phase system by measuring the concentrations of two chemical species and predicting the others by considering charge balance, mass balance, and equilibrium constant expressions. Furthermore, the acid-dissociation constant and aqueous-organic distribution coefficient can be calculated. The experiment is attractive to students because it represents a simplified model for something experienced in everyday life, namely, drug distribution in the human body. Students also gain experience with two very important analytical techniques, gas chromatography and pH measurement with a glass electrode.

Hein, John; Jeannot, Michael

2001-02-01

146

Assessment of Muscle Fatigue from TF Distributions of SEMG Signals.  

National Technical Information Service (NTIS)

Assessment of muscle fatigue involves the creation of indices based on the estimation of variables such as the instantaneous frequency (IF) and the instantaneous amplitude (IA), which can be estimated from a time-frequency (TF) distribution of a surface e...

C. Miosso C. Potes J. Pierluissi R. VonBorries

2008-01-01

147

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...

148

Independent Orbiter Assessment (IOA): Assessment of the Electrical Power Distribution and Control Subsystem, Volume 3.  

National Technical Information Service (NTIS)

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...

K. R. Schmeckpeper

1988-01-01

149

Assessment of mechanical integrity for drug-eluting renal stent with micro-sized drug reservoirs  

Microsoft Academic Search

The drug-eluting stent (DES) has become the gold standard worldwide for the treatment of cardiovascular diseases. In recent years, an innovative variation of the DES with micro-sized drug reservoirs has been introduced. It allows programmable drug delivery with both spatial and temporal control and has several potential advantages over traditional DESs. However, creating such reservoirs on the stent struts may

Hao-Ming Hsiao; Yi-Hsiang Chiu

2012-01-01

150

Innovative monotherapy trial designs for the assessment of antiepileptic drugs: a critical appraisal  

Microsoft Academic Search

Although new antiepileptic drugs are assessed initially by adding them to pre-existing treatment, it is only through monotherapy\\u000a studies that their therapeutic potential can be characterized in full. Since long-term treatment with a placebo alone is ethically\\u000a unacceptable in epilepsy, the classical monotherapy assessment of antiepileptic drugs involves randomization of newly diagnosed\\u000a patients to treatment with the investigational drug or

E. Perucca

1998-01-01

151

Internet-based assessment and self-monitoring of problematic alcohol and drug use  

Microsoft Academic Search

A Swedish web-based service (www.escreen.se) offers self-assessment and self-monitoring of alcohol and drug use via on-line screening with the Alcohol Use Disorders Identification Test (AUDIT) and the Drug Use Disorders Identification Test (DUDIT) as well as in-depth risk assessment using extended versions of both tests (Alcohol-E and DUDIT-E). Users receive individualized feedback concerning their alcohol and drug consumption and can

Kristina Sinadinovic; Anne H. Berman; Dan Hasson; Peter Wennberg

2010-01-01

152

The use of pharmacokinetic and pharmacodynamic data in the assessment of drug safety in early drug development  

PubMed Central

The pharmaceutical industry continues to look for ways to reduce drug candidate attrition throughout the drug discovery and development process. A significant cause of attrition is due to safety issues arising either as a result of animal toxicity testing or in the clinical programme itself. A factor in the assessment of safety during early drug development is the pharmacokinetic profile of the compound. This allows safety data to be considered in the light of systemic drug exposure and therefore permits a quantitative assessment. This is particularly applicable when assessing the risk of a new chemical entity (NCE) in relation to safety parameters such as QT interval prolongation, where free plasma concentrations have been shown to be predictive of this property in relation to potency in preclinical testing. Prior to actual human exposure it is therefore important to be able to predict reliably the pharmacokinetic behaviour of an NCE in order to place such safety findings into a quantitative risk context. The emerging science of pharmacogenetics is likely to further our ability to assess the risk of NCEs to populations and individuals due to genetic variance. The drug metabolizing enzyme CYP2D6 has been recognized as providing the potential to result in widely differing systemic drug exposure in the patient population due to polymorphic expression. Further knowledge is likely to add to our understanding of population differences in exposure and response and aid in the identification of risk factors. One potential strategy for improving the effectiveness of the drug discovery process is to obtain clinical pharmacokinetic data more rapidly in order to assess more accurately the potential for both efficacy and safety of an NCE. Whilst procedures and technologies are available that allow this on the microdose scale, it is important that we recognize potential limitations of these approaches in order that they can be applied beneficially.

Walker, D K

2004-01-01

153

Influence of surface chemistry of mesoporous alumina with wide pore distribution on controlled drug release.  

PubMed

The crucial role of the drug carrier surface chemical moeities on the uptake and in vitro release of drug is discussed here in a systematic manner. Mesoporous alumina with a wide pore size distribution (2-7 nm) functionalized with various hydrophilic and hydrophobic surface chemical groups was employed as the carrier for delivery of the model drug ibuprofen. Surface functionalization with hydrophobic groups resulted in low degree of drug loading (approximately 20%) and fast rate of release (85% over a period of 5 h) whereas hydrophilic groups resulted in a significantly higher drug payloads (21%-45%) and slower rate of release (12%-40% over a period of 5 h). Depending on the chemical moiety, the diffusion controlled ( proportional, varianttime(-)(0.5)) drug release was additionally observed to be dependent on the mode of arrangement of the functional groups on the alumina surface as well as on the pore characteristics of the matrix. For all mesoporous alumina systems the drug dosages were far lower than the maximum recommended therapeutic dosages (MRTD) for oral delivery. We envisage that the present study would aid in the design of delivery systems capable of sustained release of multiple drugs. PMID:19654029

Kapoor, Shobhna; Hegde, Rajesh; Bhattacharyya, Aninda J

2009-08-03

154

Assessment of antithrombotic drugs in vivo and ex vivo  

Microsoft Academic Search

The usefulness of drugs which inhibit platelet function and may be effective antithrombotic agents can only be demonstrated in clinical studies. Unfortunately, since the stimuli which cause thrombosis in patients are likely to vary extensively and since the mode of action of these drugs on such stimuli, although not completely understood, are likely to be different, the results from clinical

Michael R. Buchanan

1977-01-01

155

Assessment of AIDS Risk among Treatment Seeking Drug Abusers.  

ERIC Educational Resources Information Center

Intravenous (IV) drug abusers are at risk for contracting transmittable diseases such as acquired immunodeficiency syndrome (AIDS) and hepatitis B. This study was conducted to investigate the prevalence of risk behaviors for acquiring and transmitting AIDS and hepatitis B among treatment-seeking drug abusers (N=168). Subjects participated in a…

Black, John L.; And Others

156

Transdermal drug delivery: an assessment of skin impedance models  

Microsoft Academic Search

The variability found in skin impedance can significantly influence the effectiveness of Transdermal Drug Delivery. In order to optimize drug delivery, skin impedance frequency response must be considered. Several electrical models for skin impedance are presented in an attempt to understand the \\

Anthony F. Coston; J. K.-J. Li

2003-01-01

157

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

158

Methodologies to assess drug permeation through the blood-brain barrier for pharmaceutical research.  

PubMed

The drug discovery process for drugs that target the central nervous system suffers from a very high rate of failure due to the presence of the blood-brain barrier, which limits the entry of xenobiotics into the brain. To minimise drug failure at different stages of the drug development process, new methodologies have been developed to understand the absorption, distribution, metabolism, excretion and toxicity (ADMET) profile of drug candidates at early stages of drug development. Additionally, understanding the permeation of drug candidates is also important, particularly for drugs that target the central nervous system. During the first stages of the drug discovery process, in vitro methods that allow for the determination of permeability using high-throughput screening methods are advantageous. For example, performing the parallel artificial membrane permeability assay followed by cell-based models with interesting hits is a useful technique for identifying potential drugs. In silico models also provide interesting information but must be confirmed by in vitro models. Finally, in vivo models, such as in situ brain perfusion, should be studied to reduce a large number of drug candidates to a few lead compounds. This article reviews the different methodologies used in the drug discovery and drug development processes to determine the permeation of drug candidates through the blood-brain barrier. PMID:23801086

Passeleu-Le Bourdonnec, Céline; Carrupt, Pierre-Alain; Scherrmann, Jean Michel; Martel, Sophie

2013-06-26

159

Use of physiologically based pharmacokinetic modeling for assessment of drug-drug interactions.  

PubMed

Interactions between co-administered medicines can reduce efficacy or lead to adverse effects. Understanding and managing such interactions is essential in bringing safe and effective medicines to the market. Ideally, interaction potential should be recognized early and minimized in compounds that reach late stages of drug development. Physiologically based pharmacokinetic models combine knowledge of physiological factors with compound-specific properties to simulate how a drug behaves in the human body. These software tools are increasingly used during drug discovery and development and, when integrating relevant in vitro data, can simulate drug interaction potential. This article provides some background and presents illustrative examples. Physiologically based models are an integral tool in the discovery and development of drugs, and can significantly aid our understanding and prediction of drug interactions. PMID:22458685

Baneyx, Guillaume; Fukushima, Yumi; Parrott, Neil

2012-04-01

160

Modeling concentration distribution and deformation during convection-enhanced drug delivery into brain tissue  

Microsoft Academic Search

Convection-enhanced drug delivery is a technique where a therapeutic agent is infused under positive pressure directly into the brain tissue. For predicting the final concentration distribution and optimizing infusion rate and catheter placement, numerical models can be of great help. However, despite advances in modeling this process, often the infused agent does not reach the targeted region prescribed in the

K. Støverud; M. Darcis; R. Helmig; S. M. Hassanizadeh

2012-01-01

161

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

162

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

2012-02-03

163

Probabilistic Vulnerability Assessment Based on Power Flow and Voltage Distribution  

SciTech Connect

Risk assessment of large scale power systems has been an important problem in power system reliability study. Probabilistic technique provides a powerful tool to solve the task. In this paper, we present the results of a study on probabilistic vulnerability assessment on WECC system. Cumulant based expansion method is applied to obtain the probabilistic distribution function (PDF) and cumulative distribution function (CDF) of power flows on transmission lines and voltage. Overall risk index based on the system vulnerability analysis is calculated using the WECC system. The simulation results based on WECC system is used to demonstrate the effectiveness of the method. The methodology can be applied to the risk analysis on large scale power systems.

Ma, Jian; Huang, Zhenyu; Wong, Pak C.; Ferryman, Thomas A.

2010-04-30

164

[Distribution behavior of lipophilic drugs in the oil-in-water microemulsions].  

PubMed

Distribution behavior of lipophilic drugs in the oil-in-water (O/W) microemulsions was studied. Fluorescence spectra analysis was performed to investigate the effect of the compositions of microemulsions on the fluorescence spectra of armillarisin and ofloxacin which were used as the model drugs. The fluorescence spectra of the model drugs in the microemulsions with various amount of the compositions were compared. The results showed that the armillarisin were both localized in the interfacial film of microemulsion systems with both phenylmethanol and PEG 400 as the co-surfactants, separately. Ofloxacin was localized in the interfacial film of microemulsion systems with Gradamol GTCC as the oil phase, but in the oil pool of microemulsion systems with oleic acid/olive oil (OA/OO) (1:1) as the oil phase. Besides, it was found that the drug would have the tendency to locate in the microenvironment where the composition with the largest solubility to model drug is located, and its actual localized position would be dependent on the amount of this composition. The results indicate that the localized region of lipophilic drug in the O/W microemulsion systems is related with the solubility of the model drug in various compositions. PMID:17882963

Yao, Jing; Gu, Xiao-tian; Zhou, Jian-ping; Ping, Qi-neng; Lu, Yun

2007-07-01

165

Assessing the Persuasiveness of Drug Abuse Information. Drug Abuse Information Research Project.  

ERIC Educational Resources Information Center

|The magnitude of the effect television has on young people's lives makes it an important source of drug abuse information, but there is a question as to whether or not such information is persuasive. Some studies indicate that viewer response to anti-drug television commercials falls into four judgmental dimensions: relevant persuasion, negative…

McEwen, William J.; Wittbold, George H.

166

Causality Assessment in Drug Induced Liver Injury FDA ...  

Center for Drug Evaluation (CDER)

Text Version... Page 9. Acute hepatitis: Differential Dx Ultrasound/ CT ... Observe/ biopsy Page 10. Idiopathic Hepatitis • 22 hospitalizations/ 1,000,000 medicaid- ... More results from www.fda.gov/downloads/drugs/scienceresearch

167

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

2009-06-18

168

Assessment of mechanical integrity for drug-eluting renal stent with micro-sized drug reservoirs.  

PubMed

The drug-eluting stent (DES) has become the gold standard worldwide for the treatment of cardiovascular diseases. In recent years, an innovative variation of the DES with micro-sized drug reservoirs has been introduced. It allows programmable drug delivery with both spatial and temporal control and has several potential advantages over traditional DESs. However, creating such reservoirs on the stent struts may weaken the structure of the stent scaffolding and compromise its mechanical integrity. In this study, we propose to use this innovative stent concept in the renal indication for potential treatment of both renal artery stenosis (upstream) and its associated kidney diseases (downstream) at the same time. The effects of these micro-sized drug reservoirs on several key clinically relevant functional attributes of the drug-eluting renal stent were systematically and quantitatively investigated. Finite element models were developed to predict the mechanical integrity of a balloon-expandable stent at various stages. Results show that (1) creating drug reservoirs on a stent could impact the stent fatigue resistance to certain degrees; (2) drug reservoirs on the stent crowns lead to greater loss in all key stent attributes than reservoirs on either bar arms or connectors and (3) the proposed optimised depot stent was proven to be feasible and could triple drug capacity than the current DESs, with marginal trade-off in its key clinical attributes. These results can serve as the guidelines to help future stent designs to achieve the best combination of stent structural integrity and smart drug delivery in the future. PMID:22436070

Hsiao, Hao-Ming; Chiu, Yi-Hsiang

2012-03-22

169

Agreement Between Drugs-to-Avoid Criteria and Expert Assessments of Problematic Prescribing  

PubMed Central

Background Drugs-to-avoid criteria are commonly used to evaluate prescribing quality in elders. However, few studies have evaluated the concordance between these criteria and individualized patient assessments as measures of problem prescribing. Methods We used data on 256 outpatients from the Iowa City VA Medical Center who were age 65 and older and taking 5 or more medications. After a comprehensive patient interview, a physician/pharmacist study team recommended that certain drugs be discontinued, substituted, or reduced in dose. We evaluated the degree to which drugs considered potentially inappropriate by the drugs-to-avoid criteria of Beers and Zhan were also considered problematic by the study team, and vice versa. Results In the study cohort, 256 patients were using 3678 medications. The physician/pharmacist team identified 563 drugs (15%) as problematic, the Beers criteria flagged 214 drugs (6%) as potentially inappropriate, and the Zhan criteria flagged 91 drugs (2.5%). Kappa statistics for concordance between drugs-to-avoid criteria and expert assessments were 0.10–0.14, indicating “slight” agreement between these measures. Sixty-one percent of drugs identified as potentially inappropriate by the Beers criteria and 49% of drugs flagged by the Zhan criteria were not judged problematic by the expert reviewers. Correspondence between drugs-to-avoid criteria and expert assessment varied widely across different types of drugs. Conclusions Drugs-to-avoid criteria have limited power to differentiate between drugs and patients with and without prescribing problems identified on individualized expert review. While these criteria are useful as guides for initial prescribing decisions, they are insufficiently accurate to use as stand-alone measures of prescribing quality.

Steinman, Michael A.; Rosenthal, Gary E.; Landefeld, C. Seth; Bertenthal, Daniel; Kaboli, Peter J.

2009-01-01

170

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

171

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

172

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

173

A new approach to assess drug development performance.  

PubMed

This article suggests that successful innovation in biopharmaceuticals is strongly related to the ability of firms to move compounds forward along the drug pipeline, relatively to other companies, within the same therapeutic area. We used this intuition to build indicators of performance at the firm-level and use them to conduct empirical analysis that relies upon a comprehensive database. We consider the effect of various factors on drug development performance, including R&D funds allocation across therapeutic areas and the proportion of biological molecules in the drug development portfolio. Subsequently, we show that a correlation exists between our performance variables and the per-capita growth of biopharmaceutical firms' revenues. PMID:23337387

Rosiello, Alessandro; Dimitri, Nicola; Fiorini, Filippo

2013-01-19

174

In silico approaches to predicting cancer potency for risk assessment of genotoxic impurities in drug substances.  

PubMed

The current risk assessment approach for addressing the safety of very small concentrations of genotoxic impurities (GTIs) in drug substances is the threshold of toxicological concern (TTC). The TTC is based on several conservative assumptions because of the uncertainty associated with deriving an excess cancer risk when no carcinogenicity data are available for the impurity. It is a default approach derived from a distribution of carcinogens and does not take into account the properties of a specific chemical. The purpose of the study was to use in silico tools to predict the cancer potency (TD(50)) of a compound based on its structure. Structure activity relationship (SAR) models (classification/regression) were developed from the carcinogenicity potency database using MultiCASE and VISDOM. The MultiCASE classification models allowed the prediction of carcinogenic potency class, while the VISDOM regression models predicted a numerical TD(50). A step-wise approach is proposed to calculate predicted numerical TD(50) values for compounds categorized as not potent. This approach for non-potent compounds can be used to establish safe levels greater than the TTC for GTIs in a drug substance. PMID:20363275

Bercu, Joel P; Morton, Stuart M; Deahl, J Thom; Gombar, Vijay K; Callis, Courtney M; van Lier, Robert B L

2010-04-02

175

Assessment of Alcohol and Other Drug Disorders in the Seriously Mentally Ill  

Microsoft Academic Search

Brief assessment methods are needed to determine the presence of alcohol and drug problems in persons with severe mental illness. The purposes of this study were to determine the prevalence of alcohol and other drug problems in a rural population of 253 clients with severe mental illness and to determine the accuracy of case manager responses to specific alcohol and

Kristen L. Barry; Michael F. Fleming; James Greenley; Prudence Widlak; Svetlana Kropp; David McKee

1995-01-01

176

Assessment of Alcohol and Drug Education/Prevention Programs in the United States Army.  

National Technical Information Service (NTIS)

This report examines the U.S. Army alcohol and drug prevention/education program and assesses its effectiveness. The objectives of this project were: (a) to systematically review the available methods of drug abuse education and prevention; (b) to determi...

A. S. Morton . F. Cook

1973-01-01

177

Maternal Assessment of Infant Development: Associations with Alcohol and Drug Use in Pregnancy  

Microsoft Academic Search

Surveillance by parental concern has been advocated to assess whether formal child developmental testing is needed. To determine whether alcohol intake or illicit drug use in pregnancy is associated with differences in maternal perception of infant development, mothers with acknowledged alcohol and drug habits during pregnancy (N=120) were interviewed at 11 months' postpartum, within 1 month before infant testing by

F. N. Seagull; J. L. Mowery; P. M. Simpson; T. R. Robinson; S. S. Martier; R. J. Sokol; D. G. McCarver-May

1996-01-01

178

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

179

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...

180

Epigenetics and cancer: implications for drug discovery and safety assessment  

Microsoft Academic Search

It is necessary to determine whether chemicals or drugs have the potential to pose a threat to human health. Research conducted over the last two decades has led to the paradigm that chemicals can cause cancer either by damaging DNA or by altering cellular growth, probably via receptor-mediated changes in gene expression. However, recent evidence suggests that gene expression can

Jonathan G Moggs; Jay I Goodman; James E Trosko; Ruth A Roberts

2004-01-01

181

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

182

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.

183

Pharmacokinetics, tissue distribution and excretion of a new photodynamic drug deuxemether  

Microsoft Academic Search

Deuxemether was a new photodynamic drug effective for many kinds of solid tumor therapy, which was mainly composed of 3-(or 8-)-(1-methoxyethyl)-8-(or 3-)-(1-hydroxyethyl)-deutero-porphyrin IX (MHD) and 3,8-di(1-methoxyethyl)-deuteroporphyrin IX (DMD). The aims of this study were to elucidate its pharmacokinetic characteristics, tissue distribution, plasma protein binding and excretion properties and underlying mechanisms of deuxemether in rats based on the simultaneous determination of

Rui Wang; Haiping Hao; Guangji Wang; Haitang Xie; Meijuan Xu; Wei Wang; Hui He; Xiaoyu Li

2008-01-01

184

Towards spatially distributed quantitative assessment of tsunami inundation models  

NASA Astrophysics Data System (ADS)

This paper presents a framework and data for spatially distributed assessment of tsunami inundation models. Our associated validation test is based upon the 2004 Indian Ocean tsunami, which affords a uniquely large amount of observational data for events of this kind. Specifically, we use eyewitness accounts to assess onshore flow depths and speeds as well as a detailed inundation survey of Patong City, Thailand to compare modelled and observed inundation. Model predictions matched well the detailed inundation survey as well as altimetry data from the JASON satellite, eyewitness accounts of wave front arrival times and onshore flow speeds. Important buildings and other structures were incorporated into the underlying elevation model and are shown to have a large influence on inundation extent.

Jakeman, John Davis; Nielsen, Ole M.; Putten, Kristy Van; Mleczko, Richard; Burbidge, David; Horspool, Nick

2010-10-01

185

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

186

Behavioral assessments of two drug combinations for oral sedation  

Microsoft Academic Search

This study compares the efficacy of two drug regimens used for oral sedation in pediatric dental patients: chloral hydrate (50 mg\\/kg)\\/promethazine (1 mg\\/kg) and meperidine (1 mg\\/kg)\\/promethazine (1 mg\\/kg). Twenty-four pediatric dental patients, ASA Class I, were evaluated in this double-blind, randomized study. The patients ranged in age from 18 to 48 months. Each dental procedure under sedation was videotaped

Deirdre R. Sams; Edwin W. Cook; Janice G. Jackson; Bob L. Roebuck

1993-01-01

187

Drug Assessment Program; A Community Guide. The Drug Abuse Council Handbook Series, No. 2.  

ERIC Educational Resources Information Center

|Addiction to illicit hard drugs, and particularly opiates, has increased in the past few years. Yet, there are few comprehensive evaluations of the treatment systems, and there is little systematic planning for programs to meet current and anticipated changes in the community's need for treatment. This report has been written to assist community…

Blair, Louis H.; Sessler, John

188

Drug induced QT prolongation: the measurement and assessment of the QT interval in clinical practice.  

PubMed

There has been an increasing focus on drug induced QT prolongation including research on drug development and QT prolongation, following the removal of drugs due to torsades de pointes (TdP). Although this has improved our understanding of drug-induced QT prolongation there has been much less research aimed at helping clinicians assess risk in individual patients with drug induced QT prolongation. This review will focus on assessment of drug-induced QT prolongation in clinical practice using a simple risk assessment approach. Accurate measurement of the QT interval is best done manually, and not using the measurement of standard ECG machines. Correction for heart rate (HR) using correction formulae such as Bazett's is often inaccurate. These formulae underestimate and overestimate the duration of cardiac repolarization at low and high heart rates, respectively. Numerous cut-offs have been suggested as an indicator of an abnormal QT, but are problematic in clinical practice. An alternative approach is the QT nomogram which is a plot of QT?vs. HR. The nomogram has an 'at risk' line and QT-HR pairs above this line have been shown in a systematic study to be associated with TdP and the line is more sensitive and specific than Bazett's QTc of 440?ms or 500?ms. Plotting the QT-HR pair for patients on drugs suspected or known to cause QT prolongation allows assessment of the QT interval based on normal population QT variability. This risk assessment then allows the safer commencement of drugs therapeutically or management of drug induced effects in overdose. PMID:23167578

Isbister, Geoffrey K; Page, Colin B

2013-07-01

189

Assessing the effects of drug misuse on HIV/AIDS prevalence.  

PubMed

Drug misuse (injecting drug users-IDU) has been recognized to have a significant effect on the spread of HIV/AIDS epidemic. A deterministic model to assess the contribution of drug misuse and sex in the spread of HIV/AIDS is investigated. The threshold parameters of the model are determined and stabilities are analysed. Analysis of the reproduction number has shown that increase in drug misuse results in an increase in HIV infections. Furthermore, numerical simulations of the model show that drug misuse enhances HIV transmission and progression to AIDS. Thus, in a population with intravenous drug users, advocating for safe sex alone will not be enough to control the HIV/AIDS epidemic. PMID:23225069

Bhunu, C P; Mushayabasa, S

2012-12-06

190

Establishing the Validity of the Personality Assessment Inventory Drug and Alcohol Scales in a Corrections Sample  

ERIC Educational Resources Information Center

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…

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

2011-01-01

191

Establishing the Validity of the Personality Assessment Inventory Drug and Alcohol Scales in a Corrections Sample  

ERIC Educational Resources Information Center

|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…

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

2011-01-01

192

Training Needs of Rehabilitation Counselors concerning Alcohol and Other Drugs Abuse Assessment and Treatment  

ERIC Educational Resources Information Center

|Forty-two rehabilitation counselors participated in a study regarding perceived training needs concerning alcohol and other drug abuse (AODA) treatment and assessment. Participants reported that 85% of consumers with whom they worked had AODA issues, yet over half rated their graduate training in AODA treatment and assessment as poor, and their…

Ong, Lee Za; Cardoso, Elizabeth; Chan, Fong; Chronister, Julie; Chou, Chih Chin

2007-01-01

193

[Drugs use assessment in a group of bus drivers].  

PubMed

Bus driver is one of those tasks inherent transport activity, which involves special risks to safety and health of others and for which it is necessary, according to art. 41 of Decree No. 81/08, to check the consumption of psychoactive substances during the health surveillance. This assumption was investigated in a group of 461 bus drivers of a large trucking company. In medical history, one subject reported a previous history of opiate addiction and another, in the past, occasional taking of cannabis, and at the time of the visit, in no cases the objectivity has shown intoxication or abstinence signs, or signs of parenteral injection. Laboratory tests were found positive in one case of screening texts, not confirmed by subsequent laboratory analysis and a case of positive analysis for confirmation. The worker, temporarily suspended from driving and taken over by the Service for Drug Addiction of competence, was then reinstated in his job, having held that the absence of drug addiction. PMID:23405659

Maccà, I; Maso, S; Marcuzzo, G; Bartolucci, G B

194

In vitro assessment of drug-drug interaction potential of boceprevir associated with drug metabolizing enzymes and transporters.  

PubMed

The inhibitory effect of boceprevir (BOC), an inhibitor of hepatitis C virus nonstructural protein 3 protease was evaluated in vitro against a panel of drug-metabolizing enzymes and transporters. BOC, a known substrate for cytochrome P450 (P450) CYP3A and aldo-ketoreductases, was a reversible time-dependent inhibitor (k(inact) = 0.12 minute(-1), K(I) = 6.1 µM) of CYP3A4/5 but not an inhibitor of other major P450s, nor of UDP-glucuronosyltransferases 1A1 and 2B7. BOC showed weak to no inhibition of breast cancer resistance protein (BCRP), P-glycoprotein (Pgp), or multidrug resistance protein 2. It was a moderate inhibitor of organic anion transporting polypeptide (OATP) 1B1 and 1B3, with an IC(50) of 18 and 4.9 µM, respectively. In human hepatocytes, BOC inhibited CYP3A-mediated metabolism of midazolam, OATP1B-mediated hepatic uptake of pitavastatin, and both the uptake and metabolism of atorvastatin. The inhibitory potency of BOC was lower than known inhibitors of CYP3A (ketoconazole), OATP1B (rifampin), or both (telaprevir). BOC was a substrate for Pgp and BCRP but not for OATP1B1, OATP1B3, OATP2B1, organic cation transporter, or sodium/taurocholate cotransporting peptide. Overall, our data suggest that BOC has the potential to cause pharmacokinetic interactions via inhibition of CYP3A and CYP3A/OATP1B interplay, with the interaction magnitude lower than those observed with known potent inhibitors. Conversely, pharmacokinetic interactions of BOC, either as a perpetrator or victim, via other major P450s and transporters tested are less likely to be of clinical significance. The results from clinical drug-drug interaction studies conducted thus far are generally supportive of these conclusions. PMID:23293300

Chu, Xiaoyan; Cai, Xiaoxin; Cui, Donghui; Tang, Cuyue; Ghosal, Anima; Chan, Grace; Green, Mitchell D; Kuo, Yuhsin; Liang, Yuexia; Maciolek, Cheri M; Palamanda, Jairam; Evers, Raymond; Prueksaritanont, Thomayant

2013-01-04

195

Drug utilization research in primary health care as exemplified by physicians' quality assessment groups.  

