Science.gov

Sample records for assessing drug distribution

  1. Assessment of drug permeability distributions in two different model skins.

    PubMed

    Khan, Gul M; Frum, Yakov; Sarheed, Omar; Eccleston, Gillian M; Meidan, Victor M

    2005-10-13

    Past in vitro studies with human skin have indicated that drug permeability coefficient (Kp) distributions do not always follow a Gaussian-normal pattern. This has major statistical implications, exemplified by the fact that use of t-tests to evaluate significance is limited to normally distributed populations. Percutaneous absorption research often involves using animal or synthetic skins to simulate less readily available human skin. However, negligible work has been performed on assessing the permeability variabilities of these model membranes. This paper aims to fill this gap. To this end, four studies were undertaken representing two different drugs (caffeine and testosterone) with each drug penetrating through two different model skins (silicone membrane and pig skin). It was determined that in the silicone membrane studies, both compounds' Kp distributions could be fitted to a normal pattern. In contrast, in the pig skin studies, there were notable differences between each drug. While the testosterone Kp values could be fitted to a normal distribution, this was not possible with the caffeine Kp data, which could be fitted to a log-normal distribution. There is some evidence from the literature as well as physicochemical considerations that these outcomes may reflect general trends that are dependent upon both membrane and penetrant properties. PMID:16102922

  2. Multimodal assessment of spatial distribution of drug-tracer uptake by brain tissue after intra-arterial injections

    NASA Astrophysics Data System (ADS)

    Singh-Moon, Rajinder; Chaudhuri, Durba; Wang, Mei; Straubinger, Robert; Bigio, Irving J.; Joshi, Shailendra

    2014-02-01

    It is challenging to track the rapid changes in drug concentrations after intra-arterial (IA) administration to elucidate the pharmacokinetics of this method of drug delivery. Traditional pharmacokinetic parameters (such as protein binding) that are highly relevant to intravenous (IV) administration do not seem to apply to IA injections. Regional drug delivery is affected by the biomechanics of drug injection, resting blood flow, and local tissue extraction. In-vivo and ex-vivo, optical methods for spatial mapping of drug deposition can assist in visualizing drug distributions and aid in the screening of potential drugs and carrier candidates. We present a multimodal approach for the assessment of drug distribution in postmortem tissue specimens using diffuse reflectance spectroscopy, multispectral imaging, and confocal microscopy and demonstrate feasibility of distinguishing route of administration advantages of liposome-dye conjugate delivery. The results of this study suggest that insight on drug dynamics gained by this aggregated approach can be used to help screen and/or optimize potential drug candidates and drug delivery protocols.

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

    NASA Astrophysics Data System (ADS)

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

    2011-03-01

    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.

  4. Patterns of Drug Distribution: Implications and Issues#

    PubMed Central

    Johnson, Bruce D.

    2007-01-01

    This article delineates various patterns of illicit sales of drugs, especially at the retail (and near-retail) level, addressing a variety of central issues about drug sales and distribution documented during the past 30 years, including: a) the links between drug consumption and drug distribution activities; b) the various distribution roles; c) various levels of the distribution hierarchy; d) types of retail and wholesale markets; e) the association of drug distribution with nondrug associated criminality and violence. The article also will address the implications of drug distribution: whether various public policies such as supply reduction and source interdiction affect illicit drug markets, and how policing strategies and various law enforcement strategies can influence the involvement of individual participation in drug distribution activities. The overlooked contribution of treatment for “drug abuse” to reducing drug sales and distribution activities also will be considered as will other critical unresolved issues. PMID:14582578

  5. Distributed road assessment system

    DOEpatents

    Beer, N. Reginald; Paglieroni, David W

    2014-03-25

    A system that detects damage on or below the surface of a paved structure or pavement is provided. A distributed road assessment system includes road assessment pods and a road assessment server. Each road assessment pod includes a ground-penetrating radar antenna array and a detection system that detects road damage from the return signals as the vehicle on which the pod is mounted travels down a road. Each road assessment pod transmits to the road assessment server occurrence information describing each occurrence of road damage that is newly detected on a current scan of a road. The road assessment server maintains a road damage database of occurrence information describing the previously detected occurrences of road damage. After the road assessment server receives occurrence information for newly detected occurrences of road damage for a portion of a road, the road assessment server determines which newly detected occurrences correspond to which previously detected occurrences of road damage.

  6. Characterization and Higher-Order Structure Assessment of an Interchain Cysteine-Based ADC: Impact of Drug Loading and Distribution on the Mechanism of Aggregation.

    PubMed

    Guo, Jianxin; Kumar, Sandeep; Chipley, Mark; Marcq, Olivier; Gupta, Devansh; Jin, Zhaowei; Tomar, Dheeraj S; Swabowski, Cecily; Smith, Jacquelynn; Starkey, Jason A; Singh, Satish K

    2016-03-16

    The impact of drug loading and distribution on higher order structure and physical stability of an interchain cysteine-based antibody drug conjugate (ADC) has been studied. An IgG1 mAb was conjugated with a cytotoxic auristatin payload following the reduction of interchain disulfides. The 2-D LC-MS analysis shows that there is a preference for certain isomers within the various drug to antibody ratios (DARs). The physical stability of the unconjugated monoclonal antibody, the ADC, and isolated conjugated species with specific DAR, were compared using calorimetric, thermal, chemical denaturation and molecular modeling techniques, as well as techniques to assess hydrophobicity. The DAR was determined to have a significant impact on the biophysical properties and stability of the ADC. The CH2 domain was significantly perturbed in the DAR6 species, which was attributable to quaternary structural changes as assessed by molecular modeling. At accelerated storage temperatures, the DAR6 rapidly forms higher molecular mass species, whereas the DAR2 and the unconjugated mAb were largely stable. Chemical denaturation study indicates that DAR6 may form multimers while DAR2 and DAR4 primarily exist in monomeric forms in solution at ambient conditions. The physical state differences were correlated with a dramatic increase in the hydrophobicity and a reduction in the surface tension of the DAR6 compared to lower DAR species. Molecular modeling of the various DAR species and their conformers demonstrates that the auristatin-based linker payload directly contributes to the hydrophobicity of the ADC molecule. Higher order structural characterization provides insight into the impact of conjugation on the conformational and colloidal factors that determine the physical stability of cysteine-based ADCs, with implications for process and formulation development. PMID:26829368

  7. Multistep, effective drug distribution within solid tumors

    PubMed Central

    Shemi, Amotz; Khvalevsky, Elina Zorde; Gabai, Rachel Malka; Domb, Abraham; Barenholz, Yechezkel

    2015-01-01

    The distribution of drugs within solid tumors presents a long-standing barrier for efficient cancer therapies. Tumors are highly resistant to diffusion, and the lack of blood and lymphatic flows suppresses convection. Prolonged, continuous intratumoral drug delivery from a miniature drug source offers an alternative to both systemic delivery and intratumoral injection. Presented here is a model of drug distribution from such a source, in a multistep process. At delivery onset the drug mainly affects the closest surroundings. Such ‘priming’ enables drug penetration to successive cell layers. Tumor ‘void volume’ (volume not occupied by cells) increases, facilitating lymphatic perfusion. The drug is then transported by hydraulic convection downstream along interstitial fluid pressure (IFP) gradients, away from the tumor core. After a week tumor cell death occurs throughout the entire tumor and IFP gradients are flattened. Then, the drug is transported mainly by ‘mixing’, powered by physiological bulk body movements. Steady state is achieved and the drug covers the entire tumor over several months. Supporting measurements are provided from the LODER™ system, releasing siRNA against mutated KRAS over months in pancreatic cancer in-vivo models. LODER™ was also successfully employed in a recent Phase 1/2 clinical trial with pancreatic cancer patients. PMID:26416413

  8. Pricing, distribution, and use of antimalarial drugs.

    PubMed Central

    Foster, S. D.

    1991-01-01

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

  9. Environmental assessment requirements for live biological drugs.

    PubMed

    Sutton, Ann

    2008-02-01

    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

  10. HPMA-LMA copolymer drug carriers in oncology: an in vivo PET study to assess the tumor line-specific polymer uptake and body distribution.

    PubMed

    Allmeroth, Mareli; Moderegger, Dorothea; Gündel, Daniel; Koynov, Kaloian; Buchholz, Hans-Georg; Mohr, Kristin; Rösch, Frank; Zentel, Rudolf; Thews, Oliver

    2013-09-01

    Polymeric drug carriers aim to selectively target tumors in combination with protecting normal tissue. In this regard polymer structure and molecular weight are key factors considering organ distribution and tumor accumulation of the polymeric drug delivery system. Four different HPMA based copolymer structures (random as well as block copolymers with lauryl methacrylate as hydrophobic block) varying in molecular weight, size and resulting architecture were analyzed in two different tumor models (AT1 prostate carcinoma and Walker-256 mammary carcinoma) in vivo. Polymers were labeled with (18)F and organ/tumor uptake was followed by μPET imaging and ex vivo biodistribution. Vascular permeability was measured by dextran extravasation and vascular density by immunohistochemistry. Cellular polymer uptake was determined in vitro using fluorescence-labeled polymers. Most strikingly, the high molecular weight HPMA-LMA random copolymer demonstrated highest tumor uptake and blood pool concentration. The molecular structure (e.g., amphiphilicity) is holding a higher impact on desired in vivo properties than polymer size. The results also revealed pronounced differences between the tumor models although vascular permeability was almost comparable. Accumulation in Walker-256 carcinomas was much higher, presumably due to a better cellular uptake in this cell line and a denser vascular network in the tumors. These investigations clearly indicate that the properties of the individual tumor determine the suitability of polymeric drug carriers. The findings also illustrate the general necessity of a preclinical screening to analyze polymer uptake for each individual patient (e.g., by noninvasive PET imaging) in order to individualize polymer-based chemotherapy. PMID:23962188

  11. Optimizing distribution of pandemic influenza antiviral drugs.

    PubMed

    Singh, Bismark; Huang, Hsin-Chan; Morton, David P; Johnson, Gregory P; Gutfraind, Alexander; Galvani, Alison P; Clements, Bruce; Meyers, Lauren A

    2015-02-01

    We provide a data-driven method for optimizing pharmacy-based distribution of antiviral drugs during an influenza pandemic in terms of overall access for a target population and apply it to the state of Texas, USA. We found that during the 2009 influenza pandemic, the Texas Department of State Health Services achieved an estimated statewide access of 88% (proportion of population willing to travel to the nearest dispensing point). However, access reached only 34.5% of US postal code (ZIP code) areas containing <1,000 underinsured persons. Optimized distribution networks increased expected access to 91% overall and 60% in hard-to-reach regions, and 2 or 3 major pharmacy chains achieved near maximal coverage in well-populated areas. Independent pharmacies were essential for reaching ZIP code areas containing <1,000 underinsured persons. This model was developed during a collaboration between academic researchers and public health officials and is available as a decision support tool for Texas Department of State Health Services at a Web-based interface. PMID:25625858

  12. Optimizing Distribution of Pandemic Influenza Antiviral Drugs

    PubMed Central

    Huang, Hsin-Chan; Morton, David P.; Johnson, Gregory P.; Gutfraind, Alexander; Galvani, Alison P.; Clements, Bruce; Meyers, Lauren A.

    2015-01-01

    We provide a data-driven method for optimizing pharmacy-based distribution of antiviral drugs during an influenza pandemic in terms of overall access for a target population and apply it to the state of Texas, USA. We found that during the 2009 influenza pandemic, the Texas Department of State Health Services achieved an estimated statewide access of 88% (proportion of population willing to travel to the nearest dispensing point). However, access reached only 34.5% of US postal code (ZIP code) areas containing <1,000 underinsured persons. Optimized distribution networks increased expected access to 91% overall and 60% in hard-to-reach regions, and 2 or 3 major pharmacy chains achieved near maximal coverage in well-populated areas. Independent pharmacies were essential for reaching ZIP code areas containing <1,000 underinsured persons. This model was developed during a collaboration between academic researchers and public health officials and is available as a decision support tool for Texas Department of State Health Services at a Web-based interface. PMID:25625858

  13. Appropriately assessing renal function for drug dosing.

    PubMed

    Dong, Kimberly; Quan, David J

    2010-01-01

    Chronic kidney disease affects millions of Americans. Many drugs are eliminated from the body by the kidneys. As renal function declines due to the disease, drugs that are normally eliminated by the kidneys can accumulate, potentially leading to toxicity. Assessing kidney function in patients is essential in determining the appropriate dose of medications to achieve the desired clinical outcome while minimizing the potential for toxicity. PMID:20629469

  14. Correlates of engaging in drug distribution in a national sample.

    PubMed

    Stanforth, Evan T; Kostiuk, Marisa; Garriott, Patton O

    2016-02-01

    In this study, we examined self-reported behaviors and characteristics of individuals involved in drug distribution to identify correlates of engaging in drug-distribution behaviors. Correlates of interest included demographic characteristics, substance-use patterns, psychological impairment, and criminal involvement. Data from the 2012 National Survey on Drug Use and Health (U.S. Department of Health and Human Services, Substance Abuse & Mental Health Services Administration, 2013) were used for analyses (N = 55,108). A logistic regression analysis distinguished those who have sold drugs from those who have not sold drugs to identify correlates of engaging in drug distribution. Results showed that recency of substance use, severity of substance use, criminal activity, mental health diagnoses, substance-use treatment, and arrest history were all significantly associated with distribution behaviors. Findings indicate the importance of accounting for the heterogeneous characteristics of individuals involved in distribution behaviors when considering treatment options or criminal proceedings. (PsycINFO Database Record PMID:26502336

  15. Effects of cellular pharmacology on drug distribution in tissues.

    PubMed Central

    Rippley, R K; Stokes, C L

    1995-01-01

    The efficacy of targeted therapeutics such as immunotoxins is directly related to both the extent of distribution achievable and the degree of drug internalization by individual cells in the tissue of interest. The factors that influence the tissue distribution of such drugs include drug transport; receptor/drug binding; and cellular pharmacology, the processing and routing of the drug within cells. To examine the importance of cellular pharmacology, previously treated only superficially, we have developed a mathematical model for drug transport in tissues that includes drug and receptor internalization, recycling, and degradation, as well as drug diffusion in the extracellular space and binding to cell surface receptors. We have applied this "cellular pharmacology model" to a model drug/cell system, specifically, transferrin and the well-defined transferrin cycle in CHO cells. We compare simulation results to models with extracellular diffusion only or diffusion with binding to cell surface receptors and present a parameter sensitivity analysis. The comparison of models illustrates that inclusion of intracellular trafficking significantly increases the total transferrin concentration throughout much of the tissue while decreasing the penetration depth. Increasing receptor affinity or tissue receptor density reduces permeation of extracellular drug while increasing the peak value of the intracellular drug concentration, resulting in "internal trapping" of transferrin near the source; this could account for heterogeneity of drug distributions observed in experimental systems. Other results indicate that the degree of drug internalization is not predicted by the total drug profile. Hence, when intracellular drug is required for a therapeutic effect, the optimal treatment may not result from conditions that produce the maximal total drug distribution. Examination of models that include cellular pharmacology may help guide rational drug design and provide useful information for whole body pharmacokinetic studies. PMID:8519983

  16. 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

    2013-04-01

    ... 21 Food and Drugs 9 2013-04-01 2013-04-01 false Removal of the exemption of drugs distributed under the Federal Food, Drug and Cosmetic Act. 1310.10 Section 1310.10 Food and Drugs DRUG ENFORCEMENT... Removal of the exemption of drugs distributed under the Federal Food, Drug and Cosmetic Act. (a)...

  17. 21 CFR 1310.11 - Reinstatement of exemption for drug products distributed under the Food, Drug and Cosmetic Act.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 9 2011-04-01 2011-04-01 false Reinstatement of exemption for drug products distributed under the Food, Drug and Cosmetic Act. 1310.11 Section 1310.11 Food and Drugs DRUG ENFORCEMENT... Reinstatement of exemption for drug products distributed under the Food, Drug and Cosmetic Act. (a)...

  18. 21 CFR 1310.11 - Reinstatement of exemption for drug products distributed under the Food, Drug and Cosmetic Act.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 21 Food and Drugs 9 2013-04-01 2013-04-01 false Reinstatement of exemption for drug products distributed under the Food, Drug and Cosmetic Act. 1310.11 Section 1310.11 Food and Drugs DRUG ENFORCEMENT... Reinstatement of exemption for drug products distributed under the Food, Drug and Cosmetic Act. (a)...

  19. 21 CFR 1310.11 - Reinstatement of exemption for drug products distributed under the Food, Drug and Cosmetic Act.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 9 2010-04-01 2010-04-01 false Reinstatement of exemption for drug products distributed under the Food, Drug and Cosmetic Act. 1310.11 Section 1310.11 Food and Drugs DRUG ENFORCEMENT... Reinstatement of exemption for drug products distributed under the Food, Drug and Cosmetic Act. (a)...

  20. 21 CFR 1310.10 - Removal of the exemption of drugs distributed under the Food, Drug and Cosmetic Act.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

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

  1. 21 CFR 1310.10 - Removal of the exemption of drugs distributed under the Food, Drug and Cosmetic Act.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 9 2010-04-01 2010-04-01 false Removal of the exemption of drugs distributed under the Food, Drug and Cosmetic Act. 1310.10 Section 1310.10 Food and Drugs DRUG ENFORCEMENT... Removal of the exemption of drugs distributed under the Food, Drug and Cosmetic Act. (a) The...

  2. 21 CFR 1310.11 - Reinstatement of exemption for drug products distributed under the Food, Drug and Cosmetic Act.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 21 Food and Drugs 9 2012-04-01 2012-04-01 false Reinstatement of exemption for drug products distributed under the Food, Drug and Cosmetic Act. 1310.11 Section 1310.11 Food and Drugs DRUG ENFORCEMENT... Reinstatement of exemption for drug products distributed under the Food, Drug and Cosmetic Act. (a)...

  3. 21 CFR 1310.10 - Removal of the exemption of drugs distributed under the Federal Food, Drug and Cosmetic Act.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 21 Food and Drugs 9 2014-04-01 2014-04-01 false Removal of the exemption of drugs distributed under the Federal Food, Drug and Cosmetic Act. 1310.10 Section 1310.10 Food and Drugs DRUG ENFORCEMENT... Removal of the exemption of drugs distributed under the Federal Food, Drug and Cosmetic Act. (a)...

  4. 21 CFR 1310.10 - Removal of the exemption of drugs distributed under the Federal Food, Drug and Cosmetic Act.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 21 Food and Drugs 9 2012-04-01 2012-04-01 false Removal of the exemption of drugs distributed under the Federal Food, Drug and Cosmetic Act. 1310.10 Section 1310.10 Food and Drugs DRUG ENFORCEMENT... Removal of the exemption of drugs distributed under the Federal Food, Drug and Cosmetic Act. (a)...

  5. 21 CFR 1310.11 - Reinstatement of exemption for drug products distributed under the Food, Drug and Cosmetic Act.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 21 Food and Drugs 9 2014-04-01 2014-04-01 false Reinstatement of exemption for drug products distributed under the Food, Drug and Cosmetic Act. 1310.11 Section 1310.11 Food and Drugs DRUG ENFORCEMENT... Reinstatement of exemption for drug products distributed under the Food, Drug and Cosmetic Act. (a)...

  6. 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...

  7. Methods of assessment of antiepileptic drugs.

    PubMed Central

    Milligan, N; Richens, A

    1981-01-01

    Epilepsy is a symptom with protean manifestations and as such it is a difficult disease in which to carry out a therapeutic trial. The methods available to research workers for the assessment of new antiepileptic drugs are hampered by the fact that epilepsy is a fluctuant condition. Although it is a chronic disorder open to study using cross-over trials and within-patient comparisons, accurate assessment cannot be easily made at any one point in time. Research workers are therefore automatically placed at a time factor disadvantage and this is especially so for those searching for quick methods of evaluating new compounds. The need for a quick and reliable method of assessing a new antiepileptic drug has long been appreciated. This article will discuss the methods currently available and we will begin by considering the most commonly used method of assessment with particular reference to some of the problems involved in conducting a controlled clinical trial in epilepsy. PMID:7272157

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

    PubMed

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

    2014-10-15

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

  9. Quantitative profiling of tissue drug distribution by MS imaging.

    PubMed

    Pirman, David

    2015-01-01

    This article highlights recent advancements in the quantitative measurement of drug distribution by MS imaging (MSI). Quantitation by MSI was recently considering the primary disadvantage of MSI approaches particularly when compared with widely used autoradiography techniques. These approaches show significant progress in the area of quantitative MSI and have been used in numerous drug and metabolite distribution measurements. As quantitative limitations are overcome, the use of MSI in drug development should increase significantly providing key insights into both tissue-target validation as well as identifying off tissue-target issues with drug delivery. PMID:26495807

  10. Assessing suicidal risk with antiepileptic drugs

    PubMed Central

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

    2010-01-01

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

  11. Drug interactions evaluation: an integrated part of risk assessment of therapeutics.

    PubMed

    Zhang, Lei; Reynolds, Kellie S; Zhao, Ping; Huang, Shiew-Mei

    2010-03-01

    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. PMID:20045016

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

    SciTech Connect

    Zhang, Lei; Reynolds, Kellie S.; Zhao, Ping; Huang, Shiew-Mei

    2010-03-01

    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.