PubMed

Drugs in primary health care are often prescribed for nonrational reasons. Drug utilization research investigates the prescription of drugs with an eye to medical, social and economic causes and consequences of the prescribed drug's utilization. The results of this research show distinct differences in drug utilization in different age groups and between men and women. Indication and dosage appear irrational from a textbook point of view. This indicates nonpharmacological causes of drug utilization. To advice successfully changes for the better quality assessment groups of primary health care physicians get information about their established behavior by analysis of their prescriptions. The discussion and the comparisons in the group allow them to recognize their irrational prescribing and the social, psychological and economic reasons behind it. Guidelines for treatment are worked out which take into account the primary health care physician's situation. After a year with 6 meetings of the quality assessment groups the education process is evaluated by another drug utilization analysis on the basis of the physicians prescription. The evaluation shows a remarkable improvement of quality and cost effectiveness of the drug therapy of the participating physicians. PMID:1490778

von Ferber, L; Luciano, A; Köster, I; Krappweis, J

1992-11-01

196

Unusual phyletic distribution of peptidases as a tool for identifying potential drug targets  

PubMed Central

Eukaryote homologues of carboxypeptidases Taq have been discovered by Niemirowicz et al. in the protozoan Trypanosoma cruzi, the causative agent of Chagas' disease. This is surprising, because the peptidase family was thought to be restricted to bacteria and archaea. In this issue of the Biochemical Journal, the authors propose that the Trypanosoma carboxypeptidases are potential drug targets for treatment of the disease. The authors also propose that the presence of the genes in the zooflagellates can be explained by a horizontal transfer of an ancestral gene from a prokaryote. Because peptidases are popular drug targets, identifying parasite or pathogen peptidases that have no homologues in their hosts would be a method to select the most promising targets. To understand how unusual this phyletic distribution is among the 183 families of peptidases, several other examples of horizontal transfers are presented, as well as some unusual losses of peptidase genes.

Rawlings, Neil D.

2006-01-01

197

Prediction and Prevention of Prescription Drug Abuse: Role of Preclinical Assessment of Substance Abuse Liability  

PubMed Central

In 2011, the prevalence of prescription drug abuse exceeded that of any other illicit drug except marijuana. Consequently, efforts to curtail abuse of new medications should begin during the drug development process, where abuse liability can be identified and addressed before a candidate medication has widespread use. The first step in this process is scheduling with the Drug Enforcement Agency so that legal access is appropriately restricted, dependent upon levels of abuse risk and medical benefit. To facilitate scheduling, the Food and Drug Administration (FDA) has published guidance for industry that describes assessment of abuse liability. The purpose of this paper is to review methods that may be used to satisfy the FDA’s regulatory requirements for animal behavioral and dependence pharmacology. Methods include psychomotor activity, self-administration (an animal model of the rewarding effects of a drug), drug discrimination (an animal model of the subjective effects of a drug), and evaluation of tolerance and dependence. Data from tests conducted at RTI with known drugs of abuse illustrate typical results, and demonstrate that RTI is capable of performing these tests. While using preclinical data to predict abuse liability is an imperfect process, it has substantial predictive validity. The ultimate goal is to increase consumer safety through appropriate scheduling of new medications.

Marusich, Julie A.; Lefever, Timothy W.; Novak, Scott P.; Blough, Bruce E.; Wiley, Jenny L.

2013-01-01

198

Parameter uncertainty assessment for distributed water quality models  

NASA Astrophysics Data System (ADS)

A new method is developed by the authors that assess the parameter uncertainty in distributed water quality models for multiple outputs in an efficient and effective way. Distributed water quality models have a high number of parameters, high parameter correlations, several output variables and a complex structure leading to multiple minima in the objective function. General uncertainty/optimization methods based on random sampling as GLUE or local methods such as PEST are often not applicable for theoretical or practical reasons. Therefore, the method "ParaSol" (Parameter Solutions) is developed to perform optimization and model parameter uncertainty analysis for complex models such as distributed (water quality) models. Optimization is achieved by adapting the SCE-UA to enable it to account for multi-objective problems while not being trapped in a localized minimum. The simulations performed by the SCE-UA are further used for uncertainty analysis. Two methods have been developed that select "good" parameter solutions out of the SCE-UA simulations based on an objective threshold. The first method is based on chi-squared statistics to delineate the confidence regions around the optimum/optima. The second method uses Bayesian statistics to define high probability regions whereby it accounts for the fact that the high probability regions are likely to be sampled more densely. The application of ParaSol on the flow and sediments simulations for Honey creek (Ohio) showed that, when 2 years of daily data are used, the confidence regions are very small when the chi -squared statistics are used and even smaller when using the Bayesian statistics. The results were also used to validate the suitability of SCE-UA sampling for uncertainty analysis by comparing to 500000 Monte Carlo samples. It was shown that the SCE-UA sampling was more effective and efficient as none of the Monte Carlo samples were close to the minimum or within the confidence region defined by ParaSol.

van Griensven, A.; Meixner, T.

2003-12-01

199

Drugs  

Center for Drug Evaluation (CDER)

... Print; Share; E-mail. Home; Drugs. -. Increased risk of death from IV Tygacil. ... Information highlights risk of hepatitis B reactivation; hepatitis B reactivation ... More results from www.fda.gov/drugs

200

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

2013-04-26

201

Michigan Assessment Screening Test for Alcohol and Drugs (MAST=AD): Evaluation in a Clinical Sample  

Microsoft Academic Search

In this study, we sought to evaluate a modification of the Michigan Alcohol Screening Test designed to include problems associated with other drug abuse=dependence besides alcohol. Scores of the lifetime Michigan Assess- ment-Screening Test=Alcohol-Drug (MAST=AD) were compared to other lifetime measures of substance abuse and dependence and to psychiatric scales reflecting current or recent symptoms. Two university medical centers with

Joseph Westermeyer; Ilhan Yargic; Paul Thuras

202

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

203

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

204

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

2012-12-22

205

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

206

Assessment of urinary excretion of antimalarial drugs in large-scale chemotherapeutic eradication projects  

PubMed Central

Assessment of the urinary excretion of an antimalarial drug is a useful means of checking the amount of drug administered and the regularity of intake. The author describes the various methods available for the qualitative and quantitative estimation of antimalarial drugs in urine and discusses their relative merits, with special reference to their suitability for use in the field. He points out the difficulties involved in estimating the urinary excretion of antimalarials in large-scale chemotherapeutic eradication projects and stress the importance of simplifying testing techniques as far as possible.

Bruce-Chwatt, L. J.

1959-01-01

207

Influence of drugs of abuse and alcohol upon patients admitted to acute psychiatric wards: physician's assessment compared to blood drug concentrations.  

PubMed

In acute psychiatric services, rapid and accurate detection of psychoactive substance intake may be required for appropriate diagnosis and intervention. The aim of this study was to investigate the relationship between (a) drug influence as assessed by physicians and (b) blood drug concentrations among patients admitted to acute psychiatric wards. We also explored the possible effects of age, sex, and psychotic symptoms on physician's assessment of drug influence. In a cross-sectional study, the sample comprised 271 consecutive admissions from 2 acute psychiatric wards. At admission, the physician on call performed an overall judgment of drug influence. Psychotic symptoms were assessed with the positive subscale of the Positive and Negative Syndrome Scale. Blood samples were screened for a wide range of psychoactive substances, and quantitative results were used to calculate blood drug concentration scores. Patients were judged as being under the influence of drugs and/or alcohol in 28% of the 271 admissions. Psychoactive substances were detected in 56% of the blood samples. Altogether, 15 different substances were found; up to 8 substances were found in samples from 1 patient. Markedly elevated blood drug concentration scores were estimated for 15% of the patients. Physician's assessment was positively related to the blood drug concentration scores (r = 0.52; P < 0.001), to symptoms of excitement, and to the detection of alcohol, cannabis, and amphetamines. The study demonstrates the major impact of alcohol and drugs in acute psychiatric settings and illustrates the challenging nature of the initial clinical assessment. PMID:23609387

Mordal, Jon; Medhus, Sigrid; Holm, Bjørn; Mørland, Jørg; Bramness, Jørgen G

2013-06-01

208

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

PubMed

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 HIV risk behaviors among drug-using, street-based sex workers. Field teams recruited 52 current injection and non-injection drug users for key informant interviews and focus groups, and they conducted mapping and observation in identified high-risk neighborhoods. Key informants were offered free, voluntary counseling and HIV rapid testing. The results of the assessment indicate that in this population, drugs play an organizing role in patterns of daily activities, with sex work closely linked to the buying, selling, and using of drugs. Participants reported using multiple drugs including crack cocaine, heroin, Ecstasy and Mandrax, and their choices were based on their expectations about the functional role and behavioral and pharmacological properties of the drugs. The organization of sex work and patterns of drug use differ by gender, with males exercising more control over daily routines and drug and sexual transactions than females. Activities of female sex workers are subject to considerable control by individual pimps, many of whom also function as landlords and drug dealers. A strong hold over the overlapping economies of drugs and sex work by a few individuals extends to control of the physical and social settings in which sex is exchanged and drugs are sold and used as well as the terms under which sex work is carried out. The potential for accelerated HIV spread is considerable given the evidence of overlapping drug-using and sexual risk behaviors and the mixing patterns across drug and sexual risk networks. PMID:18678437

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

2008-08-03

209

Risk assessment for drugs of abuse in the Dutch watercycle.  

PubMed

A screening campaign of drugs of abuse (DOA) and their relevant metabolites in the aqueous environment was performed in the Netherlands. The presence of DOA, together with the potential risks for the environment and the possible human exposure to these compounds through consumption of drinking water was investigated. Sewage water (influent and effluent), surface water of the rivers Rhine and Meuse, and drinking water (raw and finished) were analysed by four different laboratories using fully in-house validated methods for a total number of 34 DOA and metabolites. In this way, data reported for several compounds could also be confirmed by other laboratories, giving extra confidence to the results obtained in this study. In total 17 and 22 DOA were detected and quantified in influent and effluent sewage samples, respectively. The tranquilizers oxazepam and temazepam, and cocaine and its metabolite benzoylecgonine were found in high concentrations in sewage water. Nine compounds were possibly not efficiently removed during treatment and were detected in surface waters. The results indicated that substantial fractions of the total load of DOA and metabolites in the rivers Rhine and Meuse enter the Netherlands from abroad. For some compounds, loads appear to increase going downstream, which is caused by a contribution from Dutch sewage water effluents. As far as data are available, no environmental effects are expected of the measured DOA in surface waters. In raw water, three DOA were detected, whereas in only one finished drinking water out of the 17 tested, benzoylecgonine was identified, albeit at a concentration below the limit of quantification (<1 ng/L). Concentrations were well below the general signal value of 1 ?g/L, which is specified for organic compounds of anthropogenic origin in the Dutch Drinking Water Act. PMID:23391332

van der Aa, Monique; Bijlsma, Lubertus; Emke, Erik; Dijkman, Ellen; van Nuijs, Alexander L N; van de Ven, Bianca; Hernández, Felix; Versteegh, Ans; de Voogt, Pim

2013-01-17

210

Pharmacokinetics, tissue distribution and excretion of a new photodynamic drug deuxemether.  

PubMed

Deuxemether was a new photodynamic drug effective for many kinds of solid tumor therapy, which was mainly composed of 3-(or 8-)-(1-methoxyethyl)-8-(or 3-)-(1-hydroxyethyl)-deutero-porphyrin IX (MHD) and 3,8-di(1-methoxyethyl)-deuteroporphyrin IX (DMD). The aims of this study were to elucidate its pharmacokinetic characteristics, tissue distribution, plasma protein binding and excretion properties and underlying mechanisms of deuxemether in rats based on the simultaneous determination of MHD and DMD. The pharmacokinetic profiles of both MHD and DMD in rats after intravenous doses were linear and best fitted to a two compartment model, characterized with a rapid distribution phase (MHD: t(1/2)alpha, 0.09-0.14 h; DMD: t 1/2 alpha, 0.07-0.11h) and a relatively slow elimination phase (MHD: t 1/2 beta, 2.03-3.20 h; DMD: t 1/2 beta, 2.51-3.20 h). The tissue distributions of MHD and DMD in rats were rather limited as evidenced from their low distribution volume (0.75-1.70 L/kg) and the results of tissue distribution study. Protein binding of MHD and DMD were moderate (65.36-89.99% for MHD; 45.43-76.23% for DMD), independent of drug concentrations and similar between human and rat plasma over a concentration range of 0.50-50.0 microg/mL. Both MHD and DMD were predominantly (>74.1%) eliminated from rats as the parent drugs through the hepatobiliary systems and finally excreted into the feces. The multidrug resistance-associated proteins 2 (MRP2) inhibitors, bromosulfophthalein and probenecid, substantially inhibited the hepatobiliary elimination of MHD and DMD while the P-gp inhibitor digoxin had little effect, suggesting that MRP2 may contribute to the rapid and extensive hepatobiliary excretion of deuxemether. There were no significant differences between MHD and DMD for all pharmacokinetic characteristics studied. In conclusion, this study provided firstly the full pharmacokinetic characteristics and mechanisms of deuxemether, which would be helpful for its clinical regiment design. PMID:18267365

Wang, Rui; Hao, Haiping; Wang, Guangji; Xie, Haitang; Xu, Meijuan; Wang, Wei; He, Hui; Li, Xiaoyu

2008-01-12

211

Electroencephalographic effects of thiopentone and its enantiomers in the rat: correlation with drug tissue distribution  

PubMed Central

To better understand the pharmacology of the thiopentone enantiomers, we studied their quantitative electroencephalographic effects and their distribution into vital tissues. Adult Wistar rats were infused with rac-, R- or S-thiopentone at 4?mg?kg?1min?1 until death ensued. The EEG signal was acquired continuously; serial arterial plasma and terminal tissue thiopentone concentrations were measured enantiospecifically. Relevant drug tissue?:?plasma distribution coefficients and plasma concentration-EEG effect relationships were determined. Doses (mg?kg?1) (mean±s.e.mean) for anaesthesia (toe pinch) and lethality (respiratory failure), respectively, decreased in the order R-thiopentone (55.8±2.4 and 176.2±11.2)> rac-thiopentone (39.3±2.1 and 97.5±3.9)> S-thiopentone (35.6±1.9 and 74.2±5.2); plasma drug concentrations (?g?ml?1) decreased in the order R-thiopentone (66.3±4.5 and 89.8±5.2)> rac-thiopentone (56.7±2.0 and 77.8±2.8)> S-thiopentone (55.0±1.9 and 64.1±2.8). Initial EEG activation was similar for all thiopentone forms. Plasma drug concentrations for the same extent of EEG deactivation reflected the potency order. After infusion of rac-thiopentone, tissue?:?plasma distribution coefficients were higher for R- than for S-thiopentone in brain and visceral regions, but not in fat or muscle. After infusion of the separate enantiomers, the relative heart?:?brain distribution ratio was for S-thiopentone was double that for R-thiopentone. The therapeutic index of R-thiopentone (3.16±0.14) was more advantageous than either rac-thiopentone (2.52±0.13) or S-thiopentone (2.10±0.14), possibly due to the relatively greater distribution into CNS tissues than heart. The data suggest that R-thiopentone could make a satisfactory single enantiomer substitute for rac-thiopentone.

Mather, Laurence E; Edwards, Stephen R; Duke, Colin C

1999-01-01

212

Surgical hemostatic agents: assessment of drugs and medical devices.  

PubMed

Surgical hemostatic agents are indicated to improve hemostasis when conventional techniques (compression, sutures or electrocoagulation) are inadequate. The National French Authority for Health (Haute Autorité de santé [HAS]) set out to assess these products (medical devices and agents) to determine their optimal utility. This evaluation included one class of products containing some form of human fibrinogen and thrombin and eight classes of medical devices and automated devices to prepare autologous fibrin. The assessment was based on a systematic review of the literature and expert opinion of health care professionals. The main measures of effectiveness of hemostatic agents were the success rate as expressed in terms of the time necessary to obtain adequate hemostasis, the volume of intra and/or postoperative blood loss, the need for blood transfusions, complication rate, duration of operations and hospital stay. A meta-analysis and 52 controlled randomized studies were selected involving cardiac or vascular surgery (19), ENT surgery (11), gastrointestinal surgery (5), urology (4), orthopedic surgery (4). Approximately half of the studies retained in this analysis evaluated blood derived agents (fibrin sealants) while the other half evaluated medical devices. The working group considered that there is not any evidence that these surgical hemostatic agents decrease the rates of transfusion, complications, reoperation, mortality, duration of operation and/or hospital stay. The working group considered that the use of surgical hemostatic agents to improve the safety of hemostasis in the absence of identified bleeding as an alternative to adequate conventional hemostasis was not justified. Surgical hemostatic agents can be used in ad hoc settings, as a complement to conventional methods to control persistent bleeding after conventional hemostatic techniques, or when abundant bleeding has led to biologic hemostatic disorders. The working group also distinguished several particular settings (mouth and dental care in patients under antiagregant or anticoagulation therapy, central nervous system surgery or acute aortic dissection). Comparative data are insufficient to determine if one product is superior to another for a specific use. To evaluate the clinical value of these products, methodologically sound clinical studies are necessary. PMID:22136914

Aubourg, R; Putzolu, J; Bouche, S; Galmiche, H; Denis, C; d'Andon, A; Maitrot, D; Partensky, C

2011-12-01

213

Criteria for assessing high-priority drug-drug interactions for clinical decision support in electronic health records  

PubMed Central

Background High override rates for drug-drug interaction (DDI) alerts in electronic health records (EHRs) result in the potentially dangerous consequence of providers ignoring clinically significant alerts. Lack of uniformity of criteria for determining the severity or validity of these interactions often results in discrepancies in how these are evaluated. The purpose of this study was to identify a set of criteria for assessing DDIs that should be used for the generation of clinical decision support (CDS) alerts in EHRs. Methods We conducted a 20-year systematic literature review of MEDLINE and EMBASE to identify characteristics of high-priority DDIs. These criteria were validated by an expert panel consisting of medication knowledge base vendors, EHR vendors, in-house knowledge base developers from academic medical centers, and both federal and private agencies involved in the regulation of medication use. Results Forty-four articles met the inclusion criteria for assessing characteristics of high-priority DDIs. The panel considered five criteria to be most important when assessing an interaction- Severity, Probability, Clinical Implications of the interaction, Patient characteristics, and the Evidence supporting the interaction. In addition, the panel identified barriers and considerations for being able to utilize these criteria in medication knowledge bases used by EHRs. Conclusions A multi-dimensional approach is needed to understanding the importance of an interaction for inclusion in medication knowledge bases for the purpose of CDS alerting. The criteria identified in this study can serve as a first step towards a uniform approach in assessing which interactions are critical and warrant interruption of a provider’s workflow.

2013-01-01

214

Assessing the Validity and Reliability of the Farsi Version of Inventory Drug-Taking Situations  

PubMed Central

Objective Inventory Drug-Taking Situations (IDTS) is a universal instrument used to determine high-risk situations resulting in drug abuse. The aim of this study was to translate this questionnaire to Farsi, and to assess its validity and reliability by applying it to Iranian drug users. Methods As a psychometric study, 300 drug users participated in a treatment program in National Center of Addiction Studies filled in a version of Inventory of Drug Taking Situations. We assessed face and content validity, internal consistency, and reliability based on the completed questionnaires, using test-retest method and confirmatory factor analysis. Results Internal consistency analysis confirmed that all subscales of IDTS were reliable (Cronbach alpha was ranging from 0.7 to 0.81). Analyses indicated that each of the subscales was unifactorial; however, unpleasant emotions had a second eigenvalue that was nearly large enough to be a second factor. Confirmatory factor analysis was used to test the fit of the data to the original version of IDTS. Based on goodness of fit indices, we found that all factors were fitted (?2/df = 1.43, GFI = 0.98, RMSEA = 0.038). The test-retest reliability was satisfactory(r > 0.6). Conclusion The Farsi version of Inventory of Drug Taking Situations was shown to be a valid and reliable instrument to apply in clinical and research settings in Iran.

Pashaei, Tahereh; Razaghi, Omran M; Foroushani, Abbas Rahimi; Tabatabaei, Mahmoud Ghazi; Moeeni, Maryam; Turner, Nigel E; Sharifi, Vandad

2013-01-01

215

Internet-based assessment and self-monitoring of problematic alcohol and drug use.  

PubMed

A Swedish web-based service (www.escreen.se) offers self-assessment and self-monitoring of alcohol and drug use via on-line screening with the Alcohol Use Disorders Identification Test (AUDIT) and the Drug Use Disorders Identification Test (DUDIT) as well as in-depth risk assessment using extended versions of both tests (Alcohol-E and DUDIT-E). Users receive individualized feedback concerning their alcohol and drug consumption and can follow their alcohol and drug use over time in personal diagrams and by writing in an electronic diary. This study describes user characteristics, service utilization patterns, and psychometric test properties for 2361 individuals who created a valid account over 20 months starting in February 2007. Problematic alcohol use according to AUDIT criteria was indicated for 67.4%, while 46.0% met DUDIT criteria for problematic drug use. Men and women accessed the service equally, with a mean age of 23 years. Internal consistency reliability figures were 0.90 for 1846 first-time AUDIT users and 0.97 for 1211 first-time DUDIT users; among 213 second-time AUDIT users reliability was 0.93, and 0.96 for 97 second-time DUDIT users. Internet-based alcohol and drug monitoring could function as a self-help tool or as a complement to substance abuse treatment. PMID:20092953

Sinadinovic, Kristina; Berman, Anne H; Hasson, Dan; Wennberg, Peter

2010-01-04

216

Assessing the bioequivalence of analogues of endogenous substances ('endogenous drugs'): considerations to optimize study design  

PubMed Central

BACKGROUND Assessment of the bioequivalence of generic versions of certain reference drugs is complicated by the presence of endogenous levels of said compounds which cannot be distinguished from externally derived compound levels following drug administration. If unaccounted for, the presence of endogenous compound biases towards equivalence in bioequivalence studies of these drugs. Bioequivalence assessments may be complicated further as disposition of the exogenous analogue can be subject to various endogenous processes resulting in nonlinear pharmacokinetics. To overcome these inherent biases a number of different strategies have been employed. AIMS To critically review methods used to overcome confounding biases in bioequivalence studies of ‘endogenous’ drugs. METHODS A literature search of the EMBASE and PubMed databases was performed. RESULTS The following strategies were identified: ablation/modulation of baseline endogenous substance levels; recruitment of ‘substance-deficient’ populations; restriction of dietary intake of the relevant substance; standardization of conditions with the potential to affect relevant homeostatic mechanisms; correction for baseline substance levels; and administration of supra-therapeutic drug doses. CONCLUSIONS On the basis of this review key study design concepts, intended to optimize the design of future bioequivalence studies of these so-called ‘endogenous drugs’, are described. The dual stable isotope method, which could be used in a specific context, is also discussed.

Dissanayake, Sanjeeva

2010-01-01

217

Chemical and structural investigation of lipid nanoparticles: drug-lipid interaction and molecular distribution  

NASA Astrophysics Data System (ADS)

Lipid nanoparticles are a promising alternative to existing carriers in chemical or drug delivery systems. A key challenge is to determine how chemicals are incorporated and distributed inside nanoparticles, which assists in controlling chemical retention and release characteristics. This study reports the chemical and structural investigation of ?-oryzanol loading inside a model lipid nanoparticle drug delivery system composed of cetyl palmitate as solid lipid and Miglyol 812® as liquid lipid. The lipid nanoparticles were prepared by high pressure homogenization at varying liquid lipid content, in comparison with the ?-oryzanol free systems. The size of the lipid nanoparticles, as measured by the photon correlation spectroscopy, was found to decrease with increased liquid lipid content from 200 to 160 nm. High-resolution proton nuclear magnetic resonance (1H-NMR) measurements of the medium chain triglyceride of the liquid lipid has confirmed successful incorporation of the liquid lipid in the lipid nanoparticles. Differential scanning calorimetric and powder x-ray diffraction measurements provide complementary results to the 1H-NMR, whereby the crystallinity of the lipid nanoparticles diminishes with an increase in the liquid lipid content. For the distribution of ?-oryzanol inside the lipid nanoparticles, the 1H-NMR revealed that the chemical shifts of the liquid lipid in ?-oryzanol loaded systems were found at rather higher field than those in ?-oryzanol free systems, suggesting incorporation of ?-oryzanol in the liquid lipid. In addition, the phase-separated structure was observed by atomic force microscopy for lipid nanoparticles with 0% liquid lipid, but not for lipid nanoparticles with 5 and 10% liquid lipid. Raman spectroscopic and mapping measurements further revealed preferential incorporation of ?-oryzanol in the liquid part rather than the solid part of in the lipid nanoparticles. Simple models representing the distribution of ?-oryzanol and lipids (solid and liquid) inside the lipid nanoparticle systems are proposed.

Anantachaisilp, Suranan; Meejoo Smith, Siwaporn; Treetong, Alongkot; Pratontep, Sirapat; Puttipipatkhachorn, Satit; Rungsardthong Ruktanonchai, Uracha

2010-03-01

218

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.

2011-01-01

219

Bioavailability Assessment of Vitamin A Self-Nanoemulsified Drug Delivery Systems in Rats: A Comparative Study  

Microsoft Academic Search

Objectives: To assess and compare the bioavailability of three different oral dosage forms of vitamin A in rats. The formulations included vitamin A self-nanoemulsified drug delivery (SNEDD) optimized formulation-filled capsule (F1), vitamin A SNEDD optimized formulation compressed tablet (F2) and vitamin A oily solution-filled capsules without any additives (control, F3). Materials and Methods: Bioavailability was assessed after a single oral

Ehab Taha; Dalia Ghorab; Abdel-azim Zaghloul

2007-01-01

220

Subjective Health Literacy and Older Adults' Assessment of Direct-to-Consumer Prescription Drug Ads  

Microsoft Academic Search

Older adults are increasingly the intended target of direct-to-consumer (DTC) prescription drug ads, but limited evidence exists as to how they assess the educational value of DTC ads and, more importantly, whether their assessment depends on their level of health literacy. In-person interviews of 170 older adults revealed that those with low subjective health literacy evaluated the educational value of

Soontae An; Nancy Muturi

2011-01-01

221

Penetration and distribution of thiocolchicoside through human skin: comparison between a commercial foam (Miotens) and a drug solution.  

PubMed

Penetration and distribution of thiocolchicoside from a commercially available foam (Miotens 0.25%, w/v) through human excised full-thickness skin were evaluated using two different in vitro apparatus: a Franz diffusion cell and a Saarbruecken penetration model-based cell. In order to evaluate the intrinsic capability of the drug to penetrate into the skin, a simple drug aqueous solution prepared at the same drug concentration as Miotens was also tested. Results showed that both apparatus were suitable to study thiocolchicoside penetration into human skin. Penetrated drug amounts were comparable using the two apparatus, probably because skin acts as "sink" for the drug. Miotens was found to significantly promote thiocolchicoside accumulation into full human skin thickness in comparison with the simple drug solution. The mixture of propylene glycol and propylene glycol diperlargonate contained into Miotens foam has been proven to be effective to promote penetration of thiocolchicoside into human skin. PMID:19051040

Aguzzi, Carola; Rossi, Silvia; Bagnasco, Michela; Lanata, Luigi; Sandri, Giuseppina; Bona, Fosca; Ferrari, Franca; Bonferoni, Maria Cristina; Caramella, Carla

2008-12-03

222

Penetration and Distribution of Thiocolchicoside through Human Skin: Comparison Between a Commercial Foam (Miotens®) and a Drug Solution  

PubMed Central

Penetration and distribution of thiocolchicoside from a commercially available foam (Miotens® 0.25%, w/v) through human excised full-thickness skin were evaluated using two different in vitro apparatus: a Franz diffusion cell and a Saarbruecken penetration model-based cell. In order to evaluate the intrinsic capability of the drug to penetrate into the skin, a simple drug aqueous solution prepared at the same drug concentration as Miotens® was also tested. Results showed that both apparatus were suitable to study thiocolchicoside penetration into human skin. Penetrated drug amounts were comparable using the two apparatus, probably because skin acts as “sink” for the drug. Miotens® was found to significantly promote thiocolchicoside accumulation into full human skin thickness in comparison with the simple drug solution. The mixture of propylene glycol and propylene glycol diperlargonate contained into Miotens® foam has been proven to be effective to promote penetration of thiocolchicoside into human skin.

Aguzzi, Carola; Rossi, Silvia; Bagnasco, Michela; Lanata, Luigi; Sandri, Giuseppina; Bona, Fosca; Ferrari, Franca; Bonferoni, Maria Cristina

2008-01-01

223

Estimating numbers of injecting drug users in metropolitan areas for structural analyses of community vulnerability and for assessing relative degrees of service provision for injecting drug users  

Microsoft Academic Search

This article estimates the population prevalence of current injection drug users (IDUs) in 96 large US metropolitan areas\\u000a to facilitate structural analyses of its predictors and sequelae and assesses the extent to which drug abuse treatment and\\u000a human immunodeficiency virus (HIV) counseling and testing are made available to drug injectors in each metropolitan area.\\u000a We estimated the total number of

Samuel R. Friedman; Barbara Tempalski; Hannah Cooper; Theresa Perlis; Marie Keem; Risa Friedman; Peter L. Flom

2004-01-01

224

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.