  13. Assessing the new medicare prescription drug law.

    PubMed

    Doherty, Robert B

    2004-09-01

    The Medicare Modernization Act (MMA) is the product of a political compromise to attract moderate Republicans and enough Democrats without losing Republican conservatives. The compromise offered more private health plans to beneficiaries while maintaining and improving traditional Medicare's benefits. This compromise did not settle the debate over the legislation, which is a major issue in the 2004 elections. Voters poorly understand the law because of its complexity. In this paper, I explain how the policy decisions made by the U.S. Congress have contributed to the law's complexity and controversy. I examine the new private health plan options that will be offered to beneficiaries, improvements made to traditional Medicare, and the impact of introducing income-based determinations into Medicare. I also discuss the impact of the drug benefit on beneficiaries in different income and assets categories and Congress's decision to prohibit the federal government from directly negotiating prices with drug manufacturers. I conclude by assessing the major claims made by critics and proponents. Both might be more circumspect in their assessments of the law's impact, since it is impossible to predict how a law of such complexity, with so many human variables, will work out in the end. The MMA is a worthwhile but imperfect effort to extend drug coverage to seniors who are most in need. It deserves neither condemnation nor indiscriminate praise but instead a commitment to help it succeed. PMID:15353431

  14. Drug product distribution systems and departmental operations.

    PubMed

    Hynniman, C E

    1991-10-01

    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

  15. Assessing Specificity of Anticancer Drugs In Vitro.

    PubMed

    Kluwe, Lan

    2016-01-01

    A procedure for assessing specificity of anticancer drugs in vitro using cultures containing both tumor and non-tumor cells is demonstrated. The key element is the quantitative determination of a tumor-specific genetic alteration in relation to a universal sequence using a dual-probe digital PCR assay and the subsequent calculation of the proportion of tumor cells. The assay is carried out on a culture containing tumor cells of an established line and spiked-in non-tumor cells. The mixed culture is treated with a test drug at various concentrations. After the treatment, DNA is prepared directly from the survived adhesive cells in wells of 96-well plates using a simple and inexpensive method, and subjected to a dual-probe digital PCR assay for measuring a tumor-specific genetic alteration and a reference universal sequence. In the present demonstration, a heterozygous deletion of the NF1 gene is used as the tumor-specific genetic alteration and a RPP30 gene as the reference gene. Using the ratio NF1/RPP30, the proportion of tumor cells was calculated. Since the dose-dependent change of the proportion of tumor cells provides an in vitro indication for specificity of the drug, this genetic and cell-based in vitro assay will likely have application potential in drug discovery. Furthermore, for personalized cancer-care, this genetic- and cell-based tool may contribute to optimizing adjuvant chemotherapy by means of testing efficacy and specificity of candidate drugs using primary cultures of individual tumors. PMID:27078035

  16. Assessing Specificity of Anticancer Drugs In Vitro

    PubMed Central

    Kluwe, Lan

    2016-01-01

    A procedure for assessing specificity of anticancer drugs in vitro using cultures containing both tumor and non-tumor cells is demonstrated. The key element is the quantitative determination of a tumor-specific genetic alteration in relation to a universal sequence using a dual-probe digital PCR assay and the subsequent calculation of the proportion of tumor cells. The assay is carried out on a culture containing tumor cells of an established line and spiked-in non-tumor cells. The mixed culture is treated with a test drug at various concentrations. After the treatment, DNA is prepared directly from the survived adhesive cells in wells of 96-well plates using a simple and inexpensive method, and subjected to a dual-probe digital PCR assay for measuring a tumor-specific genetic alteration and a reference universal sequence. In the present demonstration, a heterozygous deletion of the NF1 gene is used as the tumor-specific genetic alteration and a RPP30 gene as the reference gene. Using the ratio NF1/RPP30, the proportion of tumor cells was calculated. Since the dose-dependent change of the proportion of tumor cells provides an in vitro indication for specificity of the drug, this genetic and cell-based in vitro assay will likely have application potential in drug discovery. Furthermore, for personalized cancer-care, this genetic- and cell-based tool may contribute to optimizing adjuvant chemotherapy by means of testing efficacy and specificity of candidate drugs using primary cultures of individual tumors. PMID:27078035

  17. A Strategy for Local Drug Abuse Assessment. Technical Paper.

    ERIC Educational Resources Information Center

    Green, John O.

    This paper provides a model to assist local program planners, administrators, and other decisionmakers in the assessment of local drug abuse conditions and problems. The model presents data on which to base everyday judgments about drug abuse, to plan for drug abuse services, and to allocate limited resources on local levels. Drug abuse indicators…

  18. Laser speckle imaging of intra organ drug distribution

    PubMed Central

    Postnov, Dmitry D; Holstein-Rathlou, Niels-Henrik; Sosnovtseva, Olga

    2015-01-01

    Laminar flow in arteries causes streaming and uneven distribution of infused agents within the organ. This may lead to misinterpretation of experimental results and affect treatment outcomes. We monitor dynamical changes of superficial cortical blood flow in the rat kidney following different routes of administration of the vasoconstrictor angiotensin II. Our analysis reveals the appearance of large scale oscillations of the blood flow caused by inhomogeneous intra organ drug distribution. PMID:26713217

  19. Laser speckle imaging of intra organ drug distribution.

    PubMed

    Postnov, Dmitry D; Holstein-Rathlou, Niels-Henrik; Sosnovtseva, Olga

    2015-12-01

    Laminar flow in arteries causes streaming and uneven distribution of infused agents within the organ. This may lead to misinterpretation of experimental results and affect treatment outcomes. We monitor dynamical changes of superficial cortical blood flow in the rat kidney following different routes of administration of the vasoconstrictor angiotensin II. Our analysis reveals the appearance of large scale oscillations of the blood flow caused by inhomogeneous intra organ drug distribution. PMID:26713217

  20. Using Diaries to Assess Nonprescription Drug Use among University Students

    ERIC Educational Resources Information Center

    Acocella, Cecilia M.

    2005-01-01

    Nonprescription drug use among university students was investigated using survey and behavioral diary methodologies to assess usage of nonprescription drug use and to compare survey and diary methodologies. Surveys were completed by 183 students (136 females and 47 males) that asked how often they used nonprescription drugs and what those drugs…

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

    PubMed

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

    2015-01-01

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

  2. Assessing and managing drug-nutrient interactions.

    PubMed

    Anderson, Karl E; Greenblatt, David J

    2002-01-01

    Drug-nutrient interactions can occur through many mechanisms. The amount of protein in the diet and the presence of micronutrients, such as polycyclic aromatic hydrocarbons and indoles, can affect drug metabolism. Although furanocoumarins in grapefruit juice can interact with certain oral medications, noninteracting medications generally can be substituted. Pharmacists need to provide patients with accurate information about drug-nutrient interactions and help to clarify common misconceptions about these effects. PMID:12296543

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

    SciTech Connect

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

    2011-01-15

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

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

    ERIC Educational Resources Information Center

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

    2013-01-01

    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…

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

    ERIC Educational Resources Information Center

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

    2013-01-01

    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

  6. The economics of drug abuse: a quantitative assessment of drug demand.

    PubMed

    Hursh, Steven R; Galuska, Chad M; Winger, Gail; Woods, James H

    2005-02-01

    Behavioral economic concepts have proven useful for an overall understanding of the regulation of behavior by environmental commodities and complements a pharmacological perspective on drug abuse in several ways. First, a quantitative assessment of drug demand, equated in terms of drug potency, allows meaningful comparisons to be made among drug reinforcers within and across pharmacological classes. Second, behavioral economics provides a conceptual framework for understanding key factors, both pharmacological and environmental, that contribute to reductions in consumption of illicit drugs. Finally, behavioral economics provides a basis for generalization from laboratory and clinical studies to the development of novel behavioral and pharmacological therapies. PMID:15731502

  7. 21 CFR 1405.210 - To whom must I distribute my drug-free workplace statement?

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 9 2010-04-01 2010-04-01 false To whom must I distribute my drug-free workplace... REQUIREMENTS FOR DRUG-FREE WORKPLACE (FINANCIAL ASSISTANCE) Requirements for Recipients Other Than Individuals § 1405.210 To whom must I distribute my drug-free workplace statement? You must require that a copy...

  8. Statistical assessment of Monte Carlo distributional tallies

    SciTech Connect

    Kiedrowski, Brian C; Solomon, Clell J

    2010-12-09

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

  9. Experienced drug users assess the relative harms and benefits of drugs: a web-based survey.

    PubMed

    Carhart-Harris, Robin Lester; Nutt, David John

    2013-01-01

    A web-based survey was used to consult the opinions of experienced drug users on matters related to drug harms. We identified a rare sample of 93 drug users with personal experience with 11 different illicit drugs that are widely used in the UK. Asked to assess the relative harms of these drugs, they ranked alcohol and tobacco as the most harmful, and three "Class A" drugs (MDMA, LSD, and psilocybin) and one class B (cannabis) were ranked as the four least harmful drugs. When asked to assess the relative potential for benefit of the 11 drugs, MDMA, LSD, psilocybin, and cannabis were ranked in the top four; and when asked why these drugs are beneficial, rather than simply report hedonic properties, they referred to potential therapeutic applications (e.g., as tools to assist psychotherapy). These results provide a useful insight into the opinions of experienced drug users on a subject about which they have a rare and intimate knowledge. PMID:24377171

  10. Assessing Drug Target Association Using Semantic Linked Data

    PubMed Central

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

    2012-01-01

    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 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

  11. Assessing illicit drug use among adults with schizophrenia.

    PubMed

    Van Dorn, Richard A; Desmarais, Sarah L; Scott Young, M; Sellers, Brian G; Swartz, Marvin S

    2012-12-30

    Accurate drug use assessment is vital to understanding the prevalence, course, treatment needs, and outcomes among individuals with schizophrenia because they are thought to remain at long-term risk for negative drug use outcomes, even in the absence of drug use disorder. This study evaluated self-report and biological measures for assessing illicit drug use in the Clinical Antipsychotic Trials of Intervention Effectiveness study (N=1460). Performance was good across assessment methods, but differed as a function of drug type, measure, and race. With the Structured Clinical Interview for DSM-III-R as the criterion, self-report evidenced greater concordance, accuracy and agreement overall, and for marijuana, cocaine, and stimulants specifically, than did urinalysis and hair assays, whereas biological measures outperformed self-report for detection of opiates. Performance of the biological measures was better when self-report was the criterion, but poorer for black compared white participants. Overall, findings suggest that self-report is able to garner accurate information regarding illicit drug use among adults with schizophrenia. Further work is needed to understand the differential performance of assessment approaches by drug type, overall and as a function of race, in this population. PMID:22796100

  12. Drug distribution in wet granulation: foam versus spray.

    PubMed

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

    2013-09-01

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

  13. Assessing Website Pharmacy Drug Quality: Safer Than You Think?

    PubMed Central

    Bate, Roger; Hess, Kimberly

    2010-01-01

    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. PMID:20730049

  14. 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

    Ikeda, Osamu Kusunoki, Shinichiroh; Nakaura, Takeshi; Shiraishi, Shinya; Kawanaka, Kouichi; Tomiguchi, Seiji; Yamashita, Yasuyuki; Takamori, Hiroshi; Chikamoto, Akira; Kanemitsu, Keiichiro

    2006-06-15

    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.

  15. 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.

    PubMed

    Ikeda, Osamu; Kusunoki, Shinichiroh; Nakaura, Takeshi; Shiraishi, Shinya; Kawanaka, Kouichi; Tomiguchi, Seiji; Yamashita, Yasuyuki; Takamori, Hiroshi; Chikamoto, Akira; Kanemitsu, Keiichiro

    2006-01-01

    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. PMID:16502168

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

    PubMed

    Hanrahan, Conor T; Cole, Sabrina W

    2014-04-01

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

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

    PubMed Central

    Blakeley, Jaishri; Portnow, Jana

    2014-01-01

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

  18. 21 CFR 212.90 - What actions must I take to control the distribution of PET drug products?