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

2013-01-01

225

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

226

MRI and Image Quantitation for Drug Assessment - Growth Effects of Anabolic Steroids and Precursors  

Microsoft Academic Search

MRI and image quantitation play an expanding role in modern drug research, because MRI offers high resolution and non-invasive ability, and provides excellent soft tissue contrast. Moreover, with development of effective image segmentation and analysis methods, in-vivo and serial tissue growth measurements could be assessed. In the study, MR image acquisition and analysis protocol were established and validated for investigating

Haiying Tang; Ed X. Wu; Joseph R. Vasselli

2005-01-01

227

A decision-analysis tool for benefit-risk assessment of nonprescription drugs.  

PubMed

A decision analysis tool is proposed for regulatory assessment of nonprescription drugs. The tool is based on evaluation of each of the drug's potential benefit and risk attributes identified using a value-tree framework. The decision tool is designed as two-factor, two-stage instrument. Each attribute is independently assessed based on both the frequency of occurrence and clinical impact of the attribute. Frequency and clinical impact are scored on a 0-3 scale where a 0 score means no occurrence or no clinical impact, and a 3 means high frequency of occurrence or high clinical impact. The tool is initially used early in drug development to facilitate communication amongst stakeholders and to identify important data gaps. After new data are generated during the development program the tool is used again across the same attributes to yield a final benefit-risk assessment. In both the early assessment and subsequent evaluation use of the Group-Delphi technique and a benefit-risk trade-off heuristic may yield more consistent and coherent outputs. The tool allows regulators to maintain flexibility with respect to how final decisions are made, yet allows specificity and transparency during the evaluation. Further modifications can be incorporated to address drug-specific requirements or regulatory preferences. PMID:23381796

Brass, Eric P; Lofstedt, Ragnar; Renn, Ortwin

2013-02-04

228

Joint damage in rheumatoid arthritis: radiological assessments and the effects of anti-rheumatic drugs  

Microsoft Academic Search

Joint damage is a major problem in the long-term course of rheumatoid arthritis. It is usually assessed radiologically. In this review the methods of measuring the radiological changes are outlined, and the effects of anti-rheumatic drugs on radiological progression summarised. Two methods of scoring radiographs have become standard techniques; these are the Sharp index and the Larsen index. They both

D. L. Scott; P. A. Bacon

1985-01-01

229

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 state-of-the-art technologies in a real-world environment - wastewater effluent and source waters - for detecting six drugs [azithromycin, fluoxetine, omeprazole, levothyroxine, methamphetamine, m...

230

Assessment of primary, oxidative and excision repaired DNA damage in hospital personnel handling antineoplastic drugs.  

PubMed

The International Agency for Research on Cancer has classified several antineoplastic drugs in Group 1 (human carcinogens), among which chlorambucil, cyclophosphamide (CP) and tamoxifen, Group 2A (probable human carcinogens), among which cisplatin, etoposide, N-ethyl- and N-methyl-N-nitrosourea, and Group 2B (possible human carcinogens), among which bleomycins, merphalan and mitomycin C. The widespread use of these mutagenic/carcinogenic drugs in the treatment of cancer has led to anxiety about possible genotoxic hazards to medical personnel handling these drugs. The aim of the present study was to evaluate work environment contamination by antineoplastic drugs in a hospital in Central Italy and to assess the genotoxic risks associated with antineoplastic drug handling. The study group comprised 52 exposed subjects and 52 controls. Environmental contamination was assessed by taking wipe samples from different surfaces in preparation and administration rooms and nonwoven swabs were used as pads for the surrogate evaluation of dermal exposure, 5-fluorouracil and cytarabine were chosen as markers of exposure to antineoplastic drugs in the working environment. The actual exposure to antineoplastic drugs was evaluated by determining the urinary excretion of CP. The extent of primary, oxidative and excision repaired DNA damage was measured in peripheral blood leukocytes with the alkaline comet assay. To evaluate the role, if any, of genetic variants in the extent of genotoxic effects related to antineoplastic drug occupational exposure, the study subjects were genotyped for GSTM1, GSTT1, GSTP1 and TP53 polymorphisms. Primary DNA damage significantly increased in leukocytes of exposed nurses compared to controls. The use of personal protective equipment (i.e. gloves and/mask) was associated with a decrease in the extent of primary DNA damage. PMID:21112930

Villarini, Milena; Dominici, Luca; Piccinini, Renza; Fatigoni, Cristina; Ambrogi, Maura; Curti, Gianluca; Morucci, Piero; Muzi, Giacomo; Monarca, Silvano; Moretti, Massimo

2010-11-26

231

Assessing the efficacy of specific cerebellomodulatory drugs for use as therapy for spinocerebellar ataxia type 1.  

PubMed

Spinocerebellar ataxias are autosomal dominant diseases, associated in some types with a CAG repeat expansion, and characterised by a progressive loss of motor function. Currently, as there is no cure for most ataxias, treatment predominantly involves physical therapy. Various symptomatic drug treatments have been tried; however, published clinical studies have provided inconsistent results, likely due to small sample sizes, mixed patient populations and insensitive or subjective assessment scales. SCA1(154Q) transgenic mice display motor function impairments and ultimately a reduced number of cerebellar Purkinje neurons-characteristics comparable to most forms of sporadic and hereditary ataxias. We monitored motor function in SCA1(154Q) mice from 5 to 20 weeks of age and assessed the efficacy of four potential cerebellar modulatory drugs in attenuating deficits in rotor-rod performance. The drugs riluzole, amantadine, zolpidem and buspirone were selected based on their different mechanisms of action and their Food and Drug Administration (FDA)/Australian Therapeutic Goods Administration approval for other indications. SCA1(154Q) and C57/Bl6 wild-type mice were administered with four ascending acute doses of each drug, over 2 days. Following each dose, mice were assesed for motor function on the accelerating rotor-rod. None of the four drugs attenuated motor deficts in SCA1(154Q) mice at any dose; at FDA equivalent and higher dose administration of zolpidem and buspirone led to sedation in both strains. Our results suggest that the aforementioned drugs are likely to be ineffective for symptomatic treatment of SCA1 and most other ataxic patients and emphasise the need for comphrehensive drug studies prior to clinical use. PMID:22718440

Nag, Nupur; Tarlac, Volga; Storey, Elsdon

2013-02-01

232

Rapid assessment of drug-related HIV risk among men who have sex with men in three South African cities  

Microsoft Academic Search

The current assessment was undertaken to examine the link between drug use and sexual risk behavior among men who have sex with men (MSM) in locations known to have high prevalence rates of drug use and sexual risk behavior in Cape Town, Durban and Pretoria, South Africa. Street intercepts and purposive snowball sampling were used to recruit drug-using MSM. A

Charles Parry; Petal Petersen; Sarah Dewing; Tara Carney; Richard Needle; Karen Kroeger; Latasha Treger

2008-01-01

233

The use of rapid assessment methodology to compliment existing national assessment and surveillance data: a study among injecting drug users in Penang, Malaysia.  

PubMed

The study explores how data collated from rapid assessment can enhance those produced by national level surveillance systems, in this case the national drug information (NADI) system in Malaysia. Qualitative data were collected in keeping with internationally accepted guidance on rapid assessment methods in the field of substance use. An inductive research strategy was employed. The rapid assessment produced multiple data on local drug use practices and how these were influenced by the contexts of use. The assessment points to the importance of collecting data not only on patterns of drug use but also on the health and social consequences of drug use. We suggest that the current national drug information system places greater emphasis on behavioural and health-related variables in order to better understand the potential relationships between drug use and health-related risk, including HIV/AIDS. PMID:18312823

Vicknasingam, B; Navaratnam, V

2006-12-11

234

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.

2011-02-01

235

Investigating the relationship between drug distribution in solid lipid matrices and dissolution behaviour using Raman spectroscopy and mapping.  

PubMed

In this study, in situ and mapping Raman spectroscopic measurements were used to investigate the physical structure of solid lipid extrudates and relate the structure to dissolution behaviour. Theophylline anhydrate was extruded with tripalmitin, with and without the water-soluble polymer, polyethylene glycol 10000. Raman mapping of the extrudate cores revealed that drug particles of diverse size were dispersed in a continuous lipid phase with or without polyethylene glycol. At the surface, there was evidence of more mixing between the components. Previous characterisation by other methods suggested that the extrudate surface is covered predominantly by lipid, and the Raman mapping suggested that such a layer is in general less than a few micrometres thick. Nevertheless, the lipid layer dramatically reduced the drug dissolution rate. The extrudate cores were also mapped after a period of dissolution testing, and there was no evidence of a uniformly receding drug boundary in the extrudates during drug release. In situ Raman spectroscopy analysis during dissolution testing revealed that the drug distribution in the extrudate affected the formation of theophylline monohydrate. However, the drug release rate was primarily determined directly by drug distribution, with the solid-state behaviour of the drug having a smaller influence. PMID:19691104

Windbergs, Maike; Haaser, Miriam; McGoverin, Cushla M; Gordon, Keith C; Kleinebudde, Peter; Strachan, Clare J

2010-03-01

236

Assessing product bioequivalence for extended-release formulations and drugs with long half-lives.  

PubMed

When a drug product remains in the body for a duration of hours or days, estimating the extent of drug exposure is relatively straightforward. For immediate release (IR) dosage forms, the peak drug concentration (C(max)) and time to peak concentrations (T(max)) are typically adequate for comparing product rates of drug absorption. However, unique complexities need to be addressed when a drug remains in the system for a duration of months or years. Specifically, if the long duration of exposure is attributable to formulation effects, C(max) and T(max) may not be adequate to compare the rate of drug absorption, especially when there are multiphasic absorption processes. In this case, it may be appropriate to use partial (segmented areas) for comparing product profiles. However, the decision of how the curves are segmented is not straightforward. Points to consider are discussed in this manuscript. Alternatively, if the long half-life is due to the pharmacokinetics (PK) of the active pharmaceutical ingredient and not to formulation effects, C(max) and T(max) may be appropriate metrics for the rate of absorption but decisions regarding the duration of blood sampling needed to capture the AUC should be based upon an assessment of the inherent variability in drug absorption and elimination. Furthermore, it is important to be confident that the absorption phase is complete. In this manuscript, we explore some of the difficulties associated with determining optimal metrics for comparing the rate and extent of product release for long half life drugs when the long duration of exposure is attributable to either the inherent drug PK or to formulation effects. PMID:22413786

Gehring, R; Martinez, M

2012-04-01

237

Assessment of drug disposition in the perfused rat brain by statistical moment analysis  

SciTech Connect

Drug disposition in the brain was investigated by statistical moment analysis using an improved in situ brain perfusion technique. The right cerebral hemisphere of the rat was perfused in situ. The drug and inulin were injected into the right internal carotid artery as a rapid bolus and the venous outflow curve at the posterior facial vein was obtained. The infusion rate was adjusted to minimize the flow of perfusion fluid into the left hemisphere. The obtained disposition parameters were characteristics and considered to reflect the physicochemical properties of each drug. Antipyrine showed a small degree of initial uptake. Therefore, its apparent distribution volume (Vi) and apparent intrinsic clearance (CLint,i) were small. Diazepam showed large degrees of both influx and efflux and, thus, a large Vi. Water showed parameters intermediate between those of antipyrine and those of diazepam. Imipramine, desipramine, and propranolol showed a large CLint,i compared with those of the other drugs. The extraction ratio of propranolol significantly decreased with increasing concentrations of unlabeled propranolol in the perfusion fluid. These findings may be explained partly by the tissue binding of these drugs. In conclusion, the present method is useful for studying drug disposition in the brain.

Sakane, T.; Nakatsu, M.; Yamamoto, A.; Hashida, M.; Sezaki, H.; Yamashita, S.; Nadai, T. (Faculty of Pharmaceutical Sciences, Setsunan University, Osaka (Japan))

1991-06-01

238

Current practices in preclinical drug development: gaps in hemostasis testing to assess risk of thromboembolic injury.  

PubMed

The Health and Environmental Sciences Institute Cardiac Biomarkers Working Group surveyed the pharmaceutical development community to investigate practices in assessing hemostasis, including detection of hypocoagulable and hypercoagulable states. Scientists involved in discovery, preclinical, and clinical research were queried on laboratory evaluation of endothelium, platelets, coagulation, and fibrinolysis during safety assessment studies. Results indicated that laboratory assessment of hemostasis is inconsistent among institutions and not harmonized between preclinical and clinical studies. Hemostasis testing in preclinical drug safety studies primarily focuses on the risk of bleeding, whereas the clinical complication of thrombosis is seldom assessed. Our results reveal the need for broader utilization of biomarkers to detect altered hemostasis (e.g., endothelial and platelet activation) to improve preclinical safety assessments early in the drug development process. Survey respondents indicated a critical lack of validated markers of hypercoagulability and subclinical thrombosis in animal testing. Additional obstacles included limited blood volume, lack of cross-reacting antibodies for hemostasis testing in laboratory species, restricted availability of specialized hemostasis analyzers, and few centers of expertise in animal hemostasis testing. Establishment of translatable biomarkers of prothrombotic states in multiple species and strategic implementation of testing on an industry-wide basis are needed to better avert untoward drug complications in patient populations. PMID:22991386

Schultze, A Eric; Walker, Dana B; Turk, James R; Tarrant, Jacqueline M; Brooks, Marjory B; Pettit, Syril D

2012-09-18

239

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

240

Satellite needle distribution among injection drug users: policy and practice in two canadian cities.  

PubMed

Access to clean needles and syringes through needle exchange programs (NEPs) has reduced both high-risk behaviors and the transmission of blood-borne infections among injection drug users (IDUs). However, policies regarding "needle-for-needle" exchange versus unrestricted needle distribution remain controversial. The objective of this study was to compare sources of needles, trends in needle distribution, and the practice of satellite needle distribution (SND) among IDUs in Vancouver and Montreal. SND was defined as receiving a new syringe from another individual through trading, purchasing, borrowing, or being given the syringe outright, or supplying a syringe to another individual through trading, selling, lending, or giving a syringe outright. This was practiced by 46% of IDUs in Vancouver and 50% of IDUs in Montreal. SND was associated with borrowing used injection equipment (adjusted OR [AOR], 2.62; 95% CI: 1.85-3.71), conducting bulk needle exchanges (AOR, 1.85; 95% CI: 1.34-2.54), being married or in a common-law relationship (AOR, 1.85; 95% CI: 1.34-2.54), and regular visits to the NEP (> weekly) (AOR, 1.54; 95% CI: 1.17-2.13). In Vancouver, SND was also associated with borrowing used needles (AOR, 2.07; 95% CI: 1.22-3.52). In these two cities, despite different distribution policies, almost half of the participants reported SND, and this was associated with high risk sharing. The practice of SND appears to be an important mechanism for needle acquisition, especially for those at highest risk for HIV and hepatitis C transmission. PMID:12352156

Tyndall, Mark W; Bruneau, Julie; Brogly, Susan; Spittal, Patricia; O'Shaughnessy, Michael V; Schechter, Martin T

2002-09-01

241

In vivo assessment of the teratogenic potential of drugs in humans.  

PubMed

The difficulties in assessing the teratogenic potential of drugs used during pregnancy have been made evident by experiences with thalidomide and diethylstilbestrol (DES). In the case of thalidomide, the drug's ability to cause phocomelia tended to be species specific, and thus animal studies were unreliable indicators of teratogenicity in humans. With DES, the delayed appearance of injury, almost a generation after birth, indicates that short-term studies may fail to reveal serious effects. In both cases only the otherwise rare occurrence of the condition led to the suspicion of a cause-and-effect relationship. Although wide-spread use of drugs such as LSD, heroin, and marijuana has necessitated assessment of their teratogenic potential, a controlled investigation of their effects has so far been impossible to conduct. Both tobacco and alcohol have been associated with adverse effects on the fetus and neonate, but the precise mechanisms by which these effects occur are as yet unclear. There is also reason for concern about the teratogenic potential of environmental pollutants such as organic mercury compounds, lead, and radiation. Furthermore, the fetus may potentially be harmed if a particular drug is not administered (eg, insulin for diabetes during pregnancy). In the final analysis, any potential benefits of therapy for the mother must be weighed against known and unknown risks to the infant. Rational management requires an understanding of the physiologic and pharmacologic principles involved in each case and careful and judicious selection of drug therapy. PMID:7031539

Stern, L

1981-11-01

242

Drugs  

Center for Biologics Evaluation and Research (CBER)

Quick Links: Skip to main page content Skip to Search Skip to Topics Menu Skip to Section Content Menu Skip to Common Links. ... More results from www.fda.gov/advisorycommittees/committeesmeetingmaterials/drugs

243

Arrhythmic risk biomarkers for the assessment of drug cardiotoxicity: from experiments to computer simulations  

PubMed Central

In this paper, we illustrate how advanced computational modelling and simulation can be used to investigate drug-induced effects on cardiac electrophysiology and on specific biomarkers of pro-arrhythmic risk. To do so, we first perform a thorough literature review of proposed arrhythmic risk biomarkers from the ionic to the electrocardiogram levels. The review highlights the variety of proposed biomarkers, the complexity of the mechanisms of drug-induced pro-arrhythmia and the existence of significant animal species differences in drug-induced effects on cardiac electrophysiology. Predicting drug-induced pro-arrhythmic risk solely using experiments is challenging both preclinically and clinically, as attested by the rise in the cost of releasing new compounds to the market. Computational modelling and simulation has significantly contributed to the understanding of cardiac electrophysiology and arrhythmias over the last 40 years. In the second part of this paper, we illustrate how state-of-the-art open source computational modelling and simulation tools can be used to simulate multi-scale effects of drug-induced ion channel block in ventricular electrophysiology at the cellular, tissue and whole ventricular levels for different animal species. We believe that the use of computational modelling and simulation in combination with experimental techniques could be a powerful tool for the assessment of drug safety pharmacology.

Corrias, A.; Jie, X.; Romero, L.; Bishop, M. J.; Bernabeu, M.; Pueyo, E.; Rodriguez, B.

2010-01-01

244

Fine Mapping the Spatial Distribution and Concentration of Unlabeled Drugs within Tissue Micro-Compartments Using Imaging Mass Spectrometry  

PubMed Central

Readouts that define the physiological distributions of drugs in tissues are an unmet challenge and at best imprecise, but are needed in order to understand both the pharmacokinetic and pharmacodynamic properties associated with efficacy. Here we demonstrate that it is feasible to follow the in vivo transport of unlabeled drugs within specific organ and tissue compartments on a platform that applies MALDI imaging mass spectrometry to tissue sections characterized with high definition histology. We have tracked and quantified the distribution of an inhaled reference compound, tiotropium, within the lungs of dosed rats, using systematic point by point MS and MS/MS sampling at 200 µm intervals. By comparing drug ion distribution patterns in adjacent tissue sections, we observed that within 15 min following exposure, tiotropium parent MS ions (mass-to-charge; m/z 392.1) and fragmented daughter MS/MS ions (m/z 170.1 and 152.1) were dispersed in a concentration gradient (80 fmol-5 pmol) away from the central airways into the lung parenchyma and pleura. These drug levels agreed well with amounts detected in lung compartments by chemical extraction. Moreover, the simultaneous global definition of molecular ion signatures localized within 2-D tissue space provides accurate assignment of ion identities within histological landmarks, providing context to dynamic biological processes occurring at sites of drug presence. Our results highlight an important emerging technology allowing specific high resolution identification of unlabeled drugs at sites of in vivo uptake and retention.

Nilsson, Anna; Fehniger, Thomas E.; Gustavsson, Lena; Andersson, Malin; Kenne, Kerstin; Marko-Varga, Gyorgy; Andren, Per E.

2010-01-01

245

A framework establishing clear decision criteria for the assessment of drug efficacy.  

PubMed

Much has been published on various aspects of data analysis and reporting from clinical trials within the biopharmaceutical environment. This ranges from regulatory guidelines on the format and content of registration dossiers to recommendations on data presentation and the statistical methodologies that are appropriate for the diverse types of data one observes in clinical trials. Little has been written about designing a clinical trial analysis and reporting package that focuses on the decisions that must be made throughout the drug development process. Pharmaceutical companies today are under enormous pressure to develop drugs quickly and (cost-) efficiently. Because of this, drugs often move into the later phases of drug development before evidence from prior phases is completely understood. This provides a challenge to clinical trialists to design and execute a clinical trial programme which can expedite drug development. The statistician, as a clinical trialist, must strive to determine the optimum analytical methodology that facilitates decision making for this clinical trial programme. This paper proposes a new framework for the assessment of efficacy in drug development called the 'one programme, one p-value' framework. This framework will accelerate drug development by providing clear criteria for the decisions which must be made along the way. The 'one programme, one p-value' framework is based on the notion that the clinical trial programme comprises exploratory and confirmatory phases. The use of the likelihood function in the exploratory phase facilitates the decision whether (or when) to move into the confirmatory phase. The confirmatory phase consists of one confirmatory trial with a single hypothesis test of the drug's efficacy; hence 'one p-value'. Sponsor interaction with regulatory agencies is necessary at each decision point. Finally, the paper considers how analysis and reporting of efficacy data can be accomplished from a clinical trial programme as described. PMID:9749450

Huster, W J; Enas, G G

246

Defect distribution and reliability assessment of wind turbine blades  

Microsoft Academic Search

In this paper, two stochastic models for the distribution of defects in wind turbine blades are proposed. The first model assumes that the individual defects are completely randomly distributed in the blade. The second model assumes that the defects occur in clusters of different size, based on the assumption that one error in the production process tends to trigger several

Henrik Stensgaard Toft; Kim Branner; Peter Berring; John Dalsgaard Sørensen

2011-01-01

247

Assessment of distributed solar power systems: Issues and impacts  

Microsoft Academic Search

The installation of distributed solar-power systems presents electric utilities with a host of questions. Some of the technical and economic impacts of these systems are discussed. Among the technical interconnect issues are isolated operation, power quality, line safety, and metering options. Economic issues include user purchase criteria, structures and installation costs, marketing and product distribution costs, and interconnect costs. An

R. A. Moyle; H. Chernoff; T. C. Schweizer; J. B. Patton

1982-01-01

248

A simple method to assess loadability of radial distribution networks  

Microsoft Academic Search

This paper proposes a simple method to asses loadability in radial distribution systems. The relevant problem of voltage stability has been dealt with in past times with reference to higher voltage systems for generation and transmission. In more recent papers, the problem has been considered also at distribution level, since the new electrical energy market requirements and the increasing loadings

A. Augugliaro; L. Dusonchet; S. Favuzza; M. G. Ippolito; E. Riva Sanseverino

2005-01-01

249

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.

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

2013-01-01

250

Assessment of a micropatterned hepatocyte coculture system to generate major human excretory and circulating drug metabolites.  

PubMed

Metabolism is one of the important determinants of the overall disposition of drugs, and the profile of metabolites can have an impact on efficacy and safety. Predicting which drug metabolites will be quantitatively predominant in humans has become increasingly important in the research and development of new drugs. In this study, a novel micropatterned hepatocyte coculture system was evaluated for its ability to generate human in vivo metabolites. Twenty-seven compounds of diverse chemical structure and subject to a range of drug biotransformation reactions were assessed for metabolite profiles in the micropatterned coculture system using pooled cryopreserved human hepatocytes. The ability of this system to generate metabolites that are >10% of dose in excreta or >10% of total drug-related material in circulation was assessed and compared to previously reported data obtained in human hepatocyte suspensions, liver S-9 fraction, and liver microsomes. The micropatterned coculture system was incubated for up to 7 days without a change in medium, which offered an ability to generate metabolites for slowly metabolized compounds. The micropatterned coculture system generated 82% of the excretory metabolites that exceed 10% of dose and 75% of the circulating metabolites that exceed 10% of total circulating drug-related material, exceeds the performance of hepatocyte suspension incubations and other in vitro systems. Phase 1 and phase 2 metabolites were generated, as well as metabolites that arise via two or more sequential reactions. These results suggest that this in vitro system offers the highest performance among in vitro metabolism systems to predict major human in vivo metabolites. PMID:20595376

Wang, Wendy WeiWei; Khetani, Salman R; Krzyzewski, Stacy; Duignan, David B; Obach, R Scott

2010-07-01

251

Assessing Microbially Mediated Water Quality Problems in Distribution Systems.  

National Technical Information Service (NTIS)

This research sought to provide a review of various aspects of water quality problems that develop in distribution systems during water transmission by surveying water utility problems and responses to customer complaints and by conducting field monitorin...

W. R. Knocke G. D. Boardman

1982-01-01

252

Assessment of Distributed Generation Potential in Japanese Buildings.  

National Technical Information Service (NTIS)

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 dist...

N. Zhou C. Marnay R. Firestone W. Gao M. Nishida

2005-01-01

253

Artificial Neural Network Modeling Technique for Voltage Stability Assessment of Radial Distribution Systems  

Microsoft Academic Search

This paper presents an artificial neural network (ANN) based modeling technique for predicting the voltage stability of radial distribution systems. The modeling technique is based on a new voltage stability index for assessment of radial distribution systems Lv . The index is implemented to investigate a 33-bus distribution system. An ANN model which has an input layer with two input

M. M. Hamada; M. A. A. Wahab; N. G. A. Hemdan

2006-01-01

254

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

255

Assessment of the Role of Renal Organic Anion Transporters in Drug-Induced Nephrotoxicity  

PubMed Central

In the present review we have attempted to assess the involvement of the organic anion transporters OAT1, OAT2, OAT3, and OAT4, belonging to the SLC22 family of polyspecific carriers, in drug-induced renal damage in humans. We have focused on drugs with widely recognized nephrotoxic potential, which have previously been reported to interact with OAT family members, and whose underlying pathogenic mechanism suggests the participation of tubular transport. Thus, only compounds generally believed to cause kidney injury either by means of direct tubular toxicity or crystal nephropathy have been considered. For each drug, or class of agents, the evidence for actual transport mediated by individual OATs under in vivo conditions is discussed. We have then examined their role in the context of other carriers present in the renal proximal tubule sharing certain substrates with OATs, as these are critical determinants of the overall contribution of OAT-dependent transport to intracellular accumulation and transepithelial drug secretion, and thus the impact it may have in drug-induced nephrotoxicity.

Hagos, Yohannes; Wolff, Natascha A.

2010-01-01

256

Responses to a drug and alcohol problem assessment for primary care by ethnicity.  

PubMed

Differences in responses by ethnic group to The Drug Abuse Problem Assessment for Primary Care (DAPA-PC) were examined. The DAPA-PC is a self-administered (via computer), internet-based screening instrument with automatic scoring, patient profile for medical reference, and unique motivational messages. Results indicate differences between blacks and whites on responses to several items in these instruments. Differences in drug use were also found between the two ethnic groups in hair/urine results. The screening criteria for the DAPA-PC instrument appear to work for both the groups in this study. Differences in responses to alcohol and drug screening instruments by ethnic group should be taken into consideration when designing screening instruments for alcohol and/or other drug use and these instruments should be adapted for different ethnic groups, when necessary. The results of this study suggest that the DAPA-PC instrument is a useful alcohol and drug abuse screening instrument for both the blacks and whites in a primary care population. PMID:12211363

Zeiler, Christine A; Nemes, Susanna; Holtz, Kristen D; Landis, Richard D; Hoffman, Jeffrey

2002-01-01

257

In Vivo Assessment of Drug Efficacy against Plasmodium falciparum Malaria: Duration of Follow-Up  

Microsoft Academic Search

To determine the optimum duration of follow-up for the assessment of drug efficacy against Plasmodium falciparum malaria, 96 trial arms from randomized controlled trials (RCTs) with follow-up of 28 days or longer that were conducted between 1990 and 2003 were analyzed. These trials enrolled 13,772 patients, and partic- ipating patients comprised 23% of all patients enrolled in RCTs over the

Kasia Stepniewska; Walter R. J. Taylor; Mayfong Mayxay; Ric Price; Frank Smithuis; Jean-Paul Guthmann; Karen Barnes; Hla Yin Myint; Martin Adjuik; Piero Olliaro; Sasithon Pukrittayakamee; Sornchai Looareesuwan; Tran Tinh Hien; Jeremy Farrar; Francois Nosten; Nicholas P. J. Day; Nicholas J. White

2004-01-01

258

Instrumented In Vitro Approaches to Assess Epithelial Permeability of Drugs from Pharmaceutical Formulations  

Microsoft Academic Search

The following chapter gives an overview of instrumented approaches to investigate the interactions of orally or pulmonary\\u000a administered formulations with epithelial cell cultures in vitro. The first section is focused on the combined assessment\\u000a of drug release\\/dissolution and subsequent absorption\\/permeation for solid oral dosage forms. Experimental approaches to mimic\\u000a the complex physiologically surroundings in the gastrointestinal tract are presented as

Stephan A. Motz; Michael Bur; Ulrich F. Schaefer; Claus-Michael Lehr

259

Proficiency testing (external quality assessment) of drug detection in oral fluid  

Microsoft Academic Search

Eighteen external quality assessment (proficiency testing) samples were prepared from client specimens collected with the Intercept® oral fluid collection device and by spiking drug-free oral fluid. Samples were circulated in pairs at quarterly intervals to 13 UK and USA based laboratories for analysis by a panel of OraSure micro-plate Intercept® enzyme immunoassay kits and hyphenated mass spectrophotometric techniques. During the

Joe Clarke; John F. Wilson

2005-01-01

260

The US’ Food and Drug Administration, Normativity of Risk Assessment, GMOs, and American Democracy  

Microsoft Academic Search

The process of risk assessment of biotechnologies, such as genetically modified organisms (GMOs), has normative dimensions.\\u000a However, the US’ Food and Drug Administration (FDA) seems committed to the idea that such evaluations are objective. This\\u000a essay makes the case that the agency’s regulatory approach should be changed such that the public is involved in deciding\\u000a any ethical or social questions

Zahra Meghani

2009-01-01

261

Clinical Assessment of Drug-induced QT Prolongation in Association with Heart Rate Changes  

Microsoft Academic Search

Background: The formulas for heart rate (HR) correction of QT interval have been shown to overcorrect or undercorrect this interval with changes in HR. A Holter-monitoring method avoiding the need for any correction formulas is proposed as a means to assess drug-induced QT interval changes.Methods: A thorough QT study included 2 single doses of the ?1-adrenergic receptor blocker alfuzosin, placebo,

Fabrice Extramiana; Pierre Maison-Blanche; Marie-José Cabanis; Catherine Ortemann-Renon; Philippe Beaufils; Antoine Leenhardt

2005-01-01

262

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

2006-10-01

263

An assessment of sensing technologies for the detection of clandestine methamphetamine drug laboratories.  