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... distribution of PET drug products? 212.90 Section 212.90 Food and Drugs FOOD AND DRUG ADMINISTRATION... distribution of PET drug products? (a) Written distribution procedures. You must establish, maintain, and follow written procedures for the control of distribution of PET drug products shipped from the PET...

  19. 21 CFR 212.90 - What actions must I take to control the distribution of PET drug products?

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... distribution of PET drug products? 212.90 Section 212.90 Food and Drugs FOOD AND DRUG ADMINISTRATION... distribution of PET drug products? (a) Written distribution procedures. You must establish, maintain, and follow written procedures for the control of distribution of PET drug products shipped from the PET...

  20. 21 CFR 212.90 - What actions must I take to control the distribution of PET drug products?

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... distribution of PET drug products? 212.90 Section 212.90 Food and Drugs FOOD AND DRUG ADMINISTRATION... control the distribution of PET drug products? (a) Written distribution procedures. You must establish, maintain, and follow written procedures for the control of distribution of PET drug products shipped...

  1. 21 CFR 212.90 - What actions must I take to control the distribution of PET drug products?

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... distribution of PET drug products? 212.90 Section 212.90 Food and Drugs FOOD AND DRUG ADMINISTRATION... distribution of PET drug products? (a) Written distribution procedures. You must establish, maintain, and follow written procedures for the control of distribution of PET drug products shipped from the PET...

  2. 21 CFR 212.90 - What actions must I take to control the distribution of PET drug products?

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... distribution of PET drug products? 212.90 Section 212.90 Food and Drugs FOOD AND DRUG ADMINISTRATION... distribution of PET drug products? (a) Written distribution procedures. You must establish, maintain, and follow written procedures for the control of distribution of PET drug products shipped from the PET...

  3. Risk-benefit assessment of tocolytic drugs.

    PubMed

    Wischnik, A

    1991-01-01

    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

  4. IVAN: intelligent van for the distribution of pharmaceutical drugs.

    PubMed

    Moreno, Asier; Angulo, Ignacio; Perallos, Asier; Landaluce, Hugo; García Zuazola, Ignacio Julio; Azpilicueta, Leire; Astrain, José Javier; Falcone, Francisco; Villadangos, Jesús

    2012-01-01

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

  5. IVAN: Intelligent Van for the Distribution of Pharmaceutical Drugs

    PubMed Central

    Moreno, Asier; Angulo, Ignacio; Perallos, Asier; Landaluce, Hugo; Zuazola, Ignacio Julio García; Azpilicueta, Leire; Astrain, José Javier; Falcone, Francisco; Villadangos, Jesús

    2012-01-01

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

  6. 34 CFR 84.210 - To whom must I distribute my drug-free workplace statement?

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 34 Education 1 2010-07-01 2010-07-01 false To whom must I distribute my drug-free workplace... REQUIREMENTS FOR DRUG-FREE WORKPLACE (FINANCIAL ASSISTANCE) Requirements for Recipients Other Than Individuals § 84.210 To whom must I distribute my drug-free workplace statement? You must require that a copy...

  7. 49 CFR 32.210 - To whom must I distribute my drug-free workplace statement?

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 49 Transportation 1 2010-10-01 2010-10-01 false To whom must I distribute my drug-free workplace... REQUIREMENTS FOR DRUG-FREE WORKPLACE (FINANCIAL ASSISTANCE) Requirements for Recipients Other Than Individuals § 32.210 To whom must I distribute my drug-free workplace statement? You must require that a copy...

  8. 29 CFR 1472.210 - To whom must I distribute my drug-free workplace statement?

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 29 Labor 4 2010-07-01 2010-07-01 false To whom must I distribute my drug-free workplace statement... CONCILIATION SERVICE GOVERNMENTWIDE REQUIREMENTS FOR DRUG-FREE WORKPLACE (FINANCIAL ASSISTANCE) Requirements for Recipients Other Than Individuals § 1472.210 To whom must I distribute my drug-free...

  9. The brain slice method for studying drug distribution in the CNS

    PubMed Central

    2013-01-01

    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. PMID:23336814

  10. 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

    2012-01-01

    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. PMID:23181938

  11. [Educative game on drugs for blind individuals: development and assessment].

    PubMed

    Mariano, Monaliza Ribeiro; Rebouças, Cristiana Brasil de Almeida; Pagliuca, Lorita Marlena Freitag

    2013-08-01

    Study aimed to develop and assess an educational game on psychoactive drugs accessible to blind individuals, conducted in three steps: development of the educative game, evaluation by three special education experts, and assessment by twelve blind individuals. As a result, a board game called Drugs: staying clean was developed. In the Alpha version, experts made suggestions regarding the game rules and instructions and the board base, including square texture, game pieces, and Braille writing. In Beta version, we proceeded to the assessment by the blind participants, who suggested changes in the square texture and the addition of Velcro-type material to fix the counters on the board. Then, the Gamma version was played by the last pairs of blind players and was considered by them to be adequate. In the evaluation of the experts, the game was appropriate, as it allowed access to information on psychoactive drugs in a ludic and playful manner. PMID:24310692

  12. Assessment of drug abuser treatment needs in Rhode Island.

    PubMed Central

    McAuliffe, W E; Breer, P; Ahmadifar, N W; Spino, C

    1991-01-01

    BACKGROUND. Rhode Island's Division of Substance Abuse asked us to assess the State's drug treatment needs and make recommendations regarding its treatment system for the next three years. METHODS. We used a statewide telephone drug use survey of 5,176 households supplemented by drug-related hospital discharges, Division of Drug Control statistics, and interviews with providers, state officials, and out-of-state experts. Drug abuse was measured with items from the Diagnostic Interview Schedule. Abusers were asked if they were receiving or wanted to receive treatment. RESULTS. Survey responses, used to estimate the unmet need for drug treatment, indicated a need to triple drug treatment services. Regression models using survey data indicated that the treatment network was overly centralized in the Providence area. Interviews with state officials, clinicians, and out-of-state experts provided material for recommendations on reimbursement policy, treatment mix, quality assurance, and cost containment. CONCLUSIONS. The RI Department of Health's certificate-of-need program adopted our overall recommendation for tripling the drug treatment system as its guideline in evaluating proposals for new treatment facilities. With State funding of a new adolescent center and expansion of outpatient slots in the private sector, this recommendation has now been fully implemented. PMID:1847277

  13. In Vivo Methods for the Assessment of Topical Drug Bioavailability

    PubMed Central

    Herkenne, Christophe; Alberti, Ingo; Naik, Aarti; Kalia, Yogeshvar N.; Mathy, François-Xavier; Préat, Véronique

    2007-01-01

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

  14. Assessment of cognitive safety in clinical drug development

    PubMed Central

    Roiser, Jonathan P.; Nathan, Pradeep J.; Mander, Adrian P.; Adusei, Gabriel; Zavitz, Kenton H.; Blackwell, Andrew D.

    2016-01-01

    Cognitive impairment is increasingly recognised as an important potential adverse effect of medication. However, many drug development programmes do not incorporate sensitive cognitive measurements. Here, we review the rationale for cognitive safety assessment, and explain several basic methodological principles for measuring cognition during clinical drug development, including study design and statistical analysis, from Phase I through to postmarketing. The crucial issue of how cognition should be assessed is emphasized, especially the sensitivity of measurement. We also consider how best to interpret the magnitude of any identified effects, including comparison with benchmarks. We conclude by discussing strategies for the effective communication of cognitive risks. PMID:26610416

  15. Drug abuse in Nepal: a rapid assessment study.

    PubMed

    Chatterjee, A; Uprety, L; Chapagain, M; Kafle, K

    1996-01-01

    A rapid assessment of drug abuse in Nepal was conducted at different sites, including eight municipalities in the five development regions of the country. To interview various groups of key informants, such methods as semi-structured interviews, in-depth interviews and focus group discussions were used. A snowball sampling strategy for respondents who were drug abusers and a judgemental sampling strategy for the non-drug-using key informants were applied. About one fifth of the sample was recruited from the treatment centres and the rest from the community. Drug abusers in prison were interviewed, and secondary data from treatment centres and prisons analysed. The study revealed that the sample of drug abusers had a mean age of 23.8 years and was overwhelmingly male. Most respondents lived with their families and were either unemployed or students. About 30 per cent of the sample was married. A large majority of the sample had a family member or a close relative outside the immediate family who smoked or drank alcohol and a friend who smoked, drank or used illicit drugs. Apart from tobacco and alcohol, the major drugs of abuse were cannabis, codeine-containing cough syrup, nitrazepam tablets, buprenor-phine injections and heroin (usually smoked, rarely injected). The commonest sources of drugs were other drug-using friends, cross-border supplies from India or medicine shops. The commonest source of drug money was the family. There has been a clear trend towards the injection of buprenorphine by abusers who smoke heroin or drink codeine cough syrup. The reasons cited for switching to injections were the unavailability and rising cost of non-injectable drugs and the easy availability and relative cheapness of injectables. About a half of the injecting drug users (IDUs) commonly reported sharing injecting equipment inadequately cleaned with water. Over a half of IDUs reported visiting needle-exchange programmes at two of the study sites where such programmes were available. Infection by the human immunodeficiency virus (HIV) appears to be low among IDUs, although systematic surveillance is absent. Two thirds of the sample had experienced sexual intercourse. The last sex partners reported by respondents were commercial sex workers, wives or girl friends. Condom use was low with primary partners and relatively high with sex workers. Treatment facilities, mostly located in the central urban areas of the country, are meagre. An overwhelming majority of drug abusers felt the need to stop abusing drugs. Cost-effective drug treatment and HIV prevention programmes for IDUs are urgently needed in all areas of the country. PMID:9839033

  16. [Interplay between marketing authorization and early benefit assessment of drugs].

    PubMed

    Beinlich, Peggy; Müller-Berghaus, J; Sudhop, T; Vieths, S; Broich, K

    2015-03-01

    The early benefit assessment of newly approved drugs with new active substances or new applications that came into force on 1 January 2011 still presents a challenge to the parties involved. This article highlights the interplay between drug marketing approval and early benefit assessment. The constellation of a European, and even an international, largely harmonized, drug authorization process, with a mostly nationally regulated drug reimbursement situation causes inevitably friction, which could be reduced through joint advice discussions during the planning phase for pivotal studies. In 2013, the Federal Institute for Drugs and Medical Devices (BfArM) and the Paul Ehrlich Institute (PEI) provided 439 scientific advice procedures, compared with 98 advice meetings held at the Federal Joint Committee (G-BA), for 12 of which the BfArM or PEI provided written advice. The numbers of advice meetings held at the G-BA are increasing; however, the national competent authorities are involved in only a fraction of these. From the perspective of the national competent authorities, prompt and consistent involvement in the advice procedures regarding early benefit assessment would be useful and desirable. PMID:25566840

  17. Assessing transmissibility of HIV-1 drug resistance mutations from treated and from drug-naive individuals

    PubMed Central

    Winand, Raf; Theys, Kristof; Eusébio, Mónica; Aerts, Jan; Camacho, Ricardo J.; Gomes, Perpetua; Suchard, Marc A.; Vandamme, Anne-Mieke; Abecasis, Ana B.