PubMed

Clandestine drug laboratories involved in the production of illicit drugs represent one of the most significant social challenges facing most societies. In North America, clandestine methamphetamine production is particularly important and is associated with significant impact on health, safety, and the environment. Many of these production laboratories are temporary and capable of producing large quantities of prohibited drugs in production cycles that can often span less than 48 h, making timely discovery essential. This paper offers an assessment of sensing technologies capable of detecting the effluents commonly released during the production cycle for the various production methods. A brief review of the most common methamphetamine manufacturing processes is provided, and the target gases are identified. Each of these manufacturing processes has a unique temporal chemical signature and it is possible that this signature can be used to distinguish a methamphetamine laboratory from other legitimate sources of these gases. In the context of the target gases, this paper provides an assessment of both commercial and research stage sensor technology. The results of this assessment are used to draw conclusions about the most suitable sensing technologies for methamphetamine laboratory detection. PMID:19428203

Man, Gabriel; Stoeber, Boris; Walus, Konrad

2009-05-09

264

Using the level of Service Inventory-Revised to improve assessment and treatment in drug court.  

PubMed

More than 2,000 drug courts in the United States provide supervision and substance-abuse treatment to thousands of offenders. Yet the treatment continuum from assessment to aftercare is underexplored. The effectiveness of the Level of Service Inventory-Revised (LSI-R) as a risk assessment tool is well established. However, fewer studies have considered its use in guiding treatment strategies. In using the LSI-R, the drug court program relied on the structured interview protocol (not the risk classification scores) to identify criminogenic needs that then helped determine placement in a high- or low-needs treatment track. To evaluate the effectiveness of these treatment placement decisions, this research used the LSI-R scores to examine individual and group differences (N = 182). Significant and substantive differences at the individual and group levels were found thus providing empirical support for using the LSI-R as a link between assessment and treatment. Implications for developing standards and practice protocols for drug courts are discussed. PMID:21693454

Guastaferro, Wendy P

2011-06-20

265

Monthly spatial distributed water resources assessment: a case study  

NASA Astrophysics Data System (ADS)

Water resource conservation is of utmost importance, especially for agriculture in developing countries. Frequent occurrences of water shortage have driven more social efforts in researching on water resources spatial distribution, as the land cover changes recently have shown positive influences. For the purpose of efficient water resources management, hydrological processes under different types of land covers and soil textures are supposed to be accurately analyzed and evaluated. Recently developed distributed hydrological mode (DHM) has been a strong hydro-cycle simulation tool for inferring variability and heterogeneity of water resources distribution. In this paper, a spatially distributed Water and Energy Transfer between Soil, Plants and Atmosphere under quasi Steady State (WetSpass) model was introduced in the distributed hydro-cycle simulation on upstream Han river basin. The simulation time-step of WetSpass model was modified from originally one season to currently one month. In addition, an experiential non-linear routing algorithm was integrated into WetSpass for discharge confluence. The study area was delineated into 12 upstream to downstream routing related catchments whose land covers and soil textures were investigated and illustrated. Model verification was completed through the calibration of simulated hydrograph against observation using eleven years of continuous precipitation and meteorological data. Moreover, four criteria were used to evaluate the model performance and the calibrated results of routing parameters were discussed. Furthermore, the distribution of surface runoff generation, evapotranspiration and groundwater recharge were illustrated and analyzed considering the spatial heterogeneity of land cover and soil texture. Results showed that water resource spatial distribution and hydrological processes were closely related to land cover and soil texture and the model had achieved a success in hydro-cycle modeling of upstream Han river basin.

Wang, Yuhui; Lei, Xiaohui; Liao, Weihong; Jiang, Yunzhong; Huang, Xiaomin; Liu, Jianshe; Song, Xinshan; Wang, Hao

2012-08-01

266

Evaluation of stability and size distribution of sunflower oil-coated micro bubbles for localized drug delivery  

PubMed Central

Background Micro bubbles were initially introduced as contrast agents for ultrasound examinations as they are able to modify the signal-to-noise ratio in imaging, thus improving the assessment of clinical information on human tissue. Recent developments have demonstrated the feasibility of using these bubbles as drug carriers in localized delivery. In micro fluidics devices for generation of micro bubbles, the bubbles are formed at interface of liquid gas through a strangulation process. A device that uses these features can produce micro bubbles with small size dispersion in a single step. Methods A T-junction micro fluidic device constructed using 3D prototyping was made for the production of mono dispersed micro bubbles. These micro bubbles use sunflower oil as a lipid layer. Stability studies for micro bubbles with diameters different generated from a liquid phase of the same viscosity were conducted to evaluate whether micro bubbles can be used as drug carriers. The biocompatibility of coating layer, the ability to withstand environmental pressure variations combined with echogenicity, are key factors that they can safely play the role of drug transporters. Results The normal distribution curve with small dispersion of the diameter of bubbles validates the process of generating micro bubbles with low value of variation coefficient, i.e., 0.381 at 1.90%. The results also showed the feasibility of using sunflower oil as the lipid matrix with stable population of bubbles over 217 minutes for micro bubbles with an average diameter of 313.04 ?m and 121 minutes for micro bubbles with an average diameter of 73.74 ?m, considering bubbles with air as gaseous phase. Conclusion The results indicate that the micro fluidic device designed can be used for producing micro bubbles with low variation coefficient using sunflower oil as a coating of micro bubbles. These carriers were stable for periods of time that are long enough for clinical applications even when regular air is used as the gas phase. Improved stability can be achieved when biocompatible gas with lower permeability is used.

2012-01-01

267

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

Federal Register 2010, 2011, 2012, 2013

...scheduled under the Controlled Substances Act. Drugs with abuse potential generally include drugs that affect the central nervous system, drugs that are chemically or pharmacologically similar to other drugs with known abuse potential, and drugs...

2010-01-27

268

? Particle track autoradiographic study of the distribution of a [ 211 At]-astatinated drug in normal tissues of the mouse  

Microsoft Academic Search

Summary The microscopic distribution of the potential endoradiotherapeutic drug, 6-[211At]-astato-2-methyl-1,4-naphthoquinol bis (diphosphate salt) in normal tissues of the mouse has been studied by ?-particle track autoradiography. The uptake into critical radiosensitive tissues, especially bone marrow, colon and lung, was low.

J. S. Mitchell; I. Brown; R. N. Carpenter

1985-01-01

269

A distributed adverse drug reaction detection system using intelligent agents with a fuzzy recognition-primed decision model  

Microsoft Academic Search

Abstract Discovering unknown ,adverse drug reactions (ADRs) in postmarketing surveillance as early ,as possible is highly desirable. Nevertheless, current postmarketing surveillance methods largely rely on spontaneous reports which suffer from serious underreporting, latency, and inconsistent reporting. Thus these methods are not ideal for rapidly identifying rare ADRs. The multi-agent systems paradigm is an emerging and effective approach to tackling distributed

Yanqing Ji; Hao Ying; John Yen; Shizhuo Zhu; Daniel C. Barth-jones; Richard E. Miller; R. Michael Massanari

2007-01-01

270

Condition Assessment Technologies for Water Transmission and Distribution Systems.  

National Technical Information Service (NTIS)

As part of the U.S. Environmental Protection Agency's (EPA's) Aging Water Infrastructure Research Program, this research was conducted to identify and characterize the state of the technology for structural condition assessment of drinking water transmiss...

A. Liu B. Rajani L. Wang W. Condit Y. Kleiner

2012-01-01

271

AN ESTIMATION OF IN UTERO DRUG EXPOSURE BY DETERMINANTS OF FREQUENCY AND DISTRIBUTION OF MATERNAL DRUG CONSUMPTION  

Microsoft Academic Search

Data derived from 1,194 gravidas presenting at the observation unit of a city\\/county hospital between October 11, 1979 through December 7, 1979 were evaluated with respect to the proportion ingesting drugs during pregnancy. The mean age of the mother at the time of the interview was 22.0 years; 43.0 percent were Black; 34.0 percent Latin-American, 21.0 percent White and 2.0

ANN H ROSE

1980-01-01

272

An integrated in vitro model for simultaneous assessment of drug uptake, metabolism, and efflux.  

PubMed

The absorption, distribution, metabolism, and excretion (ADME) of drugs in vivo are to a large extent dependent on different transport and metabolism routes. Elucidation of this complex transport-metabolism interplay is a major challenge in drug development and at present no in vitro models suitable for this purpose are at hand. The aim of this study was to develop flexible, well-controlled, easy-to-use, integrated cell models, where drug transport and drug metabolism processes could be studied simultaneously. HEK293 cells stably transfected with the organic anion transporting polypeptide 1B1 (OATP1B1) were subjected to either transient transfection or adenoviral infection to introduce the genes expressing cytochrome P450 3A4 (CYP3A4), NADPH cytochrome P450 oxidoreductase (POR), cytochrome b5 (CYB5A), and multidrug resistance protein 1 (MDR1), in different combinations. Thereafter, the time and concentration-dependent transport and metabolism of two well-characterized statins, atorvastatin (acid and lactone forms) and simvastatin (acid form), were determined in the different models. The results show that CYP3A4-dependent metabolism of the more hydrophilic atorvastatin acid was dependent on OATP1B1 uptake and influenced by MDR1 efflux. In contrast, the metabolism of the more lipophilic atorvastatin lactone was not affected by active transport, whereas the metabolism of simvastatin acid was less influenced by active transport than atorvastatin acid. Our results, together with the models being applicative for any combination of drug transporters and CYP metabolizing enzymes of choice, provide proof-of-concept for the potential of the new integrated cell models presented as valuable screening tools in drug discovery and development. PMID:23822632

Neve, Etienne P A; Artursson, Per; Ingelman-Sundberg, Magnus; Karlgren, Maria

2013-07-15

273

Serotonergic Drugs, Their Postmortem Distribution in Man, and Their Effect on Serum Serotonin Levels.  

National Technical Information Service (NTIS)

The discovery of multiple serotonin receptor subtypes has encouraged the development of drugs which possess more specificity of action than their earlier-developed counterparts. These drugs have been involved in an increasing number of fatalities in the S...

K. E. Goeringer

1997-01-01

274

10 CFR 32.21 - Radioactive drug: Manufacture, preparation, or transfer for commercial distribution of capsules...  

Code of Federal Regulations, 2013 CFR

...2013-01-01 2013-01-01 false Radioactive drug: Manufacture, preparation...Concentrations and Items § 32.21 Radioactive drug: Manufacture, preparation...the form of a capsule, identified as radioactive, and to be used for its...

2013-01-01

275

Drug Resistance and Distribution of R Factors among 'Escherichia coli' Strains.  

National Technical Information Service (NTIS)

Three hundred and thirty-eight strains of 'Escherichia coli' from clinical sources were examined for their drug resistance and R factors in 1971. With reference to four drugs, i.e., tetracycline (TC), chloramphenicol (CM), streptomycin (SM) and sulfanilam...

T. Tanaka A. Kobayashi K. Ikemura H. Hashimoto S. Mitsuhashi

1974-01-01

276

Drug use during pregnancy in Sweden - assessed by the Prescribed Drug Register and the Medical Birth Register  

PubMed Central

Purpose: The purpose of this research is to study drug use during pregnancy in Sweden and agreement between use according to antenatal medical records and dispensed drugs from a pharmacy database. Patients and methods: From the Swedish Medical Birth Register (MBR), we established a population-based cohort of 102,995 women who gave birth in 2007. Using the unique personal registration number, information on dispensed drugs from the Prescribed Drug Register (PDR) was obtained prior to, during, and after the pregnancies and compared with MBR information on drug use from standardized antenatal medical records. Results: According to the PDR, 57.6% of the 102,995 women filled a prescription with at least one drug during pregnancy and 50.9% during the lactating period (until 3 months after delivery). The most dispensed drugs during pregnancy were B-lactam antibacterials and penicillins. Agreement between drugs recorded in antenatal medical records and dispensed drugs was highest for drugs used for chronic conditions. The agreement was particularly high for thyroid therapy (85.3%), anti-intestinal inflammatory drugs (80.3%), antiepileptics (69.2%), immunosuppressants (67.4%), and insulin (63.8%). Agreement for drugs used for occasional use was generally lower, ranging between 42.5% for antihistamines and 0.8% for gynecological anti-infectives. Conclusions: A large proportion of women filled a prescription during pregnancy or the lactating period. Agreement between drug use in medical antenatal records and register information from a national pharmacy database was high for drugs used for chronic conditions but low for occasional use. For occasionally used drugs, medical record and register-based data may provide incomplete exposure information because of nonreporting or noncompliance.

Stephansson, Olof; Granath, Fredrik; Svensson, Tobias; Haglund, Bengt; Ekbom, Anders; Kieler, Helle

2011-01-01

277

Assessing the capacity reliability of ageing water distribution systems  

Microsoft Academic Search

This paper presents two new efficient algorithms for estimating the capacity reliability of ageing water distribution systems recognising the uncertainties in nodal demands and the pipe capacity. Capacity reliability is defined as the probability that the nodal demand is met at or over the prescribed minimum pressure for a fixed network configuration. Uncertainties in the nodal demands and values of

Chengchao Xu; Ian Goulter; Kevin Tickle

2003-01-01

278

Status and Distribution of Cheetah in Zambia: A Preliminary Assessment  

Microsoft Academic Search

The historical and present day distribution of cheetah in Zambia appear to be similar, although the range has contracted. Liuwa Plains National Park, the northern section of the Kafue National Park and South Lu- angwa National Park still hold populations of cheetahs, although it was not possible to estimate population sizes. Cheetahs are reported from the Chimbwi plains area of

Gianetta Purchase

279

Clinical assessment of a new anaesthetic drug administration system: a prospective, controlled, longitudinal incident monitoring study.  

PubMed

A safety-orientated system of delivering parenteral anaesthetic drugs was assessed in a prospective incident monitoring study at two hospitals. Anaesthetists completed an incident form for every anaesthetic, indicating if an incident occurred. Case mix data were collected and the number of drug administrations made during procedures estimated. From February 1998 at Hospital A and from June 1999 at Hospital B, until November 2003, 74,478 anaesthetics were included, for which 59,273 incident forms were returned (a 79.6% response rate). Fewer parenteral drug errors occurred with the new system than with conventional methods (58 errors in an estimated 183,852 drug administrations (0.032%, 95% CI 0.024-0.041%) vs 268 in 550,105 (0.049%, 95% CI 0.043-0.055%) respectively, p = 0.002), a relative reduction of 35% (difference 0.017%, 95% CI 0.006-0.028%). No major adverse outcomes from these errors were reported with the new system while 11 (0.002%) were reported with conventional methods (p = 0.055). We conclude that targeted system re-design can reduce medical error. PMID:20337616

Webster, C S; Larsson, L; Frampton, C M; Weller, J; McKenzie, A; Cumin, D; Merry, Alan F

2010-03-19

280

Quality assessment of High Definition TV distribution over IP networks  

Microsoft Academic Search

High Definition (HD) content delivery over IP networks has become a reality in the market of entertainment technologies. This paper presents a professional testbed deployed to emulate a real use case of delivering high definition TV material over an IPTV network. The quality of the delivered H.264\\/AVC encoded video was evaluated by common objective video quality assessment tools in emulated

Omneya Issa; Wei Li; Hong Liu; Filippo Speranza; Ron Renaud

2009-01-01

281

Groundwater Supply in Metro Manila: Distribution, Environmental and Economic Assessment  

Microsoft Academic Search

Early studies on the groundwater supply of Metro Manila have indicated inefficient resource use that could lead to the eventual decline in the groundwater level, salt water intrusion, and other similar negative externalities. Based on the preceding premise, the paper intends to present a review and assessment of how groundwater resources are developed and utilized in Metro Manila. The study

Cristina C. David; Arlene B. Inocencio; Roberto S. Clemente; Ramon P. Abracosa; Guillermo Q. Tabios

2001-01-01

282

Distributed dynamic event tree generation for reliability and risk assessment  

Microsoft Academic Search

Level 2 probabilistic risk assessments of nuclear plants (analysis of radionuclide release from containment) may require hundreds of runs of severe accident analysis codes such as MELCOR or RELAP\\/SCDAP to analyze possible sequences of events (scenarios) that may follow given initiating events. With the advances in computer architectures and ubiquitous networking, it is now possible to utilize multiple computing and

Benjamin Rutt; Umit Catalyurek; Aram Hakobyan; Kyle Metzroth; Tunc Aldemir; Richard Denning; Sean Dunagan; David Kunsman

2006-01-01

283

Condition Assessment Modeling for Distribution Systems Using Shared Frailty Analysis  

EPA Science Inventory

Condition Assessment (CA) modeling is drawing increasing interest as a methodology for managing drinking water infrastructure. This paper develops a Cox Proportional Hazard (PH)/shared frailty model and applies it to the problem of investment in the repair and replacement of dri...

284

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

285

Assessment of the Impact of Renal Impairment on Systemic Exposure of New Molecular Entities: Evaluation of Recent New Drug Applications  

Microsoft Academic Search

The US Food and Drug Administration (FDA) is currently developing a guidance for industry to replace a previous guidance, “Pharmacokinetics in Patients With Impaired Renal Function—Study Design, Data Analysis, and Impact on Dosing and Labeling” (renal guidance) issued in May 1998. The impact of the 1998 renal guidance was assessed following a survey of 94 new drug applications (NDAs) for

Y Zhang; L Zhang; S Abraham; S Apparaju; T-C Wu; JM Strong; S Xiao; AJ Atkinson Jr; KE Thummel; JS Leeder; C Lee; GJ Burckart; LJ Lesko; S-M Huang

2009-01-01

286

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

287

DemQSAR: predicting human volume of distribution and clearance of drugs.  

PubMed

In silico methods characterizing molecular compounds with respect to pharmacologically relevant properties can accelerate the identification of new drugs and reduce their development costs. Quantitative structure-activity/-property relationship (QSAR/QSPR) correlate structure and physico-chemical properties of molecular compounds with a specific functional activity/property under study. Typically a large number of molecular features are generated for the compounds. In many cases the number of generated features exceeds the number of molecular compounds with known property values that are available for learning. Machine learning methods tend to overfit the training data in such situations, i.e. the method adjusts to very specific features of the training data, which are not characteristic for the considered property. This problem can be alleviated by diminishing the influence of unimportant, redundant or even misleading features. A better strategy is to eliminate such features completely. Ideally, a molecular property can be described by a small number of features that are chemically interpretable. The purpose of the present contribution is to provide a predictive modeling approach, which combines feature generation, feature selection, model building and control of overtraining into a single application called DemQSAR. DemQSAR is used to predict human volume of distribution (VD(ss)) and human clearance (CL). To control overtraining, quadratic and linear regularization terms were employed. A recursive feature selection approach is used to reduce the number of descriptors. The prediction performance is as good as the best predictions reported in the recent literature. The example presented here demonstrates that DemQSAR can generate a model that uses very few features while maintaining high predictive power. A standalone DemQSAR Java application for model building of any user defined property as well as a web interface for the prediction of human VD(ss) and CL is available on the webpage of DemPRED: http://agknapp.chemie.fu-berlin.de/dempred/ . PMID:22101402

Demir-Kavuk, Ozgur; Bentzien, Jörg; Muegge, Ingo; Knapp, Ernst-Walter

2011-11-20

288

Risk assessment and mitigation strategies for reactive metabolites in drug discovery and development  

Microsoft Academic Search

Drug toxicity is a leading cause of attrition of candidate drugs during drug development as well as of withdrawal of drugs post-licensing due to adverse drug reactions in man. These adverse drug reactions cause a broad range of clinically severe conditions including both highly reproducible and dose dependent toxicities as well as relatively infrequent and idiosyncratic adverse events. The underlying

Richard A. Thompson; Emre M. Isin; Yan Li; Richard Weaver; Lars Weidolf; Ian Wilson; Alf Claesson; Ken Page; Hugues Dolgos; J. Gerry Kenna

2011-01-01

289

Methods for the assessment of the effects of drugs on coronary blood flow in man.  

PubMed Central

The methods currently available for measurement of coronary blood flow in man are reviewed and their advantages and limitations discussed. Most of the techniques are invasive and involve cardiac catheterization. The least invasive isotope techniques are either not quantitative or involve expensive equipment not available in many centres. Two of the most suitable methods for assessing the effects of drugs on coronary flow are coronary sinus thermodilution and isotope washout curves using 133xenon or [125I]-iodo-antipyrine. The ideal technique for measuring coronary blood flow has yet to be developed.

Swanton, R H; Coltart, D J

1978-01-01

290

Hybrid Method to Assess Sensitive Process Interruption Costs Due to Faults in Electric Power Distribution Networks  

Microsoft Academic Search

This paper shows a new hybrid method for risk assessment regarding interruptions in sensitive processes due to faults in electric power distribution systems. This method determines indices related to long duration interruptions and short duration voltage variations (SDVV), such as voltage sags and swells in each customer supplied by the distribution network. Frequency of such occurrences and their impact on

Juan C. Cebrian; Nelson Kagan

2010-01-01

291

Assessment of energy distribution losses for increasing penetration of distributed generation  

Microsoft Academic Search

High levels of penetration of distributed generation (DG) are a new challenge for traditional electric power systems. Power injections from DGs change network power flows modifying energy losses. Although it is considered that DG reduce losses, this paper shows that this is not always true. This paper presents an approach to compute annual energy losses variations when different penetration and

Víctor H. Méndez Quezada; Juan Rivier Abbad; Tomás Gómez San Román

2006-01-01

292

Multilevel Security Assessment for the Distributed Mission Operations Network (DMON)1  

Microsoft Academic Search

This paper presents the technical and policy issues, architectural considerations, ongoing assessment results, and plans for Distributed Mission Operations Network (DMON) multi-level security (MLS) implementation. In this paper, the Combat Air Force (CAF) Distributed Mission Operations (DMO) Operations and Integration (O&I) team builds on previous Combat Air Force Distributed Mission Operations Multi-Level Security feasibility research and recommendations. Combat Air Force

Bonnie Danner; Tony Valle

293

Drug quality in South Africa: perceptions of key players involved in medicines distribution  

Microsoft Academic Search

Purpose – Substandard medicines contribute to poor public health and affect development, especially in the developing world. However knowledge of how manufacturers, distributors and providers understand the concept of drug quality and what strategies they adopt to ensure drug quality is limited, particularly in the developing world. The purpose of this paper is to explore pharmaceutical manufacturers', distributors' and providers'

Aarti Patel; Pauline Norris; Robin Gauld; Thomas Rades

2009-01-01

294

Distributive sharing among HIV-HCV co-infected injecting drug users: the preventive role of trust in one's physician.  

PubMed

This study, based on data from the MANIF 2000 cohort study, investigates the relationship between the lending of injecting equipment, drug use, and experience with HIV care. The sample comprised 224 HIV-HCV co-infected patients who reported having injected drugs in the previous six months and their 538 visits to clinical services. Longitudinal data were collected for medical status, and self-reported risk behaviors. A logistic regression GEE model was used to identify correlates of distributive sharing. After multiple adjustment, patients who reported trust in physicians were significantly less likely to report lending injection equipment while cocaine users were at increased risk. Promoting dialog between physicians and injecting drug users (IDUs) may play an important role in HIV-HCV positive prevention. PMID:21777078

Jauffret-Roustide, Marie; Cohen, Julien; Poisot-Martin, Isabelle; Spire, Bruno; Gossop, Michael; Carrieri, M Patrizia

2011-07-21

295

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.

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

2012-01-01

296

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

297

Update on World Health Organization HIV Drug Resistance Prevention and Assessment Strategy: 2004-2011  

PubMed Central

The HIV drug resistance (HIVDR) prevention and assessment strategy, developed by the World Health Organization (WHO) in partnership with HIVResNet, includes monitoring of HIVDR early warning indicators, surveys to assess acquired and transmitted HIVDR, and development of an accredited HIVDR genotyping laboratory network to support survey implementation in resource-limited settings. As of June 2011, 52 countries had implemented at least 1 element of the strategy, and 27 laboratories had been accredited. As access to antiretrovirals expands under the WHO/Joint United Nations Programme on HIV/AIDS Treatment 2.0 initiative, it is essential to strengthen HIVDR surveillance efforts in the face of increasing concern about HIVDR emergence and transmission.

Bennett, D. E.; Wainberg, M. A.; Havlir, D.; Hammer, S.; Yang, C.; Morris, L.; Peeters, M.; Wensing, A. M.; Parkin, N.; Nachega, J. B.; Phillips, A.; De Luca, A.; Geng, E.; Calmy, A.; Raizes, E.; Sandstrom, P.; Archibald, C. P.; Perriens, J.; McClure, C. M.; Hong, S. Y.; McMahon, J. H.; Dedes, N.; Sutherland, D.; Bertagnolio, S.

2012-01-01

298

Evaluation of pre-analysis loss of dependent drugs in wastewater: stability and binding assessments.  

PubMed

Wastewater analysis has the potential to provide objective and timely data on population drug consumption, but some crucial factors such as pre-analysis drug loss during sample storage and filtration could affect the accuracy and reliability of the method, and these uncertainties have yet to be fully assessed. This study was designed to evaluate analyte stability in wastewater stored under different conditions with the aim of optimizing the sample storage procedures for future studies. It also investigated whether there is significant analyte loss during filtration before sample extraction and storage after that. The studied substances and metabolites were: cotinine, cocaine and its metabolite benzoylecgonine, phenethylamines amphetamine, methamphetamine, 3,4-methylenedioxyamphetamine (MDA), 3,4-methylenedioxymethamphetamine (MDMA), opioids including codeine, methadone, 6-monoacetylmorphine (MAM) and morphine. In most situations, storing samples at 4?°C is sufficient to stabilize analytes for at least 2?weeks, and refrigeration is unnecessary during sample transportation within 3?days. However, additional measures need to be taken if unstable analytes such as cocaine and MAM are to be analyzed. No significant analyte loss was observed in the filtration process or in reconstituted extract stored at 4?°C or -20?°C for 2?weeks. By choosing stable analytes and proper storage conditions, wastewater analysis has the potential to provide accurate data for estimation of community drug use. Copyright © 2012 John Wiley & Sons, Ltd. PMID:23047767

Chen, Chang; Kostakis, Chris; Irvine, Rodney J; Felgate, Peter D; White, Jason M

2012-10-09

299

A choice procedure to assess the aversive effects of drugs in rodents.  