    2015-01-01

    Objectives: Surveillance drug resistance mutations (SDRMs) in drug-naive patients are typically used to survey HIV-1-transmitted drug resistance (TDR). We test here how SDRMs in patients failing treatment, the original source of TDR, contribute to assessing TDR, transmissibility and transmission source of SDRMs. Design: This is a retrospective observational study analyzing a Portuguese cohort of HIV-1-infected patients. Methods: The prevalence of SDRMs to protease inhibitors, nucleoside reverse transcriptase inhibitors (NRTIs) and nonnucleoside reverse transcriptase inhibitors (NNRTIs) in drug-naive and treatment-failing patients was measured for 3554 HIV-1 subtype B patients. Transmission ratio (prevalence in drug-naive/prevalence in treatment-failing patients), average viral load and robust linear regression with outlier detection (prevalence in drug-naive versus in treatment-failing patients) were analyzed and used to interpret transmissibility. Results: Prevalence of SDRMs in drug-naive and treatment-failing patients were linearly correlated, but some SDRMs were classified as outliers – above (PRO: D30N, N88D/S, L90 M, RT: G190A/S/E) or below (RT: M184I/V) expectations. The normalized regression slope was 0.073 for protease inhibitors, 0.084 for NRTIs and 0.116 for NNRTIs. Differences between SDRMs transmission ratios were not associated with differences in viral loads. Conclusion: The significant linear correlation between prevalence of SDRMs in drug-naive and in treatment-failing patients indicates that the prevalence in treatment-failing patients can be useful to predict levels of TDR. The slope is a cohort-dependent estimate of rate of TDR per drug class and outlier detection reveals comparative persistence of SDRMs. Outlier SDRMs with higher transmissibility are more persistent and more likely to have been acquired from drug-naive patients. Those with lower transmissibility have faster reversion dynamics after transmission and are associated with acquisition from treatment-failing patients. PMID:26355575

  18. Physicochemical assessment of dextran-g-poly (?-caprolactone) micellar nanoaggregates as drug nanocarriers.

    PubMed

    Saldas, Csar; Velsquez, Luis; Quezada, Caterina; Leiva, Angel

    2015-03-01

    Self-assembling polymers in aqueous solution have attracted significant attention with recent research efforts focused on the development of new strategies to design devices useful in the field of controlled drug delivery. In this context, amphiphilic copolymers having specific structural features and self-assembling behaviors in aqueous media that would enable controlled drug release over longer time periods. In this work, we report on the synthesis and characterization of a Poly (?-caprolactone)-grafted Dextran copolymer and its use in the preparation of micellar nanoaggregates. The characterization and study of the morphology, topography, size distribution and stability of micellar nanoaggregates by Transmission Electron Microscopy (TEM), Atomic Force Microscopy (AFM), Dynamic Light Scattering (DLS) and Zeta Potential (?), respectively, were carried out. Spherical-shaped morphologies and an average size of approximately 83 nm, for drug-free nanoaggregates, were observed. In addition, Zeta Potential studies showed that drug-free nanoaggregates are more stable than drug-loaded structures measured in a phosphate buffer (pH 7.2) medium. UV-vis spectrophotometry of both the drug entrapment efficiency (EE%) and in vitro drug release behavior were assessed. The EE% was determined to be 78% (w/w), and a combination of diffusion and eroding polymer matrix mechanisms for drug release were established. Finally, these results indicate that Dx-g-PCL micellar nanoaggregates are suitable for use as a potential nanocarrier having both biodegradable and biocompatible properties. PMID:25498659

  19. Understanding pharmacokinetics using realistic computational models of fluid dynamics: biosimulation of drug distribution within the CSF space for intrathecal drugs.

    PubMed

    Kuttler, Andreas; Dimke, Thomas; Kern, Steven; Helmlinger, Gabriel; Stanski, Donald; Finelli, Luca A

    2010-12-01

    We introduce how biophysical modeling in pharmaceutical research and development, combining physiological observations at the tissue, organ and system level with selected drug physiochemical properties, may contribute to a greater and non-intuitive understanding of drug pharmacokinetics and therapeutic design. Based on rich first-principle knowledge combined with experimental data at both conception and calibration stages, and leveraging our insights on disease processes and drug pharmacology, biophysical modeling may provide a novel and unique opportunity to interactively characterize detailed drug transport, distribution, and subsequent therapeutic effects. This innovative approach is exemplified through a three-dimensional (3D) computational fluid dynamics model of the spinal canal motivated by questions arising during pharmaceutical development of one molecular therapy for spinal cord injury. The model was based on actual geometry reconstructed from magnetic resonance imaging data subsequently transformed in a parametric 3D geometry and a corresponding finite-volume representation. With dynamics controlled by transient Navier-Stokes equations, the model was implemented in a commercial multi-physics software environment established in the automotive and aerospace industries. While predictions were performed in silico, the underlying biophysical models relied on multiple sources of experimental data and knowledge from scientific literature. The results have provided insights into the primary factors that can influence the intrathecal distribution of drug after lumbar administration. This example illustrates how the approach connects the causal chain underlying drug distribution, starting with the technical aspect of drug delivery systems, through physiology-driven drug transport, then eventually linking to tissue penetration, binding, residence, and ultimately clearance. Currently supporting our drug development projects with an improved understanding of systems physiology, biophysical models are being increasingly used to characterize drug transport and distribution in human tissues where pharmacokinetic measurements are difficult or impossible to perform. Importantly, biophysical models can describe emergent properties of a system, i.e. properties not identifiable through the study of the system's components taken in isolation. PMID:21132572

  20. Distributed Drug Discovery: Advancing Chemical Education through Contextualized Combinatorial Solid-Phase Organic Laboratories

    ERIC Educational Resources Information Center

    Scott, William L.; Denton, Ryan E.; Marrs, Kathleen A.; Durrant, Jacob D.; Samaritoni, J. Geno; Abraham, Milata M.; Brown, Stephen P.; Carnahan, Jon M.; Fischer, Lindsey G.; Glos, Courtney E.; Sempsrott, Peter J.; O'Donnell, Martin J.

    2015-01-01

    The Distributed Drug Discovery (D3) program trains students in three drug discovery disciplines (synthesis, computational analysis, and biological screening) while addressing the important challenge of discovering drug leads for neglected diseases. This article focuses on implementation of the synthesis component in the second-semester…

  1. Distributed Drug Discovery: Advancing Chemical Education through Contextualized Combinatorial Solid-Phase Organic Laboratories

    ERIC Educational Resources Information Center

    Scott, William L.; Denton, Ryan E.; Marrs, Kathleen A.; Durrant, Jacob D.; Samaritoni, J. Geno; Abraham, Milata M.; Brown, Stephen P.; Carnahan, Jon M.; Fischer, Lindsey G.; Glos, Courtney E.; Sempsrott, Peter J.; O'Donnell, Martin J.

    2015-01-01

    The Distributed Drug Discovery (D3) program trains students in three drug discovery disciplines (synthesis, computational analysis, and biological screening) while addressing the important challenge of discovering drug leads for neglected diseases. This article focuses on implementation of the synthesis component in the second-semester

  2. Postmortem distribution of the novel antipsychotic drug quetiapine.

    PubMed

    Hopenwasser, Jay; Mozayani, Ashraf; Danielson, Terry J; Harbin, Jeremy; Narula, Harminder S; Posey, Douglas H; Shrode, Paul W; Wilson, Stephen K; Li, Richard; Sanchez, Luis A

    2004-01-01

    The objective of this research was to determine the concentrations and distribution of the atypical antipsychotic drug, quetiapine, in postmortem tissues from eight Medical Examiner cases. Quetiapine was isolated from liquid specimens and tissue homogenates by extraction at an alkaline pH into 1-chlorobutane. The 1-chlorobutane was decanted, and quetiapine, plus the internal standard (prochlorperazine), was back-extracted into 0.1N sulfuric acid. The acid layer was made basic, and quetiapine, plus the internal standard, was re-extracted into 1-chlorobutane. Quantitation was by gradient, high-pressure liquid chromatography on a C-8 ODS (2.1 x 150 mm, 5 mu) column with acetonitrile/0.1M ammonium hydroxide (pH 10) mobile phase and a photodiode array detector set at 258 nm. The apparent linear range of the assay was from 0.05 to 5.0 microg/mL. At known concentrations of 0.1 and 0.5, interday accuracy (n = 5) was 103.8 and 107.2%, respectively. Interday precision (% cv) at the same concentrations was 9.8 and 9.0, respectively. In the cases where quetiapine was not considered to have contributed to the death, the postmortem concentrations in blood, liver, and bile ranged between 0.15 and 2.7 mg/L (n = 6), 1.3 and 9.5 mg/kg (n = 8), and 10 and 46 mg/L (n = 5), respectively. In the one case involving a quetiapine overdose, concentrations in blood (19.8 mg/L), liver (12.6 mg/kg), and bile (161 mg/L) exceeded the ranges of concentrations determined in specimens from the quetiapine-unrelated deaths. PMID:15189678

  3. Assessing dose rate distributions in VMAT plans.

    PubMed

    Mackeprang, P-H; Volken, W; Terribilini, D; Frauchiger, D; Zaugg, K; Aebersold, D M; Fix, M K; Manser, P

    2016-04-21

    Dose rate is an essential factor in radiobiology. As modern radiotherapy delivery techniques such as volumetric modulated arc therapy (VMAT) introduce dynamic modulation of the dose rate, it is important to assess the changes in dose rate. Both the rate of monitor units per minute (MU rate) and collimation are varied over the course of a fraction, leading to different dose rates in every voxel of the calculation volume at any point in time during dose delivery. Given the radiotherapy plan and machine specific limitations, a VMAT treatment plan can be split into arc sectors between Digital Imaging and Communications in Medicine control points (CPs) of constant and known MU rate. By calculating dose distributions in each of these arc sectors independently and multiplying them with the MU rate, the dose rate in every single voxel at every time point during the fraction can be calculated. Independently calculated and then summed dose distributions per arc sector were compared to the whole arc dose calculation for validation. Dose measurements and video analysis were performed to validate the calculated datasets. A clinical head and neck, cranial and liver case were analyzed using the tool developed. Measurement validation of synthetic test cases showed linac agreement to precalculated arc sector times within  ±0.4 s and doses  ±0.1 MU (one standard deviation). Two methods for the visualization of dose rate datasets were developed: the first method plots a two-dimensional (2D) histogram of the number of voxels receiving a given dose rate over the course of the arc treatment delivery. In similarity to treatment planning system display of dose, the second method displays the dose rate as color wash on top of the corresponding computed tomography image, allowing the user to scroll through the variation over time. Examining clinical cases showed dose rates spread over a continuous spectrum, with mean dose rates hardly exceeding 100 cGy min(-1) for conventional fractionation. A tool to analyze dose rate distributions in VMAT plans with sub-second accuracy was successfully developed and validated. Dose rates encountered in clinical VMAT test cases show a continuous spectrum with a mean less than or near 100 cGy min(-1) for conventional fractionation. PMID:27025897

  4. Assessing dose rate distributions in VMAT plans

    NASA Astrophysics Data System (ADS)

    Mackeprang, P.-H.; Volken, W.; Terribilini, D.; Frauchiger, D.; Zaugg, K.; Aebersold, D. M.; Fix, M. K.; Manser, P.

    2016-04-01

    Dose rate is an essential factor in radiobiology. As modern radiotherapy delivery techniques such as volumetric modulated arc therapy (VMAT) introduce dynamic modulation of the dose rate, it is important to assess the changes in dose rate. Both the rate of monitor units per minute (MU rate) and collimation are varied over the course of a fraction, leading to different dose rates in every voxel of the calculation volume at any point in time during dose delivery. Given the radiotherapy plan and machine specific limitations, a VMAT treatment plan can be split into arc sectors between Digital Imaging and Communications in Medicine control points (CPs) of constant and known MU rate. By calculating dose distributions in each of these arc sectors independently and multiplying them with the MU rate, the dose rate in every single voxel at every time point during the fraction can be calculated. Independently calculated and then summed dose distributions per arc sector were compared to the whole arc dose calculation for validation. Dose measurements and video analysis were performed to validate the calculated datasets. A clinical head and neck, cranial and liver case were analyzed using the tool developed. Measurement validation of synthetic test cases showed linac agreement to precalculated arc sector times within  ±0.4 s and doses  ±0.1 MU (one standard deviation). Two methods for the visualization of dose rate datasets were developed: the first method plots a two-dimensional (2D) histogram of the number of voxels receiving a given dose rate over the course of the arc treatment delivery. In similarity to treatment planning system display of dose, the second method displays the dose rate as color wash on top of the corresponding computed tomography image, allowing the user to scroll through the variation over time. Examining clinical cases showed dose rates spread over a continuous spectrum, with mean dose rates hardly exceeding 100 cGy min-1 for conventional fractionation. A tool to analyze dose rate distributions in VMAT plans with sub-second accuracy was successfully developed and validated. Dose rates encountered in clinical VMAT test cases show a continuous spectrum with a mean less than or near 100 cGy min-1 for conventional fractionation.

  5. Technology assessment and the Food and Drug Administration

    NASA Technical Reports Server (NTRS)

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

    1972-01-01

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

  6. Legal and Illegal Patterns of Drug Distribution in the United States

    ERIC Educational Resources Information Center

    Caliguri, Joseph P.

    1976-01-01

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

  7. Assessment of potential drug-drug interactions and its associated factors in the hospitalized cardiac patients.

    PubMed

    Murtaza, Ghulam; Khan, Muhammad Yasir Ghani; Azhar, Saira; Khan, Shujaat Ali; Khan, Tahir M

    2016-03-01

    Drug-drug interactions (DDIs) may result in the alteration of therapeutic response. Sometimes they may increase the untoward effects of many drugs. Hospitalized cardiac patients need more attention regarding drug-drug interactions due to complexity of their disease and therapeutic regimen. This research was performed to find out types, prevalence and association between various predictors of potential drug-drug interactions (pDDIs) in the Department of Cardiology and to report common interactions. This study was performed in the hospitalized cardiac patients at Ayub Teaching Hospital, Abbottabad, Pakistan. Patient charts of 2342 patients were assessed for pDDIs using Micromedex® Drug Information. Logistic regression was applied to find predictors of pDDIs. The main outcome measure in the study was the association of the potential drug-drug interactions with various factors such as age, gender, polypharmacy, and hospital stay of the patients. We identified 53 interacting-combinations that were present in total 5109 pDDIs with median number of 02 pDDIs per patient. Overall, 91.6% patients had at least one pDDI; 86.3% were having at least one major pDDI, and 84.5% patients had at least one moderate pDDI. Among 5109 identified pDDIs, most were of moderate (55%) or major severity (45%); established (24.2%), theoretical (18.8%) or probable (57%) type of scientific evidence. Top 10 common pDDIs included 3 major and 7 moderate interactions. Results obtained by multivariate logistic regression revealed a significant association of the occurrence of pDDIs in patient with age of 60 years or more (p < 0.001), hospital stay of 7 days or longer (p < 0.001) and taking 7 or more drugs (p < 0.001). We found a high prevalence for pDDIs in the Department of Cardiology, most of which were of moderate severity. Older patients, patients with longer hospital stay and with elevated number of prescribed drugs were at higher risk of pDDIs. PMID:27013915

  8. Herb–drug interactions: Review and assessment of report reliability

    PubMed Central

    Fugh-Berman, Adriane; Ernst, E

    2001-01-01

    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. PMID:11736868

  9. Assessing cardiovascular drug safety for clinical decision-making.

    PubMed

    Woosley, Raymond L; Romero, Klaus

    2013-06-01

    Optimal therapeutic decision-making requires integration of patient-specific and therapy-specific information at the point of care, particularly when treating patients with complex cardiovascular conditions. The formidable task for the prescriber is to synthesize information about all therapeutic options and match the best treatment with the characteristics of the individual patient. Computerized decision support systems have been developed with the goal of integrating such information and presenting the acceptable therapeutic options on the basis of their effectiveness, often with limited consideration of their safety for a specific patient. Assessing the safety of therapies relative to each patient is difficult, and sometimes impossible, because the evidence required to make such an assessment is either imperfect or does not exist. In addition, many of the alerts sent to prescribers by decision-support systems are not perceived as credible, and 'alert fatigue' causes warnings to be ignored putting patients at risk of harm. The CredibleMeds.org and BrugadaDrugs.org websites are prototypes for evidence-based sources of safety information that rank drugs for their risk of a specific form of drug toxicity-in these cases, drug-induced arrhythmias. Broad incorporation of this type of information in electronic prescribing algorithms and clinical decision support could speed the evolution of safe personalized medicine. PMID:23591268

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

    SciTech Connect

    Ho, Clifford Kuofei

    2004-06-01

    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.

  11. Controlling the production and distribution of drugs in communist Poland.

    PubMed

    Łotysz, Sławomir

    2014-01-01

    Between 1944 and 1989--the period of communist power in Poland--the national pharmaceutical market experienced several dramatic changes. The country was a prodigious importer of drugs following the Second World War, with a large portion of the medicine received being donated by various aid organisations. In the 1960s, Poland became a significant exporter of drugs to the Eastern Bloc countries, but dropped down the list of meaningful producers again after the post-1989 transformation. For four and a half decades the pharmaceutical market in Poland had been a scene of political and ideological struggle. The companies, owned and controlled by the state, were poorly managed, being neither innovative nor competitive. This fact, along with the state's irrational and inconsequent drug policy, caused an almost permanent shortage in drug supplies for patients: ironic for a socialist system in which universal and free health care was a basic principle. PMID:26054214

  12. Serotype distribution and drug resistance in Streptococcus pneumoniae, Palestinian Territories.

    PubMed

    Kattan, Randa; Abu Rayyan, Amal; Zheiman, Inas; Idkeidek, Suzan; Baraghithi, Sabri; Rishmawi, Nabeel; Turkuman, Sultan; Abu-Diab, Afaf; Ghneim, Riyad; Zoughbi, Madeleine; Dauodi, Rula; Ghneim, Raed; Issa, Abed-El-Razeq; Siryani, Issa; Al Qas, Randa; Liddawi, Rawan; Khamash, Hatem; Kanaan, Moein; Marzouqa, Hiyam; Hindiyeh, Musa Y

    2011-01-01

    To determine antimicrobial drug resistance of Streptococcus pneumoniae serotypes, we analyzed isolates from blood cultures of sick children residing in the West Bank before initiation of pneumococcal vaccination. Of 120 serotypes isolated, 50.8%, 73.3%, and 80.8% of the bacteremia cases could have been prevented by pneumococcal conjugate vaccines. Serotype 14 was the most drug-resistant serotype isolated. PMID:21192863

  13. Risk assessment principle for engineered nanotechnology in food and drug.

    PubMed

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

    2012-06-01

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

  14. Examining the spatial distribution of law enforcement encounters among people who inject drugs after implementation of Mexico's drug policy reform.

    PubMed

    Gaines, Tommi L; Beletsky, Leo; Arredondo, Jaime; Werb, Daniel; Rangel, Gudelia; Vera, Alicia; Brouwer, Kimberly

    2015-04-01

    In 2009, Mexico decriminalized the possession of small amounts of illicit drugs for personal use in order to refocus law enforcement resources on drug dealers and traffickers. This study examines the spatial distribution of law enforcement encounters reported by people who inject drugs (PWID) in Tijuana, Mexico to identify concentrated areas of policing activity after implementation of the new drug policy. Mapping the physical location of law enforcement encounters provided by PWID (n = 461) recruited through targeted sampling, we identified hotspots of extra-judicial encounters (e.g., physical/sexual abuse, syringe confiscation, and money extortion by law enforcement) and routine authorized encounters (e.g., being arrested or stopped but not arrested) using point density maps and the Getis-Ord Gi* statistic calculated at the neighborhood-level. Approximately half of the participants encountered law enforcement more than once in a calendar year and nearly one third of these encounters did not result in arrest but involved harassment or abuse by law enforcement. Statistically significant hotspots of law enforcement encounters were identified in a limited number of neighborhoods located in areas with known drug markets. At the local-level, law enforcement activities continue to target drug users despite a national drug policy that emphasizes drug treatment diversion rather than punitive enforcement. There is a need for law enforcement training and improved monitoring of policing tactics to better align policing with public health goals. PMID:25300503

  15. Numerical simulation on the effects of drug eluting stents at different Reynolds numbers on hemodynamic and drug concentration distribution

    PubMed Central

    2015-01-01

    Background The changes of hemodynamics and drug concentration distribution caused by the implantation of drug eluting stents (DESs) in curved vessels have significant effects on In-Stent Restenosis. Methods A 3D virtual stent with 90°curvature was modelled and the distribution of wall shear stress (WSS) and drug concentration in this model were numerically studied at Reynolds numbers of 200, 400, 600, 800. Results The results showed that (1) the intensity of secondary flow at the 45° cross-section was stronger than that at the 90° cross-section; (2) As the Reynolds number increases, the WSS decreases. When the Reynolds number reaches 600, the low-WSS region only accounts for 3% of the total area. (3) The effects of Reynolds number on drug concentration in the vascular wall decreases in proportionally and then the blood velocity increased 4 times, the drug concentration in the vascular wall decreased by about 30%. (4) The size of the high drug concentration region is inversely proportional to the Reynolds number. As the blood velocity increases, the drug concentration in the DES decreases, especially at the outer bend. Conclusions It is beneficial for the patient to decrease vigorous activities and keep calm at the beginning of the stent implantation, because a substantial amount of the drug is released in the first two months of stent implantation, thus a calm status is conducive to drug release and absorption; Subsequently, appropriate exercise which increases the blood velocity is helpful in decreasing regions of low-WSS. PMID:25602685