PubMed

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 each of two levers with concurrently available fixed-ratio 1 schedules of food reinforcement. Intravenous histamine was delivered along with food when responses were made on one of the options, and the lever on which both food and histamine were contingent was switched on a regular basis. A dose of 1.0 mg/kg/inj of histamine was effective in moving responding to the alternate lever, whereas saline, 0.1, or 0.3 mg/kg/inj of histamine were not. Histamine injections produced reliable selection of the alternate lever when they were presented on the same lever for three consecutive sessions, but not when they were switched between levers on each session. In addition, histamine produced greater selection of the alternate lever when it was presented with shorter intertrial interval durations. These findings indicate that, with appropriate parameters, the aversive effects of histamine and perhaps other drugs can be established rapidly using a concurrent choice procedure. PMID:20885811

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

2010-03-01

300

On the Use of the Beta Distribution in Probabilistic Resource Assessments  

SciTech Connect

The triangular distribution is a popular choice when it comes to modeling bounded continuous random variables. Its wide acceptance derives mostly from its simple analytic properties and the ease with which modelers can specify its three parameters through the extremes and the mode. On the negative side, hardly any real process follows a triangular distribution, which from the outset puts at a disadvantage any model employing triangular distributions. At a time when numerical techniques such as the Monte Carlo method are displacing analytic approaches in stochastic resource assessments, easy specification remains the most attractive characteristic of the triangular distribution. The beta distribution is another continuous distribution defined within a finite interval offering wider flexibility in style of variation, thus allowing consideration of models in which the random variables closely follow the observed or expected styles of variation. Despite its more complex definition, generation of values following a beta distribution is as straightforward as generating values following a triangular distribution, leaving the selection of parameters as the main impediment to practically considering beta distributions. This contribution intends to promote the acceptance of the beta distribution by explaining its properties and offering several suggestions to facilitate the specification of its two shape parameters. In general, given the same distributional parameters, use of the beta distributions in stochastic modeling may yield significantly different results, yet better estimates, than the triangular distribution.

Olea, Ricardo A., E-mail: olea@usgs.gov [U.S. Geological Survey (United States)

2011-12-15

301

Prediction of steady-state volume of distribution of acidic drugs by quantitative structure-pharmacokinetics relationships.  

PubMed

The volume of distribution (VD) is one of the most important pharmacokinetic parameters of drugs. The present study employs quantitative structure-pharmacokinetics relationships (QSPkR) to derive models for VD prediction of acidic drugs. The steady-state volume of distribution (VD(ss)) values of 132 acidic drugs were collected, the chemical structures were described by 178 molecular descriptors, and QSPkR models were derived after variable selection by genetic algorithm and stepwise regression. Models were validated by cross-validation procedures and external test set. According to the molecular descriptors selected as the most predictive for VD(ss), the presence of seven- and nine-member cycles, atom type P(5+), SH groups, and large nonionized substituents increase the VD(ss), whereas atom types S(2+) and S(4+) and polar ionized substituents decrease it. Cross-validation and external validation studies on the QSPkR models derived in the present study showed good predictive ability with mean fold error values ranging from 1.58 (cross-validation) to 2.25 (external validation). The model performance is comparable to more complicated methods requiring in vitro or in vivo experiments and superior to the existing QSPkR models concerning acidic drugs. Apart from the prediction of VD in human, present models are also useful as a curator of available pharmacokinetic databases. PMID:22170307

Zhivkova, Zvetanka; Doytchinova, Irini

2011-12-13

302

Uncertainty Distribution Associated with Estimating a Proportion in Microbial Risk Assessment  

Microsoft Academic Search

The uncertainty associated with estimates should be taken into account in quantitative risk assessment. Each input's uncertainty can be characterized through a probabilistic distribution for use under Monte Carlo simulations. In this study, the sampling uncertainty associated with estimating a low proportion on the basis of a small sample size was considered. A common application in microbial risk assessment is

Nicolas Miconnet; Marie Cornu; Annie Beaufort; Laurent Rosso; Jean-Baptiste Denis

2005-01-01

303

Analysis of Time Distribution in Traffic Accident Based on Fuzzy Assessment Method  

Microsoft Academic Search

In light of China's traffic accident status much; this paper focuses on the problem of reducing the occurrence of traffic accidents. Based on the traffic accident data within a year in certain section of Tianjin, this paper studies the application of fuzzy assessment method in analysis of time distribution of traffic accidents. We use fuzzy assessment method to get the

He Song-bai; Wei Ai-guo; Yu Dian-xiang; Tan Zhong; Wang Peng

2009-01-01

304

Literature based drug interaction prediction with clinical assessment using electronic medical records: novel myopathy associated drug interactions.  

PubMed

Drug-drug interactions (DDIs) are a common cause of adverse drug events. In this paper, we combined a literature discovery approach with analysis of a large electronic medical record database method to predict and evaluate novel DDIs. We predicted an initial set of 13197 potential DDIs based on substrates and inhibitors of cytochrome P450 (CYP) metabolism enzymes identified from published in vitro pharmacology experiments. Using a clinical repository of over 800,000 patients, we narrowed this theoretical set of DDIs to 3670 drug pairs actually taken by patients. Finally, we sought to identify novel combinations that synergistically increased the risk of myopathy. Five pairs were identified with their p-values less than 1E-06: loratadine and simvastatin (relative risk or RR?=?1.69); loratadine and alprazolam (RR?=?1.86); loratadine and duloxetine (RR?=?1.94); loratadine and ropinirole (RR?=?3.21); and promethazine and tegaserod (RR?=?3.00). When taken together, each drug pair showed a significantly increased risk of myopathy when compared to the expected additive myopathy risk from taking either of the drugs alone. Based on additional literature data on in vitro drug metabolism and inhibition potency, loratadine and simvastatin and tegaserod and promethazine were predicted to have a strong DDI through the CYP3A4 and CYP2D6 enzymes, respectively. This new translational biomedical informatics approach supports not only detection of new clinically significant DDI signals, but also evaluation of their potential molecular mechanisms. PMID:22912565

Duke, Jon D; Han, Xu; Wang, Zhiping; Subhadarshini, Abhinita; Karnik, Shreyas D; Li, Xiaochun; Hall, Stephen D; Jin, Yan; Callaghan, J Thomas; Overhage, Marcus J; Flockhart, David A; Strother, R Matthew; Quinney, Sara K; Li, Lang

2012-08-09

305

Literature Based Drug Interaction Prediction with Clinical Assessment Using Electronic Medical Records: Novel Myopathy Associated Drug Interactions  

PubMed Central

Drug-drug interactions (DDIs) are a common cause of adverse drug events. In this paper, we combined a literature discovery approach with analysis of a large electronic medical record database method to predict and evaluate novel DDIs. We predicted an initial set of 13197 potential DDIs based on substrates and inhibitors of cytochrome P450 (CYP) metabolism enzymes identified from published in vitro pharmacology experiments. Using a clinical repository of over 800,000 patients, we narrowed this theoretical set of DDIs to 3670 drug pairs actually taken by patients. Finally, we sought to identify novel combinations that synergistically increased the risk of myopathy. Five pairs were identified with their p-values less than 1E-06: loratadine and simvastatin (relative risk or RR?=?1.69); loratadine and alprazolam (RR?=?1.86); loratadine and duloxetine (RR?=?1.94); loratadine and ropinirole (RR?=?3.21); and promethazine and tegaserod (RR?=?3.00). When taken together, each drug pair showed a significantly increased risk of myopathy when compared to the expected additive myopathy risk from taking either of the drugs alone. Based on additional literature data on in vitro drug metabolism and inhibition potency, loratadine and simvastatin and tegaserod and promethazine were predicted to have a strong DDI through the CYP3A4 and CYP2D6 enzymes, respectively. This new translational biomedical informatics approach supports not only detection of new clinically significant DDI signals, but also evaluation of their potential molecular mechanisms.

Subhadarshini, Abhinita; Karnik, Shreyas D.; Li, Xiaochun; Hall, Stephen D.; Jin, Yan; Callaghan, J. Thomas; Overhage, Marcus J.; Flockhart, David A.; Strother, R. Matthew; Quinney, Sara K.; Li, Lang

2012-01-01

306

A new model for prediction of drug distribution in tumor and normal tissues: pharmacokinetics of temozolomide in glioma patients.  

PubMed

Difficulties in direct measurement of drug concentrations in human tissues have hampered the understanding of drug accumulation in tumors and normal tissues. We propose a new system analysis modeling approach to characterize drug distribution in tissues based on human positron emission tomography (PET) data. The PET system analysis method was applied to temozolomide, an important alkylating agent used in the treatment of brain tumors, as part of standard temozolomide treatment regimens in patients. The system analysis technique, embodied in the convolution integral, generated an impulse response function that, when convolved with temozolomide plasma concentration input functions, yielded predicted normal brain and brain tumor temozolomide concentration profiles for different temozolomide dosing regimens (75-200 mg/m(2)/d). Predicted peak concentrations of temozolomide ranged from 2.9 to 6.7 microg/mL in human glioma tumors and from 1.8 to 3.7 microg/mL in normal brain, with the total drug exposure, as indicated by the tissue/plasma area under the curve ratio, being about 1.3 in tumor compared with 0.9 in normal brain. The higher temozolomide exposures in brain tumor relative to normal brain were attributed to breakdown of the blood-brain barrier and possibly secondary to increased intratumoral angiogenesis. Overall, the method is considered a robust tool to analyze and predict tissue drug concentrations to help select the most rational dosing schedules. PMID:19117994

Rosso, Lula; Brock, Cathryn S; Gallo, James M; Saleem, Azeem; Price, Patricia M; Turkheimer, Federico E; Aboagye, Eric O

2009-01-01

307

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

308

The World Health Organization's global strategy for prevention and assessment of HIV drug resistance.  

PubMed

Antiretroviral treatment (ART) for HIV is being scaled up rapidly in resource-limited countries. Treatment options are simplified and standardized, generally with one potent first-line regimen and one potent alternate first-line regimen recommended. Widespread HIV drug resistance (HIVDR) was initially feared, but reports from resource-limited countries suggest that initial ART programmes are as effective as in resource-rich countries, which should limit HIV drug resistance if programme effectiveness continues during scale-up. ART interruptions must be minimized to maintain viral suppression on the first-line regimen for as long as possible. Lack of availability of appropriate second-line drugs is a concern, as is the additional accumulation of resistance mutations in the absence of viral load testing to determine failure. The World Health Organization (WHO) recommends a minimum-resource strategy for prevention and assessment of HIVDR in resource-limited countries. The WHO's Global Network HIVResNet provides standardized tools, training, technical assistance, laboratory quality assurance, analysis of results and recommendations for guidelines and public health action. National strategies focus on assessments to guide immediate public health action to improve ART programme effectiveness in minimizing HIVDR and to guide regimen selection. Globally, WHO HIVResNet collects and analyses data to support evidence-based international policies and guidelines. Financial support is provided by major international organizations and technical support from HIVDR experts worldwide. As of December 2007, 25 countries were planning or implementing the strategy; seven countries report results in this supplement. PMID:18578063

Bennett, Diane E; Bertagnolio, Silvia; Sutherland, Donald; Gilks, Charles F

2008-01-01

309

Assessment of candidate biomarkers of drug-induced hepatobiliary injury in preclinical toxicity studies.  

PubMed

This study was designed to assess the value of a set of potential markers for improved detection of liver injury in preclinical toxicity studies. Male Wistar rats were treated with drug candidates (BAY16, EMD335823, BI-3) that previously failed during development, in part due to hepatotoxicity, at two dose levels for 1, 3 and 14 days. Concentrations of lipocalin-2/NGAL and clusterin, which are frequently overexpressed and released from damaged tissues, and thiostatin, recently identified within PredTox as being elevated in urine in response to liver injury, were determined in rat urine and serum by ELISA. This was supplemented by confirmatory qRT-PCR and immunohistochemical analyses in the target organ. Serum paraoxonase-1 activity (PON1), which has been suggested as a marker of hepatotoxicity, was determined using a fluorometric assay. Clusterin and PON1 were not consistently altered in response to liver injury. In contrast, thiostatin and NGAL were increased in serum and urine of treated animals in a time- and dose-dependent manner. These changes correlated well with mRNA expression in the target organ and generally reflected the onset and degree of drug-induced liver injury. Receiver-operating characteristics (ROC) analyses supported serum thiostatin, but not NGAL, as a better indicator of drug-induced hepatobiliary injury than conventional clinical chemistry parameters, i.e. ALP, ALT and AST. Although thiostatin, an acute phase protein expressed in a range of tissues, may not be specific for liver injury, our results indicate that thiostatin may serve as a sensitive, minimally-invasive diagnostic marker of inflammation and tissue damage in preclinical safety assessment. PMID:20362651

Adler, M; Hoffmann, D; Ellinger-Ziegelbauer, H; Hewitt, P; Matheis, K; Mulrane, L; Gallagher, W M; Callanan, J J; Suter, L; Fountoulakis, M M; Dekant, W; Mally, A

2010-04-01

310

Assessing the efficacy of drugs for the acute treatment of migraine: issues in clinical trial design.  

PubMed

Clinical trials of therapies for acute migraine attacks have evolved over the years from open-label, small observational studies to highly structured randomised, controlled trials. The International Headache Society Committee on Clinical Trials in Migraine developed a tool to guide in designing scientifically sound trials. The proof of effect is best achieved in a clinical trial with: clearly defined objectives;a well-characterised study population, identified using well-validated diagnostic tools;proper randomisation and blinding;inclusion of a placebo arm, with proper balancing of patients receiving placebo and those receiving active drug;adequate study power; and appropriate statistical methods. Both parallel and crossover studies may be suitable in clinical trials of antimigraine agents, although the latter are a better choice in patient preference and bioequivalence studies. Although various efficacy measures are used to assess treatment effect, the 2-hour pain free rate (total resolution of pain within 2 hours after an initial moderate to severe headache) is preferred because it is clinically relevant and is relatively 'placebo-insensitive'. Various migraine surveys have indicated that a rapid onset of therapeutic effect is a highly desirable attribute of an antimigraine drug. Therefore, accurate measurements of treatment effect before 2 hours are becoming increasingly emphasised. Consistency of effect across multiple attacks adds to the understanding of the therapeutic efficacy of a test drug. Finally, preference and satisfaction studies allow us to assess patients' global impression of a particular treatment, weighing the positive effects on pain and associated symptoms of migraine against potential adverse effects. PMID:11888339

Ramadan, Nabih M

2002-01-01

311

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

2007-07-30

312

How extreme is extreme? An assessment of daily rainfall distribution tails  

NASA Astrophysics Data System (ADS)

The upper part of a probability distribution, usually known as the tail, governs both the magnitude and the frequency of extreme events. The tail behaviour of all probability distributions may be, loosely speaking, categorized into two families: heavy-tailed and light-tailed distributions, with the latter generating "milder" and less frequent extremes compared to the former. This emphasizes how important for hydrological design it is to assess the tail behaviour correctly. Traditionally, the wet-day daily rainfall has been described by light-tailed distributions like the Gamma distribution, although heavier-tailed distributions have also been proposed and used, e.g., the Lognormal, the Pareto, the Kappa, and other distributions. Here we investigate the distribution tails for daily rainfall by comparing the upper part of empirical distributions of thousands of records with four common theoretical tails: those of the Pareto, Lognormal, Weibull and Gamma distributions. Specifically, we use 15 029 daily rainfall records from around the world with record lengths from 50 to 172 yr. The analysis shows that heavier-tailed distributions are in better agreement with the observed rainfall extremes than the more often used lighter tailed distributions. This result has clear implications on extreme event modelling and engineering design.

Papalexiou, S. M.; Koutsoyiannis, D.; Makropoulos, C.

2013-02-01

313

Interspecies Comparison of the Tissue Distribution of Wr-2721, a Radioprotective Drug.  

National Technical Information Service (NTIS)

Pre-irradiation intravenous administration of the radioprotective drug S-2-(3-aminopropylamino)ethylphosphorothioic acid (WR-2721) has potential value in radiotherapy because it doubles the radiation resistance of normal mouse tissues while affording only...

L. C. Washburn J. J. Rafter R. L. Hayes J. M. Yuhas

1975-01-01

314

An assessment of quality of sleep and the use of drugs with sedating properties in hospitalized adult patients  

Microsoft Academic Search

BACKGROUND: Hospitalization can significantly disrupt sleeping patterns. In consideration of the previous reports of insomnia and apparent widespread use of benzodiazepines and other hypnotics in hospitalized patients, we conducted a study to assess quality of sleep and hypnotic drug use in our acute care adult patient population. The primary objectives of this study were to assess sleep disturbance and its

Luciana Frighetto; Carlo Marra; Shakeel Bandali; Kerry Wilbur; Terryn Naumann; Peter Jewesson

2004-01-01

315

A rapid assessment and its implications for a needle social marketing intervention among injecting drug users in China  

Microsoft Academic Search

A two week rapid assessment was conducted as part of a feasibility study for a needle social marketing intervention in a semi-urban community in Guangxi Autonomous Region, China, in October 1999. The aim of the rapid assessment was to collect data on local drug user values and behaviours to assist in the design of an acceptable needle social marketing intervention,

Lorraine Yap; Zunyou Wu; Wei Liu; Zhongqiang Ming; Shaoling Liang

2002-01-01

316

Improving the Decision-Making Process for Nonprescription Drugs: A Framework for Benefit–Risk Assessment  

Microsoft Academic Search

Nonprescription drugs pose unique challenges to regulators. The fact that the barriers to access are lower for nonprescription drugs as compared with prescription drugs may permit additional consumers to obtain effective drugs. However, the use of these drugs by consumers in the absence of supervision by a health-care professional may result in unacceptable rates of misuse and suboptimal clinical outcomes.

E P Brass; R Lofstedt; O Renn

2011-01-01

317

Distributive Fluvial Systems of the Chaco Plain - Satellite Image Assessment of Fluvial Form and Facies Distributions  

NASA Astrophysics Data System (ADS)

Distributive fluvial systems (DFS) dominate fluvial deposition inside modern continental sedimentary basins and are particularly extensive in modern foreland basins. The largest of these DFS are found in the Chaco Plain, Andean Foreland Basin, South America. We use published literature, field and satellite data (Landsat, Modis, and SRTM) to construct preliminary hypotheses about the geomorphic form and fluvial facies distributions on the DFSs in this basin. The Pilcomayo River DFS extends over 700 km from apex to toe. The river enters the DFS apex as a large braided river with a bankfull channel width of 2500 m. Gravels and cobbles occur in terraces cut through the apex. At ~70-km downstream the bankfull channel width is ~2000 m and the channel is dominated by fine sand with cut banks 2-3 m high. The proximal channel belt is surrounded by floodplain sediments, however many sandy abandoned channel belts are present across the DFS, indicating a mobile channel system. Abandoned channels have a similar form to the modern channel, with minor reworking by underfit meandering streams. At ~75-km downfan, the river system diminishes in size (bankfull channel width up to 2 km but generally <1.5 km) and becomes increasingly sinuous in planform. This point appears to serve as a node for a series of recently abandoned meander belts and splays associated with discrete channels surrounded by floodplain material. At 100 km downstream the planform is highly sinuous and bankfull width has decreased to 1500 m or less. Downstream of this area abandoned meander belts dominate along the flanks of the modern channel with oxbow lakes present adjacent to the active channel. At 150 km downstream the bankfull channel belt width is 500 m or less and the river bifurcates into splays and multiple active channels which extend downstream for a further 200 km. Vegetation maps derived from Modis imagery indicate an increase in tree density around the DFS at this elevation (230 m). Along the distal portion of the DFS, a springline at ~150 m elevation separates the upper, well drained, aridisol dominated dry Chaco area of the DFS from the poorly drained wet Chaco at the toe. Channels below this line remain wet, are mud-dominated, and associated soils are hydromorphic. At the termination of the DFS the main Pilcomayo channel has a bankfull width of 120 m with sediments consisting of interbedded fine sand and mudstone. The observations from the Pilcomayo can serve as important analogues for the development of DFS in ancient foreland basin successions, particularly the recognition of the radial distribution of distinct facies types and the downstream changes in soil types associated with the spring line.

Weissmann, G. S.; Hartley, A. J.; Scuderi, L.; Bhattacharyya, P.; Buehler, H.; Leleu, S.; Mather, A.

2009-12-01

318

Greater Drug Injecting Risk for HIV, HBV, and HCV Infection in a City Where Syringe Exchange and Pharmacy Syringe Distribution are Illegal  

PubMed Central

Comparing drug-injecting risk between cities that differ in the legality of sterile syringe distribution for injection drug use provides a natural experiment to assess the efficacy of legalizing sterile syringe distribution as a structural intervention to prevent human immunodeficiency virus (HIV) and other parenterally transmitted infections among injection drug users (IDUs). This study compares the parenteral risk for HIV and hepatitis B (HBV) and C (HCV) infection among IDUs in Newark, NJ, USA, where syringe distribution programs were illegal during the period when data were collected, and New York City (NYC) where they were legal. IDUs were nontreatment recruited, 2004–2006, serotested, and interviewed about syringe sources and injecting risk behaviors (prior 30 days). In multivariate logistic regression, adjusted odds ratios (AOR) and 95% confidence intervals (95% CI) for city differences are estimated controlling for potential city confounders. IDUs in Newark (n?=?214) vs. NYC (n?=?312) were more likely to test seropositive for HIV (26% vs. 5%; AOR?=?3.2; 95% CI?=?1.6, 6.1), antibody to the HBV core antigen (70% vs. 27%; AOR?=?4.4; 95% CI?=?2.8, 6.9), and antibody to HCV (82% vs. 53%; AOR?=?3.0; 95% CI?=?1.8, 4.9), were less likely to obtain syringes from syringe exchange programs or pharmacies (AOR?=?0.004; 95% CI?=?0.001, 0.01), and were more likely to obtain syringes from street sellers (AOR?=?74.0; 95% CI?=?29.9, 183.2), to inject with another IDU’s used syringe (AOR?=?2.3; 95% CI?=?1.1, 5.0), to reuse syringes (AOR?=?2.99; 95% CI?=?1.63, 5.50), and to not always inject once only with a new, sterile syringe that had been sealed in a wrapper (AOR?=?5.4; 95% CI?=?2.9, 10.3). In localities where sterile syringe distribution is illegal, IDUs are more likely to obtain syringes from unsafe sources and to engage in injecting risk behaviors. Legalizing and rapidly implementing sterile syringe distribution programs are critical for reducing parenterally transmitted HIV, HBV, and HCV among IDUs.

Zhao, Mingfang; Gyarmathy, V. Anna; Cisek, Linda; Friedman, Samuel R.; Baxter, Robert C.

2008-01-01

319

A post-trial assessment of factors influencing study drug adherence in a randomized biomedical HIV-1 prevention trial  

PubMed Central

High adherence and maintenance of blinding are critical for placebo-controlled efficacy trials of HIV-1 biomedical prevention strategies. We assessed adherence to study drug and factors affecting adherence, including perceived randomization group, in a post-trial questionnaire of participants who completed HPTN 039, a randomized, placebo-controlled trial of HSV-2 suppression with twice-daily acyclovir to reduce HIV-1 acquisition. Of the 3172 trial participants, 2003 (63%) completed the post-trial questionnaire. Of these 2003, 72% reported missing a dose of study drug less than twice a week. Study drug adherence was not compromised by perceived randomization or genital ulcer symptoms during the study. Alcohol use was cited as an adherence barrier in some populations. Assessment of study drug adherence during and at the end of trials can evaluate perceptions of randomization and adherence by randomization arm, help to better understand barriers to and motivations for adherence, and develop interventions to increase adherence for future trials.

Jacob, Shevin T.; Baeten, Jared M.; Hughes, James P.; Peinado, Jesus; Wang, Jing; Sanchez, Jorge; Reid, Stewart E.; Delany-Moretlwe, Sinead; Cowan, Frances; Fuchs, Jonathan; Koblin, Beryl; Griffith, Sam; Wald, Anna; Celum, Connie

2010-01-01

320

Rapid in vivo assessment of drug efficacy against Mycobacterium tuberculosis using an improved firefly luciferase  

PubMed Central

Objectives In vivo experimentation is costly and time-consuming, and presents a major bottleneck in anti-tuberculosis drug development. Conventional methods rely on the enumeration of bacterial colonies, and it can take up to 4 weeks for Mycobacterium tuberculosis to grow on agar plates. Light produced by recombinant bacteria expressing luciferase enzymes can be used as a marker of bacterial load, and disease progression can be easily followed non-invasively in live animals by using the appropriate imaging equipment. The objective of this work was to develop a bioluminescence-based mouse model of tuberculosis to assess antibiotic efficacy against M. tuberculosis in vivo. Methods We used an M. tuberculosis strain carrying a red-shifted derivative of the firefly luciferase gene (FFlucRT) to infect mice, and monitored disease progression in living animals by bioluminescence imaging before and after treatment with the frontline anti-tuberculosis drug isoniazid. The resulting images were analysed and the bioluminescence was correlated with bacterial counts. Results Using bioluminescence imaging we detected as few as 1.7?×?103 and 7.5?×?104 reporter bacteria ex vivo and in vivo, respectively, in the lungs of mice. A good correlation was found between bioluminescence and bacterial load in both cases. Furthermore, a marked reduction in luminescence was observed in living mice given isoniazid treatment. Conclusions We have shown that an improved bioluminescent strain of M. tuberculosis can be visualized by non-invasive imaging in live mice during an acute, progressive infection and that this technique can be used to rapidly visualize and quantify the effect of antibiotic treatment. We believe that the model presented here will be of great benefit in early drug discovery as an easy and rapid way to identify active compounds in vivo.

Andreu, Nuria; Zelmer, Andrea; Sampson, Samantha L.; Ikeh, Melanie; Bancroft, Gregory J.; Schaible, Ulrich E.; Wiles, Siouxsie; Robertson, Brian D.

2013-01-01

321

¹?F-labeled modified porous silicon particles for investigation of drug delivery carrier distribution in vivo with positron emission tomography.  

PubMed

Because of its biocompatibility and ability to accommodate a variety of payloads from poorly soluble drugs to biomolecules, porous silicon (PSi) is a lucrative material for the development of carriers for particle-mediated drug delivery. We report a successful direct one-step (18)F-radiolabeling of three types of PSi microparticles, thermally hydrocarbonized THCPSi, thermally oxidized TOPSi, and thermally carbonized TCPSi for the investigation of their biodistribution in vivo with positron emission tomography as part of their evaluation as carriers for particle-mediated drug delivery. FTIR and XPS characterization of the PSi materials after carrier-added (18)F/(19)F-radiolabeling reveals that depending on the material the (18)F-labeling is likely to be accomplished either by substitution for surface silyl hydrogen or silyl fluoride or by nucleophilic attack of (18)F(-) to Si-O-Si bridges. With the selected (18)F-radiolabeling method, good to excellent in vitro radiolabel stability in simulated gastric and intestinal fluids and in plasma is achieved for all the particle types studied. Finally, a preliminary evaluation of (18)F-THCPSi microparticle biodistribution in the rat gastrointestinal tract after oral administration is reported, illustrating the utility of using (18)F-radiolabeled PSi as imaging probes for PSi-based drug delivery carrier distribution in vivo. PMID:21875120

Sarparanta, Mirkka; Mäkilä, Ermei; Heikkilä, Teemu; Salonen, Jarno; Kukk, Edwin; Lehto, Vesa-Pekka; Santos, Hélder A; Hirvonen, Jouni; Airaksinen, Anu J

2011-09-07

322

Prediction of drug terminal half-life and terminal volume of distribution after intravenous dosing based on drug clearance, steady-state volume of distribution, and physiological parameters of the body.  