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

    PubMed

    Zolnik, Banu S; Sadrieh, Nakissa

    2009-06-21

    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 Food and Drug Administration (FDA) for approval in the future, FDA formed a Nanotechnology Task Force in 2006 to determine the critical regulatory issues regarding nanomaterials. As a result, all centers within the FDA are considering the development of guidance documents to address nanomaterial specific issues. It is well established in the literature that physico-chemical characterization (PCC) studies are crucial for nanomaterial containing drug products. However, this paper addresses the equally important topic of Absorption, Distribution, Metabolism and Excretion (ADME) studies for nanomaterials and provides examples of how physical properties affect biodistribution (i.e. the state of agglomeration, or aggregation, surface characteristics, stability of PEG). This paper also attempts to highlight some of the ADME study design issues related to nanomaterials such as the need for conducting biodistribution studies on each moiety of the multifunctional nanoparticles, dual labeled pharmacokinetic (PK) studies, and comparative PK studies on the free versus encapsulated drugs. In addition, this paper underlines the importance of long-term biodistribution and mass balance studies to understand the nanoparticle accumulation profile which may help to assess the safety and efficacy of the nanomaterial containing drug products. This review also lists some of the pre-clinical guidance documents that may help sponsors get started in developing data for inclusion in an initial investigational new drug application package for nanoscale material containing drug products. PMID:19389437

  17. Cytotoxicity assessment of porous silicon microparticles for ocular drug delivery.

    PubMed

    Korhonen, Eveliina; Rönkkö, Seppo; Hillebrand, Satu; Riikonen, Joakim; Xu, Wujun; Järvinen, Kristiina; Lehto, Vesa-Pekka; Kauppinen, Anu

    2016-03-01

    Porous silicon (PSi) is a promising material for the delivery and sustained release of therapeutic molecules in various tissues. Due to the constant rinsing of cornea by tear solution as well as the short half-life of intravitreal drugs, the eye is an attractive target for controlled drug delivery systems, such as PSi microparticles. Inherent barriers ensure that PSi particles are retained in the eye, releasing drugs at the desired speed until they slowly break down into harmless silicic acid. Here, we have examined the in vitro cytotoxicity of positively and negatively charged thermally oxidized (TOPSi) and thermally carbonized (TCPSi) porous silicon microparticles on human corneal epithelial (HCE) and retinal pigment epithelial (ARPE-19) cells. In addition to ocular assessment under an inverted microscope, cellular viability was evaluated using the CellTiter Blue™, CellTiter Fluor™, and lactate dehydrogenase (LDH) assays. CellTiter Fluor proved to be a suitable assay but due to non-specific and interfering responses, neither CellTiter Blue nor LDH assays should be used when evaluating PSi particles. Our results suggest that the toxicity of PSi particles is concentration-dependent, but at least at concentrations less than 200μg/ml, both positively and negatively charged PSi particles are well tolerated by human corneal and retinal epithelial cells and therefore applicable for delivering drug molecules into ocular tissues. PMID:26686646

  18. Effect of automated drug distribution systems on medication error rates in a short-stay geriatric unit

    PubMed Central

    Cousein, Etienne; Mareville, Julie; Lerooy, Alexandre; Caillau, Antoine; Labreuche, Julien; Dambre, Delphine; Odou, Pascal; Bonte, Jean-Paul; Puisieux, François; Decaudin, Bertrand; Coupé, Patrick

    2014-01-01

    Rationale, aims and objectives To assess the impact of an automated drug distribution system on medication errors (MEs). Methods Before-after observational study in a 40-bed short stay geriatric unit within a 1800 bed general hospital in Valenciennes, France. Researchers attended nurse medication administration rounds and compared administered to prescribed drugs, before and after the drug distribution system changed from a ward stock system (WSS) to a unit dose dispensing system (UDDS), integrating a unit dose dispensing robot and automated medication dispensing cabinet (AMDC). Results A total of 615 opportunities of errors (OEs) were observed among 148 patients treated during the WSS period, and 783 OEs were observed among 166 patients treated during the UDDS period. ME [medication administration error (MAE)] rates were calculated and compared between the two periods. Secondary measures included type of errors, seriousness of errors and risk reduction for the patients. The implementation of an automated drug dispensing system resulted in a 53% reduction in MAEs. All error types were reduced in the UDDS period compared with the WSS period (P < 0.001). Wrong dose and wrong drug errors were reduced by 79.1% (2.4% versus 0.5%, P = 0.005) and 93.7% (1.9% versus 0.01%, P = 0.009), respectively. Conclusion An automated UDDS combining a unit dose dispensing robot and AMDCs could reduce discrepancies between ordered and administered drugs, thus improving medication safety among the elderly. PMID:24917185

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

    PubMed

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

    2013-05-01

    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

  20. Drug assessment by a Pharmacy and Therapeutics committee: from drug selection criteria to use in clinical practice

    PubMed Central

    Lozano-Blázquez, Ana; Calvo-Pita, Cecilia; Carbajales-Álvarez, Mónica; Suárez-Gil, Patricio; Martínez-Martínez, Fernando; Calleja-Hernández, Miguel Ángel

    2014-01-01

    Background In Spain, hospital medicines are assessed and selected by local Pharmacy and Therapeutics committees (PTCs). Of all the drugs assessed, cancer drugs are particularly important because of their budgetary impact and the sometimes arguable added value with respect to existing alternatives. This study analyzed the PTC drug selection process and the main objective was to evaluate the degree of compliance of prescriptions for oncology drugs with their criteria for use. Methods This was a retrospective observational study (May 2007 to April 2010) of PTC-assessed drugs. The variables measured to describe the committee’s activity were number of drugs assessed per year and number of drugs included in any of these settings: without restrictions, with criteria for use, and not included in formulary. These drugs were also analyzed by therapeutic group. To assess the degree of compliance of prescriptions, a score was calculated to determine whether prescriptions for bevacizumab, cetuximab, trastuzumab, and bortezomib were issued in accordance with PTC drug use criteria. Results The PTC received requests for inclusion of 40 drugs, of which 32 were included in the hospital formulary (80.0%). Criteria for use were established for 28 (87.5%) of the drugs included. In total, 293 patients were treated with the four cancer drugs in eight different therapeutic indications. The average prescription compliance scores were as follows: bevacizumab, 83% for metastatic colorectal cancer, 100% for metastatic breast cancer, and 82.3% for non-small-cell lung cancer; cetuximab, 62.0% for colorectal cancer and 50% for head and neck cancer; trastuzumab, 95.1% for early breast cancer and 82.4% for metastatic breast cancer; and bortezomib, 63.7% for multiple myeloma. Conclusion The degree of compliance with criteria for use of cancer drugs was reasonably high. PTC functions need to be changed so that they can carry out more innovative tasks, such as monitoring conditions for drug use. PMID:25031538

  1. The Development of a Test to Assess Drug Using Behavior.

    ERIC Educational Resources Information Center

    Althoff, Michael E.

    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,…

  2. 43 CFR 43.210 - To whom must I distribute my drug-free workplace statement?

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... workplace statement? 43.210 Section 43.210 Public Lands: Interior Office of the Secretary of the Interior GOVERNMENTWIDE REQUIREMENTS FOR DRUG-FREE WORKPLACE (FINANCIAL ASSISTANCE) Requirements for Recipients Other Than Individuals § 43.210 To whom must I distribute my drug-free workplace statement? You must require that a...

  3. 40 CFR 36.210 - To whom must I distribute my drug-free workplace statement?

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... workplace statement? 36.210 Section 36.210 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY GRANTS AND OTHER FEDERAL ASSISTANCE GOVERNMENTWIDE REQUIREMENTS FOR DRUG-FREE WORKPLACE (FINANCIAL ASSISTANCE) Requirements for Recipients Other Than Individuals § 36.210 To whom must I distribute my drug-free...

  4. 15 CFR 29.210 - To whom must I distribute my drug-free workplace statement?

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... workplace statement? 29.210 Section 29.210 Commerce and Foreign Trade Office of the Secretary of Commerce GOVERNMENTWIDE REQUIREMENTS FOR DRUG-FREE WORKPLACE (FINANCIAL ASSISTANCE) Requirements for Recipients Other Than Individuals § 29.210 To whom must I distribute my drug-free workplace statement? You must require that a...

  5. 24 CFR 21.210 - To whom must I distribute my drug-free workplace statement?

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ...-free workplace statement? 21.210 Section 21.210 Housing and Urban Development Office of the Secretary, Department of Housing and Urban Development GOVERNMENTWIDE REQUIREMENTS FOR DRUG-FREE WORKPLACE (GRANTS) Requirements for Recipients Other Than Individuals § 21.210 To whom must I distribute my drug-free...

  6. 22 CFR 210.210 - To whom must I distribute my drug-free workplace statement?

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... workplace statement? 210.210 Section 210.210 Foreign Relations AGENCY FOR INTERNATIONAL DEVELOPMENT GOVERNMENTWIDE REQUIREMENTS FOR DRUG-FREE WORKPLACE (FINANCIAL ASSISTANCE) Requirements for Recipients Other Than Individuals § 210.210 To whom must I distribute my drug-free workplace statement? You must require that a...

  7. 32 CFR 26.210 - To whom must I distribute my drug-free workplace statement?

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 32 National Defense 1 2010-07-01 2010-07-01 false To whom must I distribute my drug-free workplace... DoD GRANT AND AGREEMENT REGULATIONS GOVERNMENTWIDE REQUIREMENTS FOR DRUG-FREE WORKPLACE (FINANCIAL...-free workplace statement? You must require that a copy of the statement described in § 26.205 be...

  8. 22 CFR 133.210 - To whom must I distribute my drug-free workplace statement?

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... workplace statement? 133.210 Section 133.210 Foreign Relations DEPARTMENT OF STATE MISCELLANEOUS GOVERNMENTWIDE REQUIREMENTS FOR DRUG-FREE WORKPLACE (FINANCIAL ASSISTANCE) Requirements for Recipients Other Than Individuals § 133.210 To whom must I distribute my drug-free workplace statement? You must require that a...

  9. 10 CFR 607.210 - To whom must I distribute my drug-free workplace statement?

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 10 Energy 4 2010-01-01 2010-01-01 false To whom must I distribute my drug-free workplace statement? 607.210 Section 607.210 Energy DEPARTMENT OF ENERGY (CONTINUED) ASSISTANCE REGULATIONS GOVERNMENTWIDE REQUIREMENTS FOR DRUG-FREE WORKPLACE (FINANCIAL ASSISTANCE) Requirements for Recipients Other Than...

  10. 31 CFR 20.210 - To whom must I distribute my drug-free workplace statement?

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 31 Money and Finance: Treasury 1 2013-07-01 2013-07-01 false To whom must I distribute my drug-free workplace statement? 20.210 Section 20.210 Money and Finance: Treasury Office of the Secretary of the Treasury GOVERNMENTWIDE REQUIREMENTS FOR DRUG-FREE WORKPLACE (FINANCIAL ASSISTANCE)...

  11. 31 CFR 20.210 - To whom must I distribute my drug-free workplace statement?

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 31 Money and Finance: Treasury 1 2011-07-01 2011-07-01 false To whom must I distribute my drug-free workplace statement? 20.210 Section 20.210 Money and Finance: Treasury Office of the Secretary of the Treasury GOVERNMENTWIDE REQUIREMENTS FOR DRUG-FREE WORKPLACE (FINANCIAL ASSISTANCE)...