PubMed

The steady state, V(ss), terminal volume of distribution, V(?), and the terminal half-life, t(1/2), are commonly obtained from the drug plasma concentration-time profile, C(p)(t), following intravenous dosing. Unlike V(ss) that can be calculated based on the physicochemical properties of drugs considering the equilibrium partitioning between plasma and organ tissues, t(1/2) and V(?) cannot be calculated that way because they depend on the rates of drug transfer between blood and tissues. Considering the physiological pharmacokinetic model pertinent to the terminal phase of drug elimination, a novel equation that calculates t(1/2) (and consequently V(?)) was derived. It turns out that V(ss), the total body clearance, Cl, equilibrium blood-plasma concentration ratio, r; and the physiological parameters of the body such as cardiac output, and blood and tissue volumes are sufficient for determination of terminal kinetics. Calculation of t(1/2) by the obtained equation appears to be in good agreement with the experimentally observed vales of this parameter in pharmacokinetic studies in rat, monkey, dog, and human. The equation for the determination of the pre-exponent of the terminal phase of C(p)(t) is also found. The obtained equation allows to predict t(1/2) in human assuming that V(ss) and Cl were either obtained by allometric scaling or, respectively, calculated in silico or based on in vitro drug stability measurements. For compounds that have high clearance, the derived equation may be applied to calculate r just using the routine data on Cl, V(ss), and t(1/2), rather than doing the in vitro assay to measure this parameter. PMID:23233148

Berezhkovskiy, Leonid M

2012-12-11

323

Assessment of function and clinical utility of alcohol and other drug web sites: An observational, qualitative study  

Microsoft Academic Search

Background  The increasing popularity and use of the internet makes it an attractive option for providing health information and treatment,\\u000a including alcohol\\/other drug use. There is limited research examining how people identify and access information about alcohol\\u000a or other drug (AOD) use online, or how they assess the usefulness of the information presented. This study examined the strategies\\u000a that individuals used

Frances J Kay-Lambkin; Angela White; Amanda L Baker; David J Kavanagh; Britt Klein; Judith Proudfoot; Judy Drennan; Jason Connor; Ross M Young

2011-01-01

324

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

325

In vitro assessment of drug resistance in Plasmodium falciparum in five States of India  

PubMed Central

Background & objectives: In vitro assays are an important tool to assess baseline sensitivity and monitor the drug response of Plasmodium falciparum over time and place and, therefore, can provide background information for the development and evaluation of drug policies. This study was aimed at determining the in vitro sensitivity of P. falciparum isolates to antimalarials. Methods: The in vitro activity of 108 P. falciparum isolates obtained from five States of India was evaluated using WHO microtest (Mark III) to chloroquine, monodesethylamodiaquine, dihydroartesunate and mefloquine. Samples were collected from the States of Orissa, Jharkhand, Karnataka, Goa and Chhattisgarh from September 2007 to August 2009. In addition, representative samples from different States of India cryopreserved and culture adapted in the Malaria Parasite Bank of National Institute of Malaria Research, New Delhi, were also evaluated. Results: The proportion of isolates resistant to chloroquine and monodesethylamodiaquine was 44.4 and 25 per cent, respectively. Of the 27 isolates resistant to monodesethylamodiaquine, 16 (59.3%) were cross-resistant to chloroquine. No isolate showed resistance to dihydroartesunate and mefloquine. Isolates from Orissa showed the highest degree of resistance to chloroquine and amodiaquine followed by Jharkhand. Forty two isolates were genotyped for pfcrt T76K chloroquine resistant mutation; mutations were seen in 38 (90.47%) isolates. Interpretation & conclusions: The Indian P. falciparum isolates showed a high degree of resistance to chloroquine followed by monodesethylamodiaquine. No resistance was recorded to mefloquine and dihydroartesunate.

Anvikar, Anupkumar R.; Sharma, Bhawna; Sharma, S.K.; Ghosh, S.K.; Bhatt, R.M.; Kumar, Ashwani; Mohanty, S.S.; Pillai, C.R.; Dash, A.P.; Valecha, Neena

2012-01-01

326

Using zebrafish to assess the impact of drugs on neural development and function  

PubMed Central

Background Zebrafish is becoming an increasingly attractive model organism for understanding biology and developing therapeutics, because as a vertebrate, it shares considerable similarity with mammals in both genetic compositions and tissue/organ structures, and yet remains accessible to high throughput phenotype-based genetic and small molecule compound screening. Objective/method The focus of this review is on the nervous system, which is arguably the most complex organ and known to be afflicted by more than six hundred disorders in humans. I discuss the past, present, and future of using zebrafish to assess the impact of small molecule drugs on neural development and function, in light of understanding and treating neurodevelopmental disorders such as autism, neurodegenerative disorders including Alzheimer’s, Parkinson’s, and Hungtington’s disease, and neural system dysfunctions such as anxiety/depression and addiction. Conclusion These studies hold promise to reveal fundamental mechanisms governing nervous system development and function, and to facilitate small molecule drug discovery for the many types of neurological disorders.

Guo, Su

2009-01-01

327

Lipophilicity assessment of basic drugs (log P(o/w) determination) by a chromatographic method.  

PubMed

A previously reported chromatographic method to determine the 1-octanol/water partition coefficient (log P(o/w)) of organic compounds is used to estimate the hydrophobicity of bases, mainly commercial drugs with diverse chemical nature and pK(a) values higher than 9. For that reason, mobile phases buffered at high pH to avoid the ionization of the solutes and three different columns (Phenomenex Gemini NX, Waters XTerra RP-18 and Waters XTerra MS C(18)) with appropriate alkaline-resistant stationary phases have been used. Non-ionizable substances studied in previous works were also included in the set of compounds to evaluate the consistency of the method. The results showed that all the columns provide good estimations of the log P(o/w) for most of the compounds included in this study. The Gemini NX column has been selected to calculate log P(o/w) values of the set of studied drugs, and really good correlations between the determined log P(o/w) values and those considered as reference were obtained, proving the ability of the procedure for the lipophilicity assessment of bioactive compounds with very different structures and functionalities. PMID:21820118

Pallicer, Juan M; Sales, Joaquim; Rosés, Martí; Ràfols, Clara; Bosch, Elisabeth

2011-07-08

328

Assessment of the Potential Drug Etiology of Breast Cancer: Analyses of Data from a Case-Control Drug Surveillance Study.  

National Technical Information Service (NTIS)

We explored the drug etiology of breast cancer through analyses of data from our hospital-based Case-Control Surveillance Study of medications and cancer. Over 5000 cases of incident breast cancer were included in these analyses. We carried out computer '...

L. Rosenberg

1998-01-01

329

The Detail of Drugs: Horizontal Distribution Alliances in the International Pharmaceutical Industry  

Microsoft Academic Search

The primary contribution from this research lies in the uncovering of the factors that predict the formation of horizontal distribution alliances (HDAs) as well as their success. HDAs are characterized by the joining of two firms??from the same industry??to distribute a product owned by one of the firms into a new market. Resource Dependence and Transaction Cost Analysis are the

Ursula Y. Sullivan; Anne T. Coughlan

2004-01-01

330

Efficiency evaluation of a police operation to fight the drug plague: distribution unit weight as an objective index.  

PubMed

Lod, a city near Tel-Aviv, is considered the main drug distribution center in Israel. A major police undercover operation in Lod, lasting close to a year, was terminated in May 2003. The success or failure of such an operation is frequently measured by the number of arrests made, the hierarchical level of the dealers arrested, the number of drug stations closed down, and the decrease in heroin seizures following the operation. In this work we suggest using an additional parameter, which has a scientific, objective basis, namely, comparing the changes in the average user weight unit ("dose") before and after the operation. We found that prior to the operation the average weight per unit was 1.1 g. Three months after the operation terminated the average weight per unit had decreased to 0.8 g and remained there for at least 4 months before rising again. PMID:17553081

Levy, Rina; Zelkowicz, Avraham

2007-06-06

331

Architectural Heterogeneity in Tumors Caused by Differentiation Alters Intratumoral Drug Distribution and Affects Therapeutic Synergy of Antiangiogenic Organoselenium Compound  

PubMed Central

Tumor differentiation enhances morphologic and microvascular heterogeneity fostering hypoxia that retards intratumoral drug delivery, distribution, and compromise therapeutic efficacy. In this study, the influence of tumor biologic heterogeneity on the interaction between cytotoxic chemotherapy and selenium was examined using a panel of human tumor xenografts representing cancers of the head and neck and lung along with tissue microarray analysis of human surgical samples. Tumor differentiation status, microvessel density, interstitial fluid pressure, vascular phenotype, and drug delivery were correlated with the degree of enhancement of chemotherapeutic efficacy by selenium. Marked potentiation of antitumor activity was observed in H69 tumors that exhibited a well-vascularized, poorly differentiated phenotype. In comparison, modulation of chemotherapeutic efficacy by antiangiogenic selenium was generally lower or absent in well-differentiated tumors with multiple avascular hypoxic, differentiated regions. Tumor histomorphologic heterogeneity was found prevalent in the clinical samples studied and represents a primary and critical physiological barrier to chemotherapy.

Rustum, Youcef M.; Toth, Karoly; Seshadri, Mukund; Sen, Arindam; Durrani, Farukh A.; Stott, Emily; Morrison, Carl D.; Cao, Shousong; Bhattacharya, Arup

2010-01-01

332

Blood-brain barrier in vitro models as tools in drug discovery: assessment of the transport ranking of antihistaminic drugs.  

PubMed

In the course of our validation program testing blood-brain barrier (BBB) in vitro models for their usability as tools in drug discovery it was evaluated whether an established Transwell model based on porcine cell line PBMEC/C1-2 was able to differentiate between the transport properties of first and second generation antihistaminic drugs. First generation antihistamines can permeate the BBB and act in the central nervous system (CNS), whereas entry to the CNS of second generation antihistamines is restricted by efflux pumps such as P-glycoprotein (P-gP) located in brain endothelial cells. P-gP functionality of PBMEC/C1-2 cells grown on Transwell filter inserts was proven by transport studies with P-gP substrate rhodamine 123 and P-gP blocker verapamil. Subsequent drug transport studies with the first generation antihistamines promethazine, diphenhydramine and pheniramine and the second generation antihistamines astemizole, ceterizine, fexofenadine and loratadine were accomplished in single substance as well as in group studies. Results were normalised to diazepam, an internal standard for the transcellular transport route. Moreover, effects after addition of P-gP inhibitor verapamil were investigated. First generation antihistamine pheniramine permeated as fastest followed by diphenhydramine, diazepam, promethazine and second generation antihistaminic drugs ceterizine, fexofenadine, astemizole and loratadine reflecting the BBB in vivo permeability ranking well. Verapamil increased the transport rates of all second generation antihistamines, which suggested involvement of P-gP during their permeation across the BBB model. The ranking after addition of verapamil was significantly changed, only fexofenadine and ceterizine penetrated slower than internal standard diazepam in the presence of verapamil. In summary, permeability data showed that the BBB model based on porcine cell line PBMEC/C1-2 was able to reflect the BBB in vivo situation for the transport of antihistaminc drugs and to distinguish between first and second generation antihistamines. PMID:22764578

Neuhaus, W; Mandikova, J; Pawlowitsch, R; Linz, B; Bennani-Baiti, B; Lauer, R; Lachmann, B; Noe, C R

2012-05-01

333

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

334

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

335

28 CFR 83.210 - To whom must I distribute my drug-free workplace statement?  

Code of Federal Regulations, 2013 CFR

...DEPARTMENT OF JUSTICE (CONTINUED) GOVERNMENT-WIDE REQUIREMENTS FOR DRUG-FREE...Requirements for Recipients Other Than Individuals § 83.210 To whom must...must require that a copy of the statement described in § 83...employee who will be engaged in the performance of any...

2013-07-01

336

Drug-drug interaction study to assess the effects of atorvastatin co-administration on pharmacokinetics and anti-thrombotic properties of cilostazol in male Wistar rats.  

PubMed

Cilostazol (CLZ) and atorvastatin (ATV) are often co-prescribed to treat conditions such as peripheral arterial disease. In the present study, the drug-drug interaction potential of multi-dose ATV co-administration with CLZ on both pharmacokinetics and the anti-thrombotic property of CLZ is demonstrated. The pharmacokinetic parameters of CLZ (6 mg/kg, twice daily) were determined in male Wistar rats after 7 days co-administration with ATV (5 mg/kg, once daily) in order to assess the interaction potential between CLZ and ATV on chronic treatment. In vitro metabolic inhibition and everted gut sac studies were conducted to elucidate the mechanism of this interaction. Pharmacodynamic drug-drug interaction was evaluated on anti-thrombotic models including time to occlusion, platelet aggregation and rat tail bleeding time. A validated LC-MS/MS method was employed simultaneously to quantify both ATV and CLZ in rat plasma matrix. A statistically significant increase in systemic exposure (Css(max) by ~1.75 fold; AUC by ~3.0 fold) to CLZ was observed in ATV pre-treated rats. In vitro metabolism studies using liver microsomes (RLM and HLM) demonstrated statistically significant inhibition of CLZ metabolism when co-incubated with ATV. No change in apparent permeability of CLZ was observed in the presence of ATV. Atorvastatin showed a significant delay in artery occlusion time without altering CLZ's bleeding time and platelet aggregation profile. Collectively the results of these studies provide metabolic insight into the nature of drug-drug interaction between the selected drugs. Co-administration with ATV influences the pharmacokinetics and anti-thrombotic property of CLZ. A thorough clinical investigation is required before extrapolation of data to humans. PMID:22936637

Vats, Rahul; Varanasi, Kanthikiran V S; Arla, Rambabu; Veeraraghvan, Sridhar; Rajak, Shraddha

2012-10-08

337

An assessment of the use of drug and non-drug interventions in the treatment of Ichthyophthirius multifiliis Fouquet, 1876, a protozoan parasite of freshwater fish.  

PubMed

Infection by the ciliate protozoan Ichthyophthirius multifiliis Fouquet, 1876 causes significant economic losses in freshwater aquaculture worldwide. Following the ban on the use of malachite green for treating food fish, there has been extensive research aimed at identifying suitable replacements. In this paper we critically assess drug and non-drug interventions, which have been tested for use or have been employed against this parasite and evaluate possibilities for their application in farm systems. Current treatments include the administration of formaldehyde, sodium chloride (salt), copper sulphate and potassium permanganate. However, purportedly more environmentally friendly drugs such as humic acid, potassium ferrate (VI), bronopol and the peracetic acid-based products have recently been tested and represent promising alternatives. Further investigation, is required to optimize the treatments and to establish precise protocols in order to minimize the quantity of drug employed whilst ensuring the most efficacious performance. At the same time, there needs to be a greater emphasis placed on the non-drug aspects of management strategies, including the use of non-chemical interventions focusing on the removal of free-swimming stages and tomocysts of I. multifiliis from farm culture systems. Use of such strategies provides the hope of more environmentally friendly alternatives for the control of I. multifiliis infections. PMID:22078025

Picón-Camacho, S M; Marcos-Lopez, M; Bron, J E; Shinn, A P

2011-11-14

338

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.

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

339

Morphology, drug distribution, and in vitro release profiles of biodegradable polymeric microspheres containing protein fabricated by double-emulsion solvent extraction\\/evaporation method  

Microsoft Academic Search

The surface and internal morphology, drug distribution and release kinetics at 22°C of polyesters such as PCL (polycaprolactone) and PLGA (poly(dl-lactic-co-glycolic acid)) 65:35 microspheres containing BSA (bovine serum albumin) have been investigated in order to understand the relationship amongst morphology, drug distribution and in vitro release profiles and to develop controlled release devices for marine fishes in tropical area. CLSM

Yi-Yan Yang; Tai-Shung Chung; Ngee Ping Ng

2001-01-01

340

Validation of the five-drug “Pittsburgh cocktail” approach for assessment of selective regulation of drug-metabolizing enzymes  

Microsoft Academic Search

Objectives: To determine whether the probe drugs caffeine, chlorzoxazone, dapsone, debrisoquin (INN, debrisoquine), and mephenytoin can be simultaneously administered as a metabolic cocktail to estimate in vivo cytochrome P450 (CYP) and N-acetyltransferase enzyme activities.Methods: Fourteen healthy nonsmoking male volunteers (mean age ± SD, 21.6 ± 2.2 years) received 100 mg caffeine, 250 mg chlorzoxazone, 100 mg dapsone, 10 mg debrisoquin,

Reginald F. Frye; Gary R. Matzke; Adedayo Adedoyin; James A. Porter; Robert A. Branch

1997-01-01

341

Assessment of an abstinence-oriented, outpatient drug addiction service in Greece.  

PubMed

The 'Athena' service is an abstinence-oriented, outpatient substance addiction unit in Greece. To appraise the operation of the service, 459 clients who contacted the unit during a 3-yr. period were assessed in terms of treatment retention and situation upon discharge from the program; 182 of them had four or more appointments with the service and were thoroughly assessed using a battery of measures pertaining to their situation at discharge and their patterns of abuse and related problems. Most help-seekers were single, unemployed, young men who regularly used heroin (89%) intravenously (35%). From those who got involved in the therapeutic process (40%), 72% had positively modified their drug abuse by the time of discharge from the program (mean duration of treatment: approx. three months); the largest improvement (42%) was recorded in their psychological condition. Treatment retention was significantly higher for cannabis abusers than heroin addicts; longer treatment duration was significantly associated with a positive situation at discharge, while higher education was associated with a less favorable outcome regarding the abuse of the principal substance. These findings suggest that such outpatient programs may help a significant number of individuals who get involved in the therapeutic process and should be considered effective for treatment of substance abuse among the diversity of treatment modalities. PMID:17688121

Paparrigopoulos, Thomas; Liappas, John; Mellos, Eleftherios; Rabavilas, Andreas

2007-06-01

342

In vitro approach to study the influence of the cardiac output distribution on drug concentration  

Microsoft Academic Search

Summary  Blood flow is not constant during the day, not only due to cardiac output variation but to the variable blood flow fraction\\u000a supplied to the organs. To what extent these variations could affect the relative drug concentration between two different\\u000a tissues, is the purpose of this work. In order to study that, a device was designed which took into account

P. Fagiolino; F. Wilson; E. Samaniego; M. Vázquez

2003-01-01

343

Development of novel, 384-well high-throughput assay panels for human drug transporters: drug interaction and safety assessment in support of discovery research.  

PubMed

Transporter proteins are known to play a critical role in affecting the overall absorption, distribution, metabolism, and excretion characteristics of drug candidates. In addition to efflux transporters (P-gp, BCRP, MRP2, etc.) that limit absorption, there has been a renewed interest in influx transporters at the renal (OATs, OCTs) and hepatic (OATPs, BSEP, NTCP, etc.) organ level that can cause significant clinical drug-drug interactions (DDIs). Several of these transporters are also critical for hepatobiliary disposition of bilirubin and bile acid/salts, and their inhibition is directly implicated in hepatic toxicities. Regulatory agencies took action to address transporter-mediated DDI with the goal of ensuring drug safety in the clinic and on the market. To meet regulatory requirements, advanced bioassay technology and automation solutions were implemented for high-throughput transporter screening to provide structure-activity relationship within lead optimization. To enhance capacity, several functional assay formats were miniaturized to 384-well throughput including novel fluorescence-based uptake and efflux inhibition assays using high-content image analysis as well as cell-based radioactive uptake and vesicle-based efflux inhibition assays. This high-throughput capability enabled a paradigm shift from studying transporter-related issues in the development space to identifying and dialing out these concerns early on in discovery for enhanced mechanism-based efficacy while circumventing DDIs and transporter toxicities. PMID:24062352

Tang, Huaping; Shen, Ding Ren; Han, Yong-Hae; Kong, Yan; Balimane, Praveen; Marino, Anthony; Gao, Mian; Wu, Sophie; Xie, Dianlin; Soars, Matthew G; O'Connell, Jonathan C; Rodrigues, A David; Zhang, Litao; Cvijic, Mary Ellen

2013-10-01

344

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...sample collection systems for drugs of abuse testing. (a) Over-the-counter (OTC) test sample collection systems for drugs of abuse testing (§...

2010-04-01

345

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...sample collection systems for drugs of abuse testing. (a) Over-the-counter (OTC) test sample collection systems for drugs of abuse testing (§...

2009-04-01

346

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

Code of Federal Regulations, 2013 CFR

...Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT...sample collection systems for drugs of abuse testing. (a) Over-the-counter (OTC) test sample collection systems for drugs of abuse testing (§...

2013-04-01

347

Drug-eluting stents in percutaneous coronary intervention: a benefit-risk assessment.  

PubMed

Drug-eluting stent (DES) therapy has represented a very significant milestone in the evolution of percutaneous coronary intervention (PCI) therapy. This review attempts to provide a balanced overview of the unprecedented wealth of data generated on this new technology, by examining the evidence bases for anti-restenotic efficacy, safety and cost effectiveness. The performance of a DES may be related to each of its three components: stent backbone; carrier polymer (to control drug-release kinetics); and active drug. In terms of anti-restenotic efficacy, the most appropriate parameters to examine are target lesion revascularization, angiographic restenosis and late luminal loss. The principal safety parameters are overall mortality, myocardial infarction (MI) and stent thrombosis. Anti-restenotic superiority of DES over bare metal stents (BMS) has been demonstrated across a spectrum of disease from straightforward 'vanilla lesions' through higher disease complexity in pivotal clinical trials to phase IV studies of efficacy in 'off-label' populations. The treatment effect of DES versus BMS is consistent in terms of a reduction in the need for repeat intervention of the order of 35-70%. Regarding differential efficacy of first-generation DES, a benefit may exist in favour of the Cypher (sirolimus-eluting) stent over Taxus (paclitaxel-eluting), particularly in high-risk lesion subsets. The second-generation approved devices are the Endeavor (zotarolimus-eluting) and Xience (everolimus-eluting) DES. While all four of these stents are permanent polymer-based, the current focus of development is towards DES platforms that are devoid of durable polymer, the presence of which has been implicated in late adverse events. In terms of safety concerns raised in relation to DES therapy, it is reasonable to conclude the following at 4- to 5-year post-stent implantation: (i) that there is no increased risk of death or MI with DES (neither is there a general signal of mortality reduction with DES) compared with BMS; and (ii) there is very little, if any, overall increased risk of stent thrombosis with DES compared with BMS, although a difference in the time distribution of thrombotic events after PCI may exist, i.e. a slight excess of events with BMS in the first 6 months and with DES beyond 12 months. Duration of dual anti-platelet therapy after stenting is a central issue and is also, at present, a matter of clinical equipoise. A threshold for cost effectiveness likely exists where the price premium associated with DES is approximately euro 450. On the balance of benefit and risk data available, DES implantation should be the preferred approach across the spectrum of patients with obstructive coronary disease who require PCI therapy. PMID:19670915

Byrne, Robert A; Sarafoff, Nikolaus; Kastrati, Adnan; Schömig, Albert

2009-01-01

348

Customer Security Assessment in Distribution Networks With High Penetration of Wind Power  

Microsoft Academic Search

A novel methodology is proposed for the customer security assessment with high penetration of wind power in modern distribution networks. The customer security is quantified through customer damage costs by operating wind farms without standing reserve, which causes an inadequate supply of power to meet loads at some operating conditions. Necessary reserve to mitigate intermittency of wind is quantified through

Dilan Jayaweera; Graeme Burt; James R. McDonald

2007-01-01

349

Assessment of the quantities and distribution of K East Basin floor sludge constituents  

Microsoft Academic Search

Floor sludge constituent masses and their spatial distribution within K East Basin were calculated. This information will be beneficial in the assessing the acceptability of K Basin sludge in the Tank Waste Remediation System and in the design and\\/or operational practices related to retrieval and handling of this K Basin sludge. Calculations were made based on results from recent laboratory

1996-01-01

350

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

351

Assessment of Student Work on Geographically Distributed Information Technology Project Teams  

Microsoft Academic Search

There are issues in assessing the contributions of individual students on geographically distributed student teams working on information technology projects. At Pace University we have been using real-world student projects in capstone computing courses for about ten years. While the courses were conducted in a classroom environment during the early years, the current course has been essentially online for the

Charles C. Tappert; Allen Stix

2009-01-01

352

A methodology for the assessment of short duration voltage variations in electric power distribution systems  

Microsoft Academic Search

This paper deals with a new methodology for the assessment of power quality indices in electric power distribution systems. Power quality indices concerning short duration voltage variations, i.e. voltage sags and swells, are particularly introduced taking into account the needs for establishing power quality standards. The paper also presents a new proposal for a measurement protocol, a testing procedure to

N. Kagan; E. L. Ferrari; N. M. Matsuo; S. X. Duarte; J. L. Cavaretti; A. Tenorio; L. R. Souza

2002-01-01

353

The automated micronucleus assay for early assessment of genotoxicity in drug discovery.  

PubMed

Recent publications on the automated in vitro micronucleus assay show predictive values higher than 85% for the classification of in vitro aneugens, clastogens and non-genotoxic compounds. In the present work, the CHO-k1 micronucleus assay in combination with cellular imaging was further evaluated. Firstly, the effect of a range of S9 concentrations on micronucleus formation and cytotoxicity was investigated. Subsequently, the reproducibility and predictivity of the micronucleus assay on CHO-k1 cells was investigated with a set of four compounds. Then, a larger set of compounds (n=44) was tested on CHO-k1 cells and inter-laboratory correlation was calculated. Finally, cellular imaging was compared with flow cytometry for in vivo assessment of micronucleus formation. The concentration of S9 had a significant impact on micronucleus formation and cytotoxicity. In addition, calculations of relative cell count (RCC) and cytokinesis-block proliferation index (CBPI) showed to be complementary to cytotoxicity assessment. The CHO-k1 micronucleus assay correctly classified the four reference compounds, with a dose-response relationship and low variability. Based on a larger set of compounds, the assay proved to be reliable with a sensitivity of 94% (n=31) and a specificity of 85% (n=13). A correlation coefficient of 97% was obtained when the lowest observable adverse effect levels (LOAELs) from our study were compared with those published by Diaz et al. (2007) [10]. In conclusion, the in vitro CHO-k1 micronucleus assay combined with cellular imaging is a predictive assay appropriate for genotoxicity screening at early stages of drug development. In addition, for in vivo assessment of micronucleus formation, we preferred to use flow cytometry rather than cell imaging. PMID:23159395

Tilmant, K; Gerets, H H J; De Ron, P; Cossu-Leguille, C; Vasseur, P; Dhalluin, S; Atienzar, F A

2012-11-15

354

How extreme is extreme? An assessment of daily rainfall distribution tails  

NASA Astrophysics Data System (ADS)

The upper part of a probability distribution, usually known as the tail, governs both the magnitude and the frequency of extreme events. The tail behaviour of all probability distributions may be, loosely speaking, categorized in two families: heavy-tailed and light-tailed distributions, with the latter generating more "mild" and infrequent extremes compared to the former. This emphasizes how important for hydrological design is to assess correctly the tail behaviour. Traditionally, the wet-day daily rainfall has been described by light-tailed distributions like the Gamma, although heavier-tailed distributions have also been proposed and used, e.g. the Lognormal, the Pareto, the Kappa, and others. Here, we investigate the issue of tails for daily rainfall by comparing the upper part of empirical distributions of thousands of records with four common theoretical tails: those of the Pareto, Lognormal, Weibull and Gamma distributions. Specifically, we use 15 029 daily rainfall records from around the world with record lengths from 50 to 163 yr. The analysis shows that heavier-tailed distributions are in better agreement with the observed rainfall extremes than the more often used lighter tailed distributios, with clear implications on extreme event modelling and engineering design.

Papalexiou, S. M.; Koutsoyiannis, D.; Makropoulos, C.

2012-05-01

355

Assessment of CYP3A-mediated drug-drug interaction potential for victim drugs using an in vivo rat model.  

PubMed

The present study aims to determine if an in vivo rat model of drug-drug interaction (DDI) could be useful to discriminate a sensitive (buspirone) from a 'non-sensitive' (verapamil) CYP3A substrate, using ketoconazole and ritonavir as perpetrator drugs. Prior to in vivo studies, ketoconazole and ritonavir were shown to inhibit midazolam hydroxylation with IC50 values of 350?±?60 nm and 11?±?3 nm, respectively, in rat liver microsomes (RLM). Buspirone and verapamil were also shown to be substrates of recombinant rat CYP3A1/3A2. In the rat model, the mean plasma AUC0-inf of buspirone (10 mg/kg, p.o.) was increased by 7.4-fold and 12.8-fold after co-administration with ketoconazole and ritonavir (20 mg/kg, p.o.), respectively. The mean plasma AUC0-inf of verapamil (10 mg/kg, p.o.) was increased by 3.0-fold and 4.8-fold after co-administration with ketoconazole and ritonavir (20 mg/kg, p.o.), respectively. Thus, the rat DDI model correctly identified buspirone as a sensitive CYP3A substrate (>5-fold AUC change) in contrast to verapamil. In addition, for both victim drugs, the extent of DDI when co-administered was greater with ritonavir compared with ketoconazole, in line with their in vitro CYP3A inhibition potency in RLM. In conclusion, our study extended the rat DDI model applicability to two additional victim/perpetrator pairs. In addition, we suggest that use of this model would increase our confidence in estimation of the DDI potential for victim drugs in early discovery. Copyright © 2013 John Wiley & Sons, Ltd. PMID:23873286

Rioux, Nathalie; Bellavance, Edith; Bourg, Serge; Garneau, Michel; Ribadeneira, Maria D; Duan, Jianmin

2013-08-14

356

Assessment of the quality and structural integrity of a complex glycoprotein mixture following extraction from the formulated biopharmaceutical drug product.  