  12. 31 CFR 20.210 - To whom must I distribute my drug-free workplace statement?

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 31 Money and Finance: Treasury 1 2014-07-01 2014-07-01 false To whom must I distribute my drug-free workplace statement? 20.210 Section 20.210 Money and Finance: Treasury Office of the Secretary of the Treasury GOVERNMENTWIDE REQUIREMENTS FOR DRUG-FREE WORKPLACE (FINANCIAL ASSISTANCE)...

  13. 31 CFR 20.210 - To whom must I distribute my drug-free workplace statement?

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 31 Money and Finance: Treasury 1 2010-07-01 2010-07-01 false To whom must I distribute my drug-free workplace statement? 20.210 Section 20.210 Money and Finance: Treasury Office of the Secretary of the Treasury GOVERNMENTWIDE REQUIREMENTS FOR DRUG-FREE WORKPLACE (FINANCIAL ASSISTANCE)...

  14. 31 CFR 20.210 - To whom must I distribute my drug-free workplace statement?

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 31 Money and Finance: Treasury 1 2012-07-01 2012-07-01 false To whom must I distribute my drug-free workplace statement? 20.210 Section 20.210 Money and Finance: Treasury Office of the Secretary of the Treasury GOVERNMENTWIDE REQUIREMENTS FOR DRUG-FREE WORKPLACE (FINANCIAL ASSISTANCE)...

  15. Treating Women Drug Abusers: Action Therapy and Trauma Assessment

    PubMed Central

    Uhler, Ann S.; Parker, Olga V.

    2002-01-01

    The authors suggest that action therapy, a group of techniques including psychodrama, drama therapy, and role training, warrants research attention to determine whether it is well suited to the special characteristics and needs of women clients. In addition, the authors call on researchers to develop a new standardized tool for counselors to use during initial interviews to determine whether women presenting for drug abuse treatment also have significant issues related to trauma. The authors believe the use of unassisted clinical judgment for trauma assessment in first interviews may drive patients away by probing for painful information that clients are not yet ready to confront or divulge. PMID:18567963

  16. Treating women drug abusers: action therapy and trauma assessment.

    PubMed

    Uhler, Ann S; Parker, Olga V

    2002-07-01

    The authors suggest that action therapy, a group of techniques including psychodrama, drama therapy, and role training, warrants research attention to determine whether it is well suited to the special characteristics and needs of women clients. In addition, the authors call on researchers to develop a new standardized tool for counselors to use during initial interviews to determine whether women presenting for drug abuse treatment also have significant issues related to trauma. The authors believe the use of unassisted clinical judgment for trauma assessment in first interviews may drive patients away by probing for painful information that clients are not yet ready to confront or divulge. PMID:18567963

  17. Investigation on fabrication process of dissolving microneedle arrays to improve effective needle drug distribution.

    PubMed

    Wang, Qingqing; Yao, Gangtao; Dong, Pin; Gong, Zihua; Li, Ge; Zhang, Kejian; Wu, Chuanbin

    2014-10-23

    The dissolving microneedle array (DMNA) offers a novel potential approach for transdermal delivery of biological macromolecular drugs and vaccines, because it can be as efficient as hypodermic injection and as safe and patient compliant as conventional transdermal delivery. However, effective needle drug distribution is the main challenge for clinical application of DMNA. This study focused on the mechanism and control of drug diffusion inside DMNA during the fabrication process in order to improve the drug delivery efficiency. The needle drug loading proportion (NDP) in DMNAs was measured to determine the influences of drug concentration gradient, needle drying step, excipients, and solvent of the base solution on drug diffusion and distribution. The results showed that the evaporation of base solvent was the key factor determining NDP. Slow evaporation of water from the base led to gradual increase of viscosity, and an approximate drug concentration equilibrium was built between the needle and base portions, resulting in NDP as low as about 6%. When highly volatile ethanol was used as the base solvent, the viscosity in the base rose quickly, resulting in NDP more than 90%. Ethanol as base solvent did not impact the insertion capability of DMNAs, but greatly increased the in vitro drug release and transdermal delivery from DMNAs. Furthermore, the drug diffusion process during DMNA fabrication was thoroughly investigated for the first time, and the outcomes can be applied to most two-step molding processes and optimization of the DMNA fabrication. PMID:25446513

  18. Developability assessment of clinical drug products with maximum absorbable doses.

    PubMed

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

    2012-05-10

    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

  19. 77 FR 44177 - Antimicrobial Animal Drug Sales and Distribution Reporting

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-07-27

    ... antibiotic resistance concluded that sales and distribution information as currently collected by FDA does... spread of antimicrobial resistance in connection with the use of medically important antibiotics in food... this document publishes in the Federal Register.) 1. U.S. General Accounting Office,...

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

    PubMed Central

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

    2014-01-01

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

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

    PubMed

    Funk, Ryan S; Krise, Jeffrey P

    2012-05-01

    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 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-β-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

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

    PubMed Central

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

    2014-01-01

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

  3. Oncology drug health technology assessment recommendations: Canadian versus UK experiences

    PubMed Central

    Chabot, Isabelle; Rocchi, Angela

    2014-01-01

    Background Canada has two health technology assessment (HTA) agencies responsible for oncology drug funding recommendations: the Institut National d’Excellence en Santé et Services Sociaux (INESSS) for the province of Québec and the pan-Canadian Oncology Drug Review for the rest of Canada. The objective of the research was to review and compare the recommendations of these two agencies alongside an international comparator – the National Institute for Health and Care Excellence (NICE) in the United Kingdom – with respect to their recommendations records and the influence of clinical and cost-effectiveness evidence on the recommendations. Methods Recommendations were identified from the three agencies from January 1, 2002 to June 1, 2013. Recommendations were limited to five cancer sites (lung, breast, colon, kidney, blood) and to metastatic/advanced settings. Descriptive analyses examined the frequency of positive recommendations and factors related to a positive recommendation. For each recommendation, only publicly available information posted on the agency website was used to abstract data. Results There was a wide variation in the rate of positive recommendations, ranging from 48% for NICE to 95% for Canada’s national process (among the 74% of its recommendations that were publicly posted). Interagency agreement was low, with full agreement for only six of the 14 drugs commonly reviewed by all three agencies. Evidence of a survival gain was not necessary for a positive recommendation; progression-free survival was acceptable. Different approaches were taken when addressing unacceptable cost-effectiveness. NICE was most likely to yield a negative recommendation on these grounds, whereas Canada’s national process was most likely to yield a positive recommendation with a required pricing arrangement. Conclusion In this analysis, the primary reason for the observed divergence between agency recommendations appeared to be the availability of mechanisms in each jurisdiction to address cost-effectiveness subsequent to the HTA assessment process. Furthermore, caution is needed when interpreting cross-agency comparisons between HTA agencies, as recommendations may not correspond directly to subsequent funding decisions and actual patient access. This may be a concern, given the high international profile of assessments conducted by the reviewed HTA agencies. PMID:25075196

  4. Effect of heterogeneous microvasculature distribution on drug delivery to solid tumour

    NASA Astrophysics Data System (ADS)

    Zhan, Wenbo; Gedroyc, Wladyslaw; Xu, Xiao Yun

    2014-11-01

    Most of the computational models of drug transport in vascular tumours assume a uniform distribution of blood vessels through which anti-cancer drugs are delivered. However, it is well known that solid tumours are characterized by dilated microvasculature with non-uniform diameters and irregular branching patterns. In this study, the effect of heterogeneous vasculature on drug transport and uptake is investigated by means of mathematical modelling of the key physical and biochemical processes in drug delivery. An anatomically realistic tumour model accounting for heterogeneous distribution of blood vessels is reconstructed based on magnetic resonance images of a liver tumour. Numerical simulations are performed for different drug delivery modes, including direct continuous infusion and thermosensitive liposome-mediated delivery, and the anti-cancer effectiveness is evaluated through changes in tumour cell density based on predicted intracellular concentrations. Comparisons are made between regions of different vascular density, and between the two drug delivery modes. Our numerical results show that both extra- and intra-cellular concentrations in the liver tumour are non-uniform owing to the heterogeneous distribution of tumour vasculature. Drugs accumulate faster in well-vascularized regions, where they are also cleared out more quickly, resulting in less effective tumour cell killing in these regions. Compared with direct continuous infusion, the influence of heterogeneous vasculature on anti-cancer effectiveness is more pronounced for thermosensitive liposome-mediated delivery.

  5. Quantitative Assessment of Distributed Energy Resource Benefits

    SciTech Connect

    Hadley, S.W.

    2003-05-22

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

  6. 78 FR 36787 - Rechanneling the Current Cardiac Risk Paradigm: Arrhythmia Risk Assessment During Drug...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-06-19

    ... HUMAN SERVICES Food and Drug Administration Rechanneling the Current Cardiac Risk Paradigm: Arrhythmia... (FDA), the Cardiac Safety Research Consortium, and the International Life Sciences Institute's Health... the Current Cardiac Risk Paradigm: Arrhythmia Risk Assessment During Drug Development Without...

  7. 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 Central

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

    2015-01-01

    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

  8. Reducing attrition in drug development: smart loading preclinical safety assessment.

    PubMed

    Roberts, Ruth A; Kavanagh, Stefan L; Mellor, Howard R; Pollard, Christopher E; Robinson, Sally; Platz, Stefan J

    2014-03-01

    Entry into the crucial preclinical good laboratory practice (GLP) stage of toxicology testing triggers significant R&D investment yet >20% of AstraZeneca's potential new medicines have been stopped for safety reasons in this GLP phase alone. How could we avoid at least some of these costly failures? An analysis of historical toxicities that caused stopping ('stopping toxicities') showed that >50% were attributable to target organ toxicities emerging within 2 weeks of repeat dosing or to acute cardiovascular risks. By frontloading 2-week repeat-dose toxicity studies and a comprehensive assessment of cardiovascular safety, we anticipate a potential 50% reduction in attrition in the GLP phase. This will reduce animal use overall, save significant R&D costs and improve drug pipeline quality. PMID:24269835

  9. Film Technique for Assessing Attitudes toward Drug Users.

    ERIC Educational Resources Information Center

    Ahlgren, Andrew; Eburne, Norman

    1981-01-01

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

  10. Experimental models to study drug distributions in tissue using MALDI mass spectrometry imaging.

    PubMed

    Végvári, Ákos; Fehniger, Thomas E; Rezeli, Melinda; Laurell, Thomas; Döme, Balázs; Jansson, Bo; Welinder, Charlotte; Marko-Varga, György

    2013-12-01

    Requirements for patient safety and improved efficacy are steadily increasing in modern healthcare and are key drivers in modern drug development. New drug characterization assays are central in providing evidence of the specificity and selectivity of drugs. Meeting this need, matrix-assisted laser desorption ionization-mass spectrometry imaging (MALDI-MSI) is used to study drug localization within microenvironmental tissue compartments. Thin sections of human lung tumor and rat xenograft tissues were exposed to pharmaceutical drugs by either spotting or submerging. These drugs, the epidermal growth factor receptor antagonists, erlotinib (Tarceva) and gefitinib (Iressa), and the acetylcholine