PubMed

Biological drugs represent an important and rapidly growing class of therapeutics useful in the treatment of a variety of disorders ranging from cancer to inflammation to infectious diseases. Unlike single chemical entities, the recombinant production of these drugs in living cells confers considerable structural and chemical heterogeneity to the biologically derived protein product that constitutes the active pharmaceutical ingredient (API). In mammalian based expression systems, much of this diversity is conferred through heterogeneous protein glycosylation. These post-translational modifications can have significant effects on the structure, biological function, and pharmacological properties of the API. In addition, the bulk proteins that comprise the API are further formulated through the use of multiple excipients designed to ensure product stability, solubility, and lot-to-lot consistency. Unfortunately, these matrices can interfere with commonly available analytical methods used in the thorough chemical characterization of the biological drug product. At the same time, a demonstration of the suitable extraction of the bulk drug substance in a manner and form that does not destabilize the active ingredient or introduce any structural bias with direct reference to the original drug product is both critical and necessary. Here, we use recombinant human follicle stimulating hormone (follitropin alpha for injection) from a pharmaceutical source as an example to illustrate a suitable purification strategy to effectively extract the bulk drug substance from the formulated drug product with high purity and yield. We assess the suitability of this extraction method in preserving the structural integrity and overall quality of the drug substance relative to the formulated drug product, placing a particular emphasis on glycosylation as a key product attribute. In so doing, we demonstrate that it is possible to effectively extract the active pharmaceutical ingredient from a formulated biological drug product in a manner that is consequently sufficient for its use in comparability studies. PMID:20800406

Liu, Cuihua; Dong, Shiming; Xu, Xiao-Jin; Yin, Yan; Shriver, Zachary; Capila, Ishan; Myette, James; Venkataraman, Ganesh

2010-08-06

357

Can light absorption and photostability data be used to assess the photosafety risks in patients for a new drug molecule?  

Microsoft Academic Search

Photosafety assessments are recommended for all new drug candidates intended for clinical use. In 2002, Testing guidances were issued by the regulatory authorities in the USA (2003) and Europe (2002). A key requirement is to measure the absorption of UV–visible light by a compound in the 290–700nm range and to assess photostability. Further photosafety evaluation is recommended for molecules which

Brian Henry; Christopher Foti; Karen Alsante

2009-01-01

358

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

359

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

360

Regulatory perspective on the importance of ADME assessment of nanoscale material containing drugs  

Microsoft Academic Search

The promise of nanoscale material containing drug products to treat complex diseases is mounting. According to the literature, in addition to the liposomes, micelles, emulsions, there are novel drug delivery systems such as dendrimers and metal colloids at different stages of pre-clinical and clinical development. With the anticipation that more nanoscale material containing drug products will be submitted to the

Banu S. Zolnik; Nakissa Sadrieh

2009-01-01

361

Assessing Tumor-Related Signs and Symptoms to Support Cancer Drug Approval  

Microsoft Academic Search

Cancer causes premature death and significant, often devastating, symptoms. While prolongation of survival is an obvious end point for new cancer drug approval, the US Food and Drug Administration (FDA) has also utilized end points that evaluate patient symptoms. In this article we discuss the end points, evidence, and analyses supporting cancer drug approvals based on evaluations of tumor-related signs

Grant Williams; Richard Pazdur; Robert Temple

2004-01-01

362

Assessing Maternal Perceptions of Harmful Effects of Drug Use During Pregnancy  

Microsoft Academic Search

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

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

2003-01-01

363

Individual differences in reactivity to the rewarding\\/aversive properties of drugs: Assessment by taste and place conditioning  

Microsoft Academic Search

The ability of individual differences in the strength of conditioned taste avoidance (CTA) to predict strength of place conditioning produced by the same drug was assessed. In Phase 1, rats were assigned to High CTA and Low CTA groups on the basis of their intake of saccharin solution previously paired with morphine, amphetamine, lithium, or fenfluramine. In Phase 2, the

Sylvie D. Turenne; Carrie Miles; Linda A. Parker; Shepard Siegel

1996-01-01

364

Initial Validation of a Subtle Trauma Symptom Screening Scale Embedded in a Needs Assessment Given to Women Entering Drug Treatment  

Microsoft Academic Search

Trauma-informed treatment suggests that all women entering alcohol and other drug treatment be screened for past exposure to violence and current trauma symptoms, but sometimes clients are reluctant to reveal this information. The purpose of this study was to validate a subgroup of items from a needs assessment given to women upon admission to residential substance use disorder treatment. These

Melinda Hohman; Lori Roads; Rosalind Corbett

2010-01-01

365

Modelling of Mouse Experimental Colitis by Global Property Screens: A Holistic Approach to Assess Drug Effects in Inflammatory Bowel Disease  

Microsoft Academic Search

Preclinical disease models play an important role in the establishment of new treatment paradigms, identification of biomarkers and assessment of drug efficacy and safety. However, the accuracy of these models in context of the human disease are sometimes questioned, e.g. due to trials failing to confirm efficacy in humans. We suggest that one reason behind this gap in predictability may

Johan Gottfries; Silvia Melgar; Erik Michaëlsson

2012-01-01

366

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

367

Hair and urine testing to assess drugs of abuse consumption in couples undergoing assisted reproductive technology (ART)  

Microsoft Academic Search

For the first time in Europe hair and urine testing have been applied to assess drugs of abuse consumption in couples undergoing assisted reproductive technology and the eventual association of toxic habits with other lifestyle, health status and sociodemographic factors was also investigated.Couples attending five assisted reproduction centers in Rome were invited to join the study. When they presented at

Simona Pichini; Roberto De Luca; Manuela Pellegrini; Emilia Marchei; Maria Concetta Rotolo; Roberta Spoletini; Paola D’Aloja; Roberta Pacifici; Claudia Mortali; Giulia Scaravelli

368

Impact of injection drug use on distribution and severity of chronic venous disorders  

PubMed Central

We examined chronic venous disorders (CVD) in persons who injected illicit drugs. The study design was cross-sectional, comparative stratified by age, gender, ethnicity, as well as by three types of drug use (noninjection; arm or upper body injection only; and legs with or without upper body injection). Subjects completed demographic, health, and substances abuse questionnaires and were evaluated using the clinical component of the Clinical-Etiology-Anatomy-Pathophysiology Classification. Seven hundred and thirteen participants were evaluated. Those who injected in the legs ± arms had significantly worse CVD. Thirty-nine percent of leg ± arm injectors vs. 4.2% or noninjectors or arm only injectors had moderate to severe CVD. Persons who injected in the legs ± arms were 9.14 times more likely to develop venous ulcers than those that injected in the arms and upper body only and 34.64 times more likely as those who never injected. CVD was associated with injecting in the groin, legs and feet as compared with other sites. The pattern of disorders associated with leg injection is consistent with the underlying pathology of chronic venous insufficiency.

Pieper, Barbara; Templin, Thomas N.; Kirsner, Robert S.; Birk, Thomas J.

2009-01-01

369

Age related changes in fractional elimination pathways for drugs: assessing the impact of variable ontogeny on metabolic drug-drug interactions.  

PubMed

The magnitude of any metabolic drug-drug interactions (DDIs) depends on fractional importance of inhibited pathway which may not necessarily be the same in young children when compared to adults. The ontogeny pattern of cytochrome P450 (CYP) enzymes (CYPs 1A2, 2B6, 2C8, 2C9, 2C18/19, 2D6, 2E1, 3A4) and renal function were analyzed systematically. Bootstrap methodology was used to account for variability, and to define the age range over which statistical differences existed between each pair of specific pathways. A number of DDIs were simulated (Simcyp Pediatric v12) for virtual compounds to highlight effects of age on fractional elimination and consequent magnitude of DDI. For a theoretical drug metabolized 50% by each of CYP2D6 and CYP3A4 pathways at birth, co-administration of ketoconazole (3 mg/kg) resulted in a 1.65-fold difference between inhibited versus uninhibited AUC compared to 2.4-fold in 1 year olds and 3.2-fold in adults. Conversely, neonates could be more sensitive to DDI than adults in certain scenarios. Thus, extrapolation from adult data may not be applicable across all pediatric age groups. The use of pediatric physiologically based pharmacokinetic (p-PBPK) models may offer an interim solution to uncovering potential periods of vulnerability to DDI where there are no existing clinical data derived from children. PMID:23720017

Salem, Farzaneh; Johnson, Trevor N; Barter, Zoe E; Leeder, J Steven; Rostami-Hodjegan, Amin

2013-05-30

370

Substance distribution in a cochlea model using different pump rates for cochlear implant drug delivery electrode prototypes.  

PubMed

Several studies using animals have shown the protective effects of neurotrophic factors (NF) on spiral ganglion cells (SGC). This is of particular importance since the number of SGCs is considered to be among the factors defining the efficacy of cochlear implants. A device for local inner ear treatment is therefore of great interest. As described previously, we modified a Contour(TM) cochlear implant electrode, to examine the inbuilt canal to be used for fluid release [Paasche, G., Gibson, P., Averbeck, T., Becker, H., Lenarz, T., Stöver, T., 2003. Technical report: modification of a cochlear implant electrode for drug delivery to the inner ear. Otol. Neurotol. 24, 222-227]. In the present study, three different electrode prototypes with openings of the delivery channel at various locations along the electrode array were examined to determine distribution of dye in a cochlea model over time. We compared dye delivery with: (a) release of the dye at the tip, (b) release of the dye at the tip and the side of the electrode, and (c) release of the dye only at the side of the electrode (6 mm from the tip). A mechanical pump was used to drive the system at pump rates of 100, 10, and 1 microl/h. Dye concentration changes along the length of the whole cochlea were investigated. Mean values for all experimental conditions show that the distribution along the array is fastest with two outlets whereas the distribution via a single outlet at the side of the electrode array is not considered to be sufficient. The established experimental setup provides the possibility of investigating prototypes of a fluid based drug delivery system for the treatment of inner ear pathologies in combination with electrical stimulation. PMID:16337758

Paasche, Gerrit; Bögel, Lars; Leinung, Martin; Lenarz, Thomas; Stöver, Timo

2005-12-07

371

Preclinical assessment of CNS drug action using eye movements in mice  

PubMed Central

The drug development process for CNS indications is hampered by a paucity of preclinical tests that accurately predict drug efficacy in humans. Here, we show that a wide variety of CNS-active drugs induce characteristic alterations in visual stimulus–induced and/or spontaneous eye movements in mice. Active compounds included sedatives and antipsychotic, antidepressant, and antiseizure drugs as well as drugs of abuse, such as cocaine, morphine, and phencyclidine. The use of quantitative eye-movement analysis was demonstrated by comparing it with the commonly used rotarod test of motor coordination and by using eye movements to monitor pharmacokinetics, blood-brain barrier penetration, drug-receptor interactions, heavy metal toxicity, pharmacologic treatment in a model of schizophrenia, and degenerative CNS disease. We conclude that eye-movement analysis could complement existing animal tests to improve preclinical drug development.

Cahill, Hugh; Rattner, Amir; Nathans, Jeremy

2011-01-01

372

In vitro approach to assess the potential for risk of idiosyncratic adverse reactions caused by candidate drugs.  

PubMed

Idiosyncratic adverse drug reactions (IADRs) in humans can result in a broad range of clinically significant toxicities leading to attrition during drug development as well as postlicensing withdrawal or labeling. IADRs arise from both drug and patient related mechanisms and risk factors. Drug related risk factors, resulting from parent compound or metabolites, may involve multiple contributory mechanisms including organelle toxicity, effects related to compound disposition, and/or immune activation. In the current study, we evaluate an in vitro approach, which explored both cellular effects and covalent binding (CVB) to assess IADR risks for drug candidates using 36 drugs which caused different patterns and severities of IADRs in humans. The cellular effects were tested in an in vitro Panel of five assays which quantified (1) toxicity to THLE cells (SV40 T-antigen-immortalized human liver epithelial cells), which do not express P450s, (2) toxicity to a THLE cell line which selectively expresses P450 3A4, (3) cytotoxicity in HepG2 cells in glucose and galactose media, which is indicative of mitochondrial injury, (4) inhibition of the human bile salt export pump, BSEP, and (5) inhibition of the rat multidrug resistance associated protein 2, Mrp2. In addition, the CVB Burden was estimated by determining the CVB of radiolabeled compound to human hepatocytes and factoring in both the maximum prescribed daily dose and the fraction of metabolism leading to CVB. Combining the aggregated results from the in vitro Panel assays with the CVB Burden data discriminated, with high specificity (78%) and sensitivity (100%), between 27 drugs, which had severe or marked IADR concern, and 9 drugs, which had low IADR concern, we propose that this integrated approach has the potential to enable selection of drug candidates with reduced propensity to cause IADRs in humans. PMID:22646477

Thompson, Richard A; Isin, Emre M; Li, Yan; Weidolf, Lars; Page, Ken; Wilson, Ian; Swallow, Steve; Middleton, Brian; Stahl, Simone; Foster, Alison J; Dolgos, Hugues; Weaver, Richard; Kenna, J Gerry

2012-05-31

373

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

374

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.

2011-01-01

375

Toward a model of drug relapse: An assessment of the validity of the reinstatement procedure  

PubMed Central

Background and Rationale The reinstatement model is widely used animal model of relapse to drug addiction. However, the model’s validity is open to question. Objective We assess the reinstatement model in terms of criterion and construct validity. Research highlights and Conclusions We find that the reinstatement model has adequate criterion validity in the broad sense of the term, as evidenced by the fact that reinstatement in laboratory animals is induced by conditions reported to provoke relapse in humans. The model’s criterion validity in the narrower sense, as a medication screen, seems promising for relapse to heroin, nicotine, and alcohol. For relapse to cocaine, criterion validity has not yet established, primarily because clinical studies have examined medication’s effects on reductions in cocaine intake rather than relapse during abstinence. The model’s construct validity faces more substantial challenges and is yet to be established, but we argue that some of the criticisms of the model in this regard may have been overstated.

Epstein, David H.; Preston, Kenzie L.; Stewart, Jane; Shaham, Yavin

2006-01-01

376

Captopril as treatment for patients with pulmonary hypertension. Problem of variability in assessing chronic drug treatment.  

PubMed Central

We gave captopril, an angiotensin converting-enzyme inhibitor, to four patients with unexplained pulmonary hypertension to see if it would lower pulmonary arterial pressure or pulmonary vascular resistance. The patients were studied at rest and during supine bicycle exercise, before and after 48 hours of captopril treatment (up to 450 mg/day). During the treatment, each patient was monitored, with systemic and pulmonary pressures measured hourly, and cardiac output every two to four hours. We found no significant effect of captopril, either at rest or with exercise, on the cardiac output, pulmonary artery pressure, or pulmonary vascular resistance, measured at the end of 48 hours treatment. We noted, however, that during the 48 hour period, all patients showed pronounced swings in their pulmonary and systemic artery pressures and cardiac outputs that had no relation to the administration of captopril or time of day. We conclude that captopril appears to be ineffective in causing a sustained reduction in the pulmonary artery pressure or pulmonary vascular resistance in patients with primary pulmonary hypertension. It appears, however, that these patients experience spontaneous variability in their pulmonary resistance from hour to hour which needs to be further studied before a reliable assessment of long-term drug treatment can be made.

Rich, S; Martinez, J; Lam, W; Rosen, K M

1982-01-01

377

Development of Polysorbate 80/Phospholipid mixed micellar formation for docetaxel and assessment of its in vivo distribution in animal models  

NASA Astrophysics Data System (ADS)

Docetaxel (DTX) is a very important member of taxoid family. Despite several alternative delivery systems reported recently, DTX formulated by Polysorbate 80 and alcohol (Taxotere®) is still the most frequent administration in clinical practice. In this study, we incorporated DTX into Polysorbate 80/Phospholipid mixed micelles and compared its structural characteristics, pharmacokinetics, biodistribution, and blood compatibility with its conventional counterparts. Results showed that the mixed micelles loaded DTX possessed a mean size of approximately 13 nm with narrow size distribution and a rod-like micelle shape. In the pharmacokinetics assessment, there was no significant difference between the two preparations ( P > 0.05), which demonstrated that the DTX in the two preparations may share a similar pharmacokinetic process. However, the Polysorbate 80/Phospholipid mixed micelles can increase the drug residence amount of DTX in kidney, spleen, ovary and uterus, heart, and liver. The blood compatibility assessment study revealed that the mixed micelles were safe for intravenous injection. In conclusion, Polysorbate 80/Phospholipid mixed micelle is safe, can improve the tumor therapeutic effects of DTX in the chosen organs, and may be a potential alternative dosage form for clinical intravenous administration of DTX.

Song, Hua; Geng, Hongquan; Ruan, Jing; Wang, Kan; Bao, Chenchen; Wang, Juan; Peng, Xia; Zhang, Xueqing; Cui, Daxiang

2011-04-01

378

Physical evidence in drug intelligence, Part 1: rationale based on hierarchic distribution of drugs using pyrolysis gas chromatography –mass spectrometry as an example  

Microsoft Academic Search

A complementary intelligence-gathering tool is described for drug-crime investigation. Scientific analysis and interpretation of packaging materials from seized shipments of illicit drugs will assist law enforcement by creating a more holistic description of each seizure, thus allowing further inferences to be drawn and ultimately assisting in a more thorough understanding of the flow of drugs to or within a particular

Juuso Huttunen; Chris Austin; Michael Dawson; Claude Roux; James Robertson

2007-01-01

379

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.

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

2012-01-01

380

Drug Addiction  

Microsoft Academic Search

Drug addiction causes an enormous burden to patients, families, and societies. This chapter summarizes current concepts of\\u000a drug addiction, epidemiology, etiology, pathogenesis, pathology, clinical course, laboratory findings, assessment, and treatment\\u000a of drug addiction. Pathologic consequences from drugs of abuse (e.g., opioids, sedatives, amphetamines, cocaine, cannabis,\\u000a nicotine, phencyclidine [PCP], hallucinogens) are explained as well. The understanding of drug addiction has improved

Joseph Westermeyer; Gihyun Yoon

381

Preclinical assessment of drug-induced proarrhythmias: role of the arterially perfused rabbit left ventricular wedge preparation.  

PubMed

Drug-induced torsade de pointes (TdP) is a rare but lethal side effect of many cardiovascular and non-cardiovascular drugs. It has led to black box warnings or even withdrawal of many useful compounds from the market and is one of the major stumbling blocks for new drug development. The critical need for a better test that can predict the TdP liability of a candidate drug has led to the development of multiple preclinical models. Each of these models has it own merits and limitations in preclinical testing for TdP liability; however, most of these models have not been adequately validated, so their precise sensitivity and specificity remain largely unknown. Recent blinded validation studies have demonstrated that the rabbit left ventricular wedge preparation can predict drug-induced TdP with an extremely high sensitivity and specificity. As a matter of fact, the wedge technique was initially developed primarily for studying the electrical heterogeneity of myocardium and the cellular basis of QT prolongation and TdP. Naturally then, the electrophysiological data obtained from the wedge takes into account every critical factor associated with the development of TdP. The TdP scores generated using the wedge technique have been shown to assess the torsadogenic potential of the drugs in a predictable fashion. This review elaborates on the current and prospective role of the rabbit left ventricular wedge preparation in preclinical assessment of drug-induced proarrhythmias including but not limited to TdP. PMID:18423604

Wang, Dongqi; Patel, Chinmay; Cui, Changcong; Yan, Gan-Xin

2008-03-15

382

Are work stressors related to employee substance use? The importance of temporal context assessments of alcohol and illicit drug use.  

PubMed

In this study, the author explored the relations of 2 work stressors (work overload and job insecurity) to employee alcohol use and illicit drug use. The primary goal was to explore the importance of temporal context (before work, during the workday, and after work) in the assessment of substance use compared with context-free (overall) assessments. Data were collected from a national sample of U.S. workers (N = 2,790) who took part in a broad cross-sectional survey on workplace health and safety. Consistent with past research, the results fail to support a relation between work stressors and overall measures of alcohol and illicit drug use. However, the results support the relation of work stressors to alcohol and illicit drug use before work, during the workday, and after work. These results provide support for both the stress-induced substance use and stress response dampening propositions of the tension-reduction hypothesis. When exploring the work environment as a potential cause of employee substance use, these results underscore the importance of measures that assess alcohol and illicit drug use in terms of their temporal relation to the workday. PMID:18211145

Frone, Michael R

2008-01-01

383

Rapid assessment of drug use and sexual HIV risk patterns among vulnerable drugusing populations in Cape Town, Durban and Pretoria, South Africa  

Microsoft Academic Search

This exploratory study examines the links between drug use and high-risk sexual practices and HIV in vulnerable drug-using populations in South Africa, including commercial sex workers (CSWs), men who have sex with men (MSM), injecting drug users (IDUs) and non-injecting drug users who are not CSWs or MSM (NIDUs). A rapid assessment ethnographic study was undertaken using observation, mapping, key

Charles Parry; Petal Petersen; Tara Carney; Sarah Dewing; Richard Needle

2008-01-01

384

PS3-7: Improving the Detection of Drug-Induced Liver Injury with an Electronic Causality Assessment Tool  

PubMed Central

Background/Aims The Roussel Uclaf Causality Assessment Method (RUCAM) is the most commonly used algorithm to evaluate drug-induced liver injury (DILI). It uses 7 criteria to assess causality and provides a total score ranging from ?9 to 15, which is stratified into 5 categories describing the likelihood of DILI ranging from ‘Highly Probable’ to ‘Excluded’. An electronic RUCAM (eRUCAM) was previously developed at Kaiser Permanente Southern California (KPSC) with the Observational Medical Outcomes Partnership and GlaxoSmithKline to detect DILI in an electronic medical record. The study aim was to identify areas of improvement for future iterations of the eRUCAM based on results from chart review. Methods The eRUCAM was used to score potential cases of DILI identified in patients taking at least one of 14 drugs commonly associated with DILI. Patients were required to be at least 18 years of age and have 12 months of continuous membership plus drug benefit prior to drug initiation. A random sample of 20 patients without pre-existing liver disease was selected for chart review to perform quality assurance on the programming specifications and identify areas for improvement in the algorithm. A hepatologist manually scored each patient using the paper-based RUCAM. Scores from the hepatologist were compared to those from the eRUCAM using the Wilcoxon signed rank test. Qualitative findings from chart review regarding future improvements to the algorithm were summarized. Results The total score from eRUCAM was identical to those of the hepatologist for 6 cases (30%). The absolute difference between the hepatologist and eRUCAM scores was greatest for Criteria 5, which assesses non-drug causes of liver injury (P =0.001). Differences in scores were not statistically significant for other remaining criteria. Issues that were identified with Criteria 5 included: inadequate time windows for identifying non-drug causes, failure to consider laboratory results (e.g., hepatitis serology), incomplete lists of ICD-9 codes for non-drug causes, and inability to extract information from physician progress notes. Conclusions Future work related to the development of an electronic causality assessment tool based on the RUCAM should focus on improving Criteria 5 by using wider time windows to identify non-drug cases, laboratory results, and natural language processing.

Shin, Janet; Hunt, Christine; Niu, Fang; Papay, Julie; Murray, Rich; Powell, Gregory; Reisinger, Steph; Cheetham, T. Craig

2013-01-01

385

PS3-7: Improving the Detection of Drug-Induced Liver Injury with an Electronic Causality Assessment Tool.  

PubMed

Background/Aims The Roussel Uclaf Causality Assessment Method (RUCAM) is the most commonly used algorithm to evaluate drug-induced liver injury (DILI). It uses 7 criteria to assess causality and provides a total score ranging from -9 to 15, which is stratified into 5 categories describing the likelihood of DILI ranging from 'Highly Probable' to 'Excluded'. An electronic RUCAM (eRUCAM) was previously developed at Kaiser Permanente Southern California (KPSC) with the Observational Medical Outcomes Partnership and GlaxoSmithKline to detect DILI in an electronic medical record. The study aim was to identify areas of improvement for future iterations of the eRUCAM based on results from chart review. Methods The eRUCAM was used to score potential cases of DILI identified in patients taking at least one of 14 drugs commonly associated with DILI. Patients were required to be at least 18 years of age and have 12 months of continuous membership plus drug benefit prior to drug initiation. A random sample of 20 patients without pre-existing liver disease was selected for chart review to perform quality assurance on the programming specifications and identify areas for improvement in the algorithm. A hepatologist manually scored each patient using the paper-based RUCAM. Scores from the hepatologist were compared to those from the eRUCAM using the Wilcoxon signed rank test. Qualitative findings from chart review regarding future improvements to the algorithm were summarized. Results The total score from eRUCAM was identical to those of the hepatologist for 6 cases (30%). The absolute difference between the hepatologist and eRUCAM scores was greatest for Criteria 5, which assesses non-drug causes of liver injury (P =0.001). Differences in scores were not statistically significant for other remaining criteria. Issues that were identified with Criteria 5 included: inadequate time windows for identifying non-drug causes, failure to consider laboratory results (e.g., hepatitis serology), incomplete lists of ICD-9 codes for non-drug causes, and inability to extract information from physician progress notes. Conclusions Future work related to the development of an electronic causality assessment tool based on the RUCAM should focus on improving Criteria 5 by using wider time windows to identify non-drug cases, laboratory results, and natural language processing. PMID:24086006

Shin, Janet; Hunt, Christine; Niu, Fang; Papay, Julie; Murray, Rich; Powell, Gregory; Reisinger, Steph; Cheetham, T Craig

2013-09-01

386

The integration of renewable energy sources into electric power distribution systems. Volume 1: National assessment  

SciTech Connect

Renewable energy technologies such as photovoltaic, solar thermal electricity, and wind turbine power are environmentally beneficial sources of electric power generation. The integration of renewable energy sources into electric power distribution systems can provide additional economic benefits because of a reduction in the losses associated with transmission and distribution lines. Benefits associated with the deferment of transmission and distribution investment may also be possible for cases where there is a high correlation between peak circuit load and renewable energy electric generation, such as photovoltaic systems in the Southwest. Case studies were conducted with actual power distribution system data for seven electric utilities with the participation of those utilities. Integrating renewable energy systems into electric power distribution systems increased the value of the benefits by about 20 to 55% above central station benefits in the national regional assessment. In the case studies presented in Vol. II, the range was larger: from a few percent to near 80% for a case where costly investments were deferred. In general, additional savings of at least 10 to 20% can be expected by integrating at the distribution level. Wind energy systems were found to be economical in good wind resource regions, whereas photovoltaic systems costs are presently a factor of 2.5 too expensive under the most favorable conditions.

Barnes, P.R.; Van Dyke, J.W. [Oak Ridge National Lab., TN (United States); Tesche, F.M. [6714 Norway Road, Dallas, TX (United States); Zaininger, H.W. [Zaininger Engineering Co., San Jose, CA (United States)

1994-06-01

387

The integration of renewable energy sources into electric power distribution systems. Volume 1: National assessment  

NASA Astrophysics Data System (ADS)

Renewable energy technologies such as photovoltaic, solar thermal electricity, and wind turbine power are environmentally beneficial sources of electric power generation. The integration of renewable energy sources into electric power distribution systems can provide additional economic benefits because of a reduction in the losses associated with transmission and distribution lines. Benefits associated with the deferment of transmission and distribution investment may also be possible for cases where there is a high correlation between peak circuit load and renewable energy electric generation, such as photovoltaic systems in the Southwest. Case studies were conducted with actual power distribution system data for seven electric utilities with the participation of those utilities. Integrating renewable energy systems into electric power distribution systems increased the value of the benefits by about 20 to 55% above central station benefits in the national regional assessment. In the case studies presented in Vol. 2, the range was larger: from a few percent to near 80% for a case where costly investments were deferred. In general, additional savings of at least 10 to 20% can be expected by integrating at the distribution level. Wind energy systems were found to be economical in good wind resource regions, whereas photovoltaic systems costs are presently a factor of 2.5 too expensive under the most favorable conditions.

Barnes, P. R.; Vandyke, J. W.; Tesche, F. M.; Zaininger, H. W.

1994-06-01

388

Dog left ventricular midmyocardial myocytes for assessment of drug-induced delayed repolarization: short-term variability and proarrhythmic potential  

PubMed Central

Background and purpose: Evaluation of the potential for delayed ventricular repolarization and proarrhythmia by new drugs is essential. We investigated if dog left ventricular midmyocardial myocytes (LVMMs) that can be used as a preclinical model to assess drug effects on action potential duration (APD) and whether in these cells, short-term variability (STV) or triangulation could predict proarrhythmic potential. Experimental approach: Beagle LVMMs and Purkinje fibres (PFs) were used to record APs. Effects of six reference drugs were assessed on APD at 50% (APD50) and 90% (APD90) of repolarization, STV(APD), triangulation (ratio APD90/APD50) and incidence of early afterdepolarizations (EADs) at 1 and 0.5 Hz. Key results: LVMMs provided stable recordings of AP, which were not affected by four sequential additions of dimethyl sulphoxide. Effects of dofetilide, d-sotalol, cisapride, pinacidil and diltiazem, but not of terfenadine, on APD in LVMMs were found to be comparable with those recorded in PFs. LVMMs, but not PFs, exhibited a proarrhythmic response to IKr blockers. Incidence of EADs was not related to differences in AP prolongation or triangulation, but corresponded to beat-to-beat variability of repolarization, here quantified as STV of APD. Conclusions and implications: LVMMs provide a suitable preclinical model to assess the effects of new drugs on APD and also yield additional information about putative indicators of proarrhythmia that add value to an integrated QT/TdP risk assessment. Our findings support the concept that increased STV(APD) may predict drug-induced proarrhythmia. This article is part of a themed section on QT safety. To view this issue visit http://www3.interscience.wiley.com/journal/121548564/issueyear?year=2010

Abi-Gerges, Najah; Valentin, Jean-Pierre; Pollard, Chris E

2010-01-01

389

Radiation safety assessment of a system of small reactors for distributed energy.  

PubMed

A passively safe small reactor for a distributed energy system, PSRD, is an integral type of light-water reactor with a thermal output of 100 or 300 MW aimed to be used for supplying district heat, electricity to small grids, and so on. Candidate locations for the PSRD as a distributed energy source are on-ground, deep underground, and in a seaside pit in the vicinity of the energy consumption area. Assessments of the radiation safety of a PSRD were carried out for three cases corresponding to normal operation, shutdown and a hypothetical postulated accident for several siting candidates. Results of the radiation safety assessment indicate that the PSRD design has sufficient shielding performance and capability and that the exposure to the general public is very low in the case of a hypothetical accident. PMID:16381690

Odano, N; Ishida, T

2005-01-01

390

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

391

Use of Toxoplasma gondii Expressing b-Galactosidase for Colorimetric Assessment of Drug Activity In Vitro  

Microsoft Academic Search

A microtiter assay for drug evaluation has been developed with a strain of Toxoplasma gondii that expresses bacterial b-galactosidase. By using chlorophenol red-b-D-galactopyranoside (CPRG) as the substrate for b-galactosidase, the efficacy of a drug against the parasite can be determined with a colorimetric readout. Drugs known to have activity against T. gondii (specifically, pyrimethamine, sulfadiazine, atovaquone, and clindamycin) were tested,

DIANE C. MCFADDEN; FRANK SEEBER; JOHN C. BOOTHROYD

1997-01-01

392

Similarity Between Obesity and Drug Addiction as Assessed by Neurofunctional Imaging  

Microsoft Academic Search

Overeating in obese individuals shares similarities with the loss of control and compulsive drug taking behavior observed in drug-addicted subjects. The mechanism of these behaviors is not well understood. Our prior studies with positron emission tomography (PET) in drug-addicted subjects documented reductions in striatal dopamine (DA) D2 receptors. In pathologically obese subjects, we found reductions in striatal DA D2 receptors

Gene-Jack Wang; Nora D. Volkow; Panayotis K. Thanos; Joanna S. Fowler

2004-01-01

393

Performance assessment of density functional theory-based models using orbital momentum distributions  

Microsoft Academic Search

The performance of a number of established and widely used density functional theory (DFT) methods (B3LYP, Bhandh, BP86, PW91, Vosko, Wilk, and Nusair (VWN), LB94, PBe0, statistical average of orbital potentials (SAOP) and X3LYP) and the Hartree–Fock (HF) method has been assessed using the 7? orbital momentum distributions (MDs) of nitrous oxide (N2O). The DFT methods are combined with a

Feng Wang; Wenning Pang; Patrick Duffy

2012-01-01

394

A molecular marker-based assessment of sedimentary organic matter sources and distributions in Florida Bay  

Microsoft Academic Search

Seven surface sediment samples covering the general geographical area of Florida Bay were examined through the measurement\\u000a of 13C isotopic abundance and lipid classes to assess the distributions and sources of organic matter (OM) in this estuarine environment.\\u000a The bulk ?13Corg value shifted from a more isotopically depleted (?19.9‰) to a more isotopically enriched (?13.5‰) signal along the NE to

Yunping Xu; Ralph N. Mead; Rudolf Jaffe ´

2006-01-01

395

Yawning frequency and distribution in preterm and near term infants assessed throughout 24-h recordings  

Microsoft Academic Search

Yawning has been observed in foetuses and preterm infants. The aim of this study was to assess the frequency and the 24h distribution of yawning in preterm infants.Twelve low-risk infants between 31 and 40 weeks of post-conceptional age (PCA) were continuously video-recorded for 24h in their incubator. Spontaneous yawning was defined as opening of the mouth to its full extension

Fiorenza Giganti; Marie J. Hayes; Giovanni Cioni; Piero Salzarulo

2007-01-01

396

Drug binding affinities and potencies are best described by a log-normal distribution and use of geometric means  

SciTech Connect

(-)-Norepinephrine (NE) is used as an internal standard in their in vitro adrenergic assays, and the concentration of NE which produces a half-maximal inhibition of specific radioligand binding (affinity; K/sub I/), or half-maximal contractile response (potency; ED/sub 50/) has been measured numerous times. The goodness-of-fit test for normality was performed on both normal (Gaussian) or log /sub 10/-normal frequency histograms of these data using the SAS Univariate procedure. Specific binding of /sup 3/H-prazosin to rat liver (..cap alpha../sub 1/-), /sup 3/H rauwolscine to rat cortex (..cap alpha../sub 2/-) and /sup 3/H-dihydroalprenolol to rat ventricle (..beta../sub 1/-) or rat lung (..beta../sub 2/-receptors) was inhibited by NE; the distributions of NE K/sub I/'s at all these sites were skewed to the right, with highly significant (p < 0.01) deviations from normality. However, these data were better described by log-normal distributions. Similar results were obtained with ED/sub 50/'s of NE in isolated rabbit aorta (..cap alpha../sub 1/), phenoxybenzamine-treated dog saphenous vein (..cap alpha../sub 2/) and guinea pig atrium (..beta../sub 1/). The vasorelaxant potency of atrial natriuretic hormone in histamine-contracted rabbit aorta also was better described by a log-normal distribution, indicating that log-normalcy is probably a general phenomenon of drug-receptor interactions. Because data of this type appear to be log-normally distributed, geometric means should be used in parametric statistical analyses.

Stanisic, D.; Hancock, A.A.; Kyncl, J.J.; Lin, C.T.; Bush, E.N.

1986-03-05

397

Drug effects on distribution of [3H]3,4-methylenedioxymethamphetamine in mice.  

PubMed

The present study was undertaken to examine the drug interactions between 3,4-methylenedioxymethamphetamine (MDMA) and paroxetine or several compounds including the 3,4-methylenedioxybenzyl (piperonyl) group in mice. The time course of radioactivity in the mouse brain after i.v. administration of the tracer amount (approximately 70 ng/kg) of [3H]MDMA was altered significantly by coinjection of carrier MDMA (15 mg/kg) or by pretreatment with paroxetine (10 mg/kg, i.p., 5 min). Furthermore, the radioactivity in the brain 60 min after injection of [3H]MDMA was increased significantly by pretreatment with paroxetine, but not by pretreatment with 6-nitroquipazine, fluoxetine, clomipramine, GBR 12909 or desipramine, indicating that paroxetine-induced alteration of the brain radioactivity was not due to the inhibitory effect of 5-hydroxytryptamine (5-HT) uptake of paroxetine. The radioactivity in the brain 60 min after injection of [3H]MDMA was increased significantly by pretreatment with 3,4-methylenedioxyamphetamine (MDA), MDMA, 1-piperonylpiperazine and N, alpha-dimethylpiperonylamine, but not by pretreatment with piperonylacetone, piperonyl butoxide and piperonyl isobutyrate. HPLC analyses indicated that the alteration of brain radioactivity 60 min after injection of [3H]MDMA was, in part, due to inhibition in the metabolism of [3H]MDMA to radioactive metabolite(s). The present results suggest that a specific mechanism for the 3,4-methylenedioxyphenyl group which rapidly alters the disposition and metabolism of [3H]MDMA may exist in brain and peripheral organs of mice. PMID:8097718

Hashimoto, K; Maeda, H; Hirai, K; Goromaru, T

1993-04-01

398

[Therapeutic drugs, illicit poisons and environmental chemicals in breast milk--assessing the risk].  

PubMed

Our knowledge about the transfer of drugs and environmental chemicals into breast milk has increased in the last years. This review is mainly based on recently published literature and focuses on all drugs and environmental substances with documented effects on lactation and the nursing infant. Our aim is to provide brief information for physicians who are counseling breastfeeding mothers. PMID:1749623

Male, C; Pietschnig, B; Eder, B; Huemer, C; Haschke, F

1991-01-01

399

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

PubMed Central

Plasmodium vivax (Pv) is the second most important human malaria parasite. Recent data indicate that the impact of Pv malaria on the health and economies of the developing world has been dramatically underestimated. Pv has a unique feature in its life cycle. Uninucleate sporozoites (spz), after invasion of human hepatocytes, either proceed to develop into tens of thousands of merozoites within the infected hepatocytes or remain as dormant forms called hypnozoites, which cause relapses of malaria months to several years after the primary infection. Elimination of malaria caused by Pv will be facilitated by developing a safe, highly effective drug that eliminates Pv liver stages, including hypnozoites. Identification and development of such a drug would be facilitated by the development of a medium to high throughput assay for screening drugs against Pv liver stages. We undertook the present pilot study to (1) assess the feasibility of producing large quantities of purified, vialed, cryopreserved Pv sporozoites and (2) establish a system for culturing the liver stages of Pv in order to assess the effects of drugs on the liver stages of Pv. We used primaquine (PQ) to establish this assay model, because PQ is the only licensed drug known to clear all Pv hepatocyte stages, including hypnozoites, and the effect of PQ on Pv hepatocyte stage development in vitro has not previously been reported. We report that we have established the capacity to reproducibly infect hepatoma cells with purified, cyropreserved Pv spz from the same lot, quantitate the primary outcome variable of infected hepatoma cells and demonstrate the inhibitory activity of primaquine on the infected hepatoma cells. We have also identified small parasite forms that may be hypnozoites. These data provide the foundation for finalizing a medium throughput, high content assay to identify new drugs for the elimination of all Pv liver stages.

Chattopadhyay, Rana; Velmurugan, Soundarapandian; Chakiath, Chinnamma; Andrews Donkor, Lucy; Milhous, Wilbur; Barnwell, John W.; Collins, William E.; Hoffman, Stephen L.

2010-01-01

400

Unapproved Drugs Initiative  

Center for Drug Evaluation (CDER)

... Drugs with potential safety risks; Drugs that lack evidence of effectiveness; Health fraud drugs; ... once the risk-based assessment has been ... More results from www.fda.gov/drugs/guidancecomplianceregulatoryinformation/enforcementactivitiesbyfda

401

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.

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

2012-01-01

402

A post-trial assessment of factors influencing study drug adherence in a randomized biomedical HIV-1 prevention trial.  

PubMed

High adherence and maintenance of blinding are critical for placebo-controlled efficacy trials of HIV-1 biomedical prevention strategies. We assessed adherence to study drug and factors affecting adherence, including perceived randomization group, in a post-trial questionnaire of participants who completed HPTN 039, a randomized, placebo-controlled trial of HSV-2 suppression with twice-daily acyclovir to reduce HIV-1 acquisition. Of the 3172 trial participants, 2003 (63%) completed the post-trial questionnaire. Of these 2003, 72% reported missing a dose of study drug less than twice a week. Study drug adherence was not compromised by perceived randomization or genital ulcer symptoms during the study. Alcohol use was cited as an adherence barrier in some populations. Assessment of study drug adherence during and at the end of trials can evaluate perceptions of randomization and adherence by randomization arm, help to better understand barriers to and motivations for adherence, and develop interventions to increase adherence for future trials. PMID:21104007

Jacob, Shevin T; Baeten, Jared M; Hughes, James P; Peinado, Jesús; Wang, Jing; Sanchez, Jorge; Reid, Stewart E; Delany-Moretlwe, Sinead; Cowan, Frances; Fuchs, Jonathan D; Koblin, Beryl; Griffith, Sam; Wald, Anna; Celum, Connie

2011-07-01

403

Evaluation of characteristic deuterium distributions of ephedrines and methamphetamines by NMR spectroscopy for drug profiling.  

PubMed

We have established a method for quantitative analysis of the deuterium contents (D/H) at the phenyl, methine, benzyl, N-methyl and methyl groups of l-ephedrine/HCl, d-pseudoephedrine/HCl and methamphetamine/HCl by 2H NMR spectroscopy. Comparison of the 5 position-specific D/H values of l-ephedrine/HCl and d-pseudoephedrine/HCl prepared by three methods (chemical synthesis, semichemical synthesis, and biosynthesis) showed that chemically synthesized ephedrines and semisynthetic ephedrines have highly specific distributions of deuterium at the methine position and at the benzyl position, compared with the other positions. The classification of several methamphetamine samples seized in Japan in terms of the D/H values at these two positions clearly showed that the methamphetamine samples had been synthesized from ephedrines extracted from Ephedra plants or semisynthetic ephedrines but not from synthetic ephedrine. This isotope ratio analysis method should be useful to trace the origins of seized methamphetamine in Southeast Asia. PMID:18271510

Matsumoto, Teruki; Urano, Yasuteru; Makino, Yukiko; Kikura-Hanajiri, Ruri; Kawahara, Nobuo; Goda, Yukihiro; Nagano, Tetsuo

2008-02-15

404

The Valley of Death in anticancer drug development: a re-assessment  

PubMed Central

The past decade has seen an explosion in our understanding of cancer biology and with it many new potential disease targets. Yet our ability to translate these advances into therapies is poor, with a failure rate approaching 90%. Much discussion has been devoted to this so-called ‘Valley of Death’ in anticancer drug development, but the problem persists. Could we have overlooked some straight-forward explanations to this highly complex problem? Important aspects of tumor physiology, drug pharmacokinetics, preclinical models, drug delivery, and clinical translation are not often emphasized and could be critical. This perspective summarizes current views on the problem and suggests feasible alternatives.

Adams, David J.

2012-01-01

405

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

406

Comparison of computed tomography- and optical image-based assessment of liposome distribution.  

PubMed

The use of multimodal imaging as a tool to assess the in vivo pharmacokinetics and biodistribution of nanocarriers is important in understanding the nature of their in vivo transport. The current study reports the development of a nano-sized liposomal computed tomographic (CT)/optical imaging probe carrying iohexol and Cy5.5 and its use in micro-CT and optical imaging to quantitatively assess the whole-body (macroscopic), intratumoral, and microscopic distribution over a period of 8 days. These multimodal liposomes have a vascular half-life of 30.3 ± 8.9 hours in mice bearing subcutaneous H520 non-small cell lung cancer tumors, with the maximum liposome accumulation in tumor achieved 48 hours postinjection. The in vivo liposome distribution and stability were quantitatively assessed using both micro-CT and fluorescence molecular tomography. The combination of CT and optical imaging enables visualization of the liposomes at the whole-body, tumor, and cellular scales with high sensitivity. Such noninvasive tracking of therapeutic vehicles at the macro- and microscale is important for informed and rational development of novel nanocarrier systems. PMID:23490441

Huang, Huang; Dunne, Michael; Lo, John; Jaffray, David A; Allen, Christine

2013-05-01

407

CYP Induction-Mediated Drug Interactions: in Vitro Assessment and Clinical Implications  

Microsoft Academic Search

Cytochrome P450 (CYP) induction-mediated interaction is one of the major concerns in clinical practice and for the pharmaceutical\\u000a industry. There are two major issues associated with CYP induction: a reduction in therapeutic efficacy of comedications and\\u000a an induction in reactive metabolite-induced toxicity. Because CYP induction is a metabolic liability in drug therapy, it is\\u000a highly desirable to develop new drug

Jiunn H. Lin

2006-01-01

408

Assessment of the stability of 30 antipsychotic drugs in stored blood specimens.  

PubMed

The stability of 30 common antipsychotics (APs) in spiked whole blood was investigated over ten weeks in a preliminary experiment (designated "P experiment"). Pools of blank blood spiked with drugs at two different therapeutic levels were stored at four different temperatures: 20 °C, 4 °C, -20 °C, and -60 °C and extracted once weekly in duplicate, using a previously published method. A loss of >15% of the initial drug concentration was considered to indicate possible instability and the respective drugs were selected for further investigation in a final experiment (designated "F experiment"). Eight APs (chlorpromazine, chlorprothixene, fluspirilene, droperidol, olanzapine, thioridazine, triflupromazine, and ziprasidone) were incorporated into the F experiment. The same conditions were used in both experiments, however only a high therapeutic drug concentration was chosen for the F experiment and the storage time was extended to 20 weeks. All drugs of interest in the F experiment showed significant losses after 20 weeks of storage under at least one storage condition. The most notable results involved olanzapine, where losses of almost 100% in all storage temperatures were observed. Drug degradation in fluspirilene samples was significant after 20 weeks under all storage conditions. Overall, extensive degradation was seen with approximately 80% drug loss when stored at 20 °C and 4 °C with samples also seriously affected by degradation of up to 50% when stored at -20 °C and -60 °C, respectively. Ziprasidone remained stable when stored at 4 °C, -20 °C, and -60 °C over 9 weeks, however significant degradation was observed when stored at 20 °C, with a loss of almost 100% after 20 weeks of storage. The time period and temperature of storage of biological samples can have a significant influence on the stability of several APs. It is therefore important to be aware of potential changes in drug concentrations during storage when interpreting analytical results. PMID:21441006

Saar, Eva; Gerostamoulos, Dimitri; Drummer, Olaf H; Beyer, Jochen

2011-03-26

409

Analysis of rapid heart rate variability in the assessment of anticholinergic drug effects in humans  

Microsoft Academic Search

Anticholinergic agents have widespread therapeutic indications in clinical medicine. In addition, certain other drug groups–such as neuroleptics, antidepressants and antihistamines–possess distinct anticholinergic properties that reduce tolerance and compliance. Especially in patients with heart disease, attention should be paid to cardiac anticholinergic drug effects. The analysis of short-term heart rate variability (HRV) provides a noninvasive tool to estimate vagal cholinergic outflow.

Jani Penttilä; Tom Kuusela; Harry Scheinin

2005-01-01

410

Assessment of crystalline disorder in cryo-milled samples of indomethacin using atomic pair-wise distribution functions.  

PubMed

The aim of this study was to investigate the usefulness of the atomic pair-wise distribution function (PDF) to detect the extension of disorder/amorphousness induced into a crystalline drug using a cryo-milling technique, and to determine the optimal milling times to achieve amorphisation. The PDF analysis was performed on samples of indomethacin obtained by cryogenic ball milling (cryo-milling) for different periods of time. X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), polarised light microscopy (PLM) and solid state nuclear magnetic resonances (ss-NMR) were also used to analyse the cryo-milled samples. The high similarity between the ?-indomethacin cryogenic ball milled samples and the crude ?-indomethacin indicated that milled samples retained residual order of the ?-form. The PDF analysis encompassed the capability of achieving a correlation with the physical properties determined from DSC, ss-NMR and stability experiments. Multivariate data analysis (MVDA) was used to visualize the differences in the PDF and XRPD data. The MVDA approach revealed that PDF is more efficient in assessing the introduced degree of disorder in ?-indomethacin after cryo-milling than MVDA of the corresponding XRPD diffractograms. The PDF analysis was able to determine the optimal cryo-milling time that facilitated the highest degree of disorder in the samples. Therefore, it is concluded that the PDF technique may be used as a complementary tool to other solid state methods and that further investigations are warranted to elucidate the capabilities of this technique. PMID:21182911

Bøtker, Johan P; Karmwar, Pranav; Strachan, Clare J; Cornett, Claus; Tian, Fang; Zujovic, Zoran; Rantanen, Jukka; Rades, Thomas

2010-12-21

411

BSEP inhibition: in vitro screens to assess cholestatic potential of drugs.  

PubMed

Bile salt export pump (BSEP, ABC11) is a membrane protein that is localized in the cholesterol-rich canalicular membrane of hepatocytes. Its function is to eliminate unconjugated and conjugated bile acids/salts from hepatocyte into the bile. In humans there is no compensatory mechanism for the loss of this transporter. Mutations of BSEP result in a genetic disease, called progressive familial intrahepatic cholestasis type 2 (PFIC2), that is characterized with decreased biliary bile salt secretion, leading to decreased bile flow and accumulation of bile salts inside the hepatocyte, inflicting damage. BSEP inhibitor drugs produce similar bile salt retention that may lead to severe cholestasis and liver damage. Drug-induced liver injury is a relevant clinical issue, in severe cases ending in liver transplantation. Therefore, measurement of BSEP inhibition by candidate drugs has high importance in drug discovery and development. Although several methods are suitable to detect BSEP-drug interactions, due to interspecies differences in bile acid composition, differences in hepatobiliary transporter modulation, they have limitations. This review summarizes appropriate in vitro methods that could be able to predict BSEP-drug candidate interactions in humans before the start of clinical phases. PMID:22120137

Kis, Emese; Ioja, Enik?; Rajnai, Zsuzsa; Jani, Márton; Méhn, Dóra; Herédi-Szabó, Krisztina; Krajcsi, Peter

2011-11-18

412

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.

2013-01-01

413

Assessing the use of global land cover data for guiding large area population distribution modelling.  

PubMed

Gridded population distribution data are finding increasing use in a wide range of fields, including resource allocation, disease burden estimation and climate change impact assessment. Land cover information can be used in combination with detailed settlement extents to redistribute aggregated census counts to improve the accuracy of national-scale gridded population data. In East Africa, such analyses have been done using regional land cover data, thus restricting application of the approach to this region. If gridded population data are to be improved across Africa, an alternative, consistent and comparable source of land cover data is required. Here these analyses were repeated for Kenya using four continent-wide land cover datasets combined with detailed settlement extents and accuracies were assessed against detailed census data. The aim was to identify the large area land cover dataset that, combined with detailed settlement extents, produce the most accurate population distribution data. The effectiveness of the population distribution modelling procedures in the absence of high resolution census data was evaluated, as was the extrapolation ability of population densities between different regions. Results showed that the use of the GlobCover dataset refined with detailed settlement extents provided significantly more accurate gridded population data compared to the use of refined AVHRR-derived, MODIS-derived and GLC2000 land cover datasets. This study supports the hypothesis that land cover information is important for improving population distribution model accuracies, particularly in countries where only coarse resolution census data are available. Obtaining high resolution census data must however remain the priority. With its higher spatial resolution and its more recent data acquisition, the GlobCover dataset was found as the most valuable resource to use in combination with detailed settlement extents for the production of gridded population datasets across large areas. PMID:23576839

Linard, Catherine; Gilbert, Marius; Tatem, Andrew J

2010-05-25

414

Rapid and accurate assessment of seizure liability of drugs by using an optimal support vector machine method.  

PubMed

Drug-induced seizures are a serious adverse effect and assessment of seizure risk usually takes place at the late stage of drug discovery process, which does not allow sufficient time to reduce the risk by chemical modification. Thus early identification of chemicals with seizure liability using rapid and cheaper approaches would be preferable. In this study, an optimal support vector machine (SVM) modeling method has been employed to develop a prediction model of seizure liability of chemicals. A set of 680 compounds were used to train the SVM model. The established SVM model was then validated by an independent test set comprising 175 compounds, which gave a prediction accuracy of 86.9%. Further, the SVM-based prediction model of seizure liability was compared with various preclinical seizure assays, including in vitro rat hippocampal brain slice, in vivo zebrafish larvae assay, mouse spontaneous seizure model, and mouse EEG model. In terms of predictability, the SVM model was ranked just behind the mouse EEG model, but better than the rat brain slice and zebrafish models. Nevertheless, the SVM model has considerable advantages compared with the preclinical seizure assays in speed and cost. In summary, the SVM-based prediction model of seizure liability established here offers potential as a cheaper, rapid and accurate assessment of seizure liability of drugs, which could be used in the seizure risk assessment at the early stage of drug discovery. The prediction model is freely available online at http://www.sklb.scu.edu.cn/lab/yangsy/download/ADMET/seizure_pred.tar. PMID:21641989

Zhang, Hui; Li, Wei; Xie, Yang; Wang, Wen-Jing; Li, Lin-Li; Yang, Sheng-Yong

2011-05-27

415

Comparison of Individual and Pooled Stool Samples for the Assessment of Soil-Transmitted Helminth Infection Intensity and Drug Efficacy  

PubMed Central

Background In veterinary parasitology samples are often pooled for a rapid assessment of infection intensity and drug efficacy. Currently, studies evaluating this strategy in large-scale drug administration programs to control human soil-transmitted helminths (STHs; Ascaris lumbricoides, Trichuris trichiura, and hookworm), are absent. Therefore, we developed and evaluated a pooling strategy to assess intensity of STH infections and drug efficacy. Methods/Principal Findings Stool samples from 840 children attending 14 primary schools in Jimma, Ethiopia were pooled (pool sizes of 10, 20, and 60) to evaluate the infection intensity of STHs. In addition, the efficacy of a single dose of mebendazole (500 mg) in terms of fecal egg count reduction (FECR; synonym of egg reduction rate) was evaluated in 600 children from two of these schools. Individual and pooled samples were examined with the McMaster egg counting method. For each of the three STHs, we found a significant positive correlation between mean fecal egg counts (FECs) of individual stool samples and FEC of pooled stool samples, ranging from 0.62 to 0.98. Only for A. lumbricoides was any significant difference in mean FEC of the individual and pooled samples found. For this STH species, pools of 60 samples resulted in significantly higher FECs. FECR for the different number of samples pooled was comparable in all pool sizes, except for hookworm. For this parasite, pools of 10 and 60 samples provided significantly higher FECR results. Conclusion/Significance This study highlights that pooling stool samples holds promise as a strategy for rapidly assessing infection intensity and efficacy of administered drugs in programs to control human STHs. However, further research is required to determine when and how pooling of stool samples can be cost-effectively applied along a control program, and to verify whether this approach is also applicable to other NTDs.

Mekonnen, Zeleke; Meka, Selima; Ayana, Mio; Bogers, Johannes; Vercruysse, Jozef; Levecke, Bruno

2013-01-01

416

Cytotoxic and genotoxic effects of megazol, an anti-Chagas' disease drug, assessed by different short-term tests.  

PubMed

Cyto- and genotoxicity induced by drugs can limit the dose and duration of treatment, can adversely affect patient quality of life, and may be life-threatening. Two drugs are currently being used for treatment of the acute phase of Chagas' disease and both have serious undesirable effects. In this research, cyto- and genotoxic activity of the nitroimidazole-tiadiazole derivative CL 64855 2-amino-5-(1-methyl-5-nitro-2-imidazolyl)-1,3,4-thiadiazole (megazol), a promising alternative drug, was evaluated in vitro with different short-term tests: (a) induction of recombination events and mutation in the yeast Saccharomyces cerevisiae D7 strain, with and without induction of cytochrome P-450; DNA damage (single and double strand breaks, alkali-labile sites, etc.) by the Comet assay in different mammalian cells. S. cerevisiae did not show a significant increase of mutant and recombinant event frequency, both with and without cytochrome P-450. On the other hand, the cytochrome complex appeared to detoxify the drug with respect to cytotoxicity. Results in rat and mouse fresh leukocytes showed a dose-response relation of drug-induced DNA damage. Findings in treated VERO cells suggested a complex treatment time-DNA damage relationship and the possible induction of repair mechanisms. Furthermore, bleomycin effects were increased in rat cells by simultaneous administration of megazol. Megazol shows different biological activity in relation to cellular types and experimental conditions (with or without cytochrome P-450, short/long time of exposure, with or without other genotoxins), thus suggesting a modulation of effectiveness by different physiological/biochemical conditions of cells. The findings could be useful to evaluate new megazol-derived compounds and to assess the risks/benefits relationship for each drug. PMID:12429351

Poli, Paola; Aline de Mello, Michele; Buschini, Annamaria; Mortara, Renato Arruda; Northfleet de Albuquerque, Cristina; da Silva, Solange; Rossi, Carlo; Zucchi, Tânia Maria Araújo Domingues

2002-12-01

417

Assessing the performance of the log-normal distribution with left truncated survival data  

NASA Astrophysics Data System (ADS)

This research focuses on assessing the performance of the log-normal distribution with left truncated and right censored (LTRC) survival data. Simulation studies were carried out to compare the bias, standard error and root mean square error (RMSE) of the parameter estimates for two different models for which the model ignores left truncation (model 1) and left truncation is accounted for (model 2) when right censored (setting 1) or complete observations (setting 2) are available. The results demonstrate that the bias and RMSE of the parameter estimates for model 1 are relatively higher compared to model 2 for both settings. Furthermore, the standard error appears to be underestimated for model 1 compared to model 2. Finally, a coverage probability study was conducted to assess the performance of Wald confidence interval estimates.

Manoharan, Thirunanthini; Arasan, Jayanthi

2013-09-01

418

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.

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

2006-01-01

419

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.

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

420

Determination of the distribution of light, optical properties, drug concentration, and tissue oxygenation in-vivo in human prostate during motexafin lutetium-mediated photodynamic therapy  

Microsoft Academic Search

It is desirable to quantify the distribution of the light fluence rate, the optical properties, the drug concentration, and the tissue oxygenation for photodynamic therapy (PDT) of prostate cancer. We have developed an integrated system to determine these quantities before and after PDT treatment using motorized probes. The optical properties (absorption (?a), transport scattering (?s?), and effective attenuation (?eff) coefficients)

Timothy C. Zhu; Jarod C. Finlay; Stephen M. Hahn

2005-01-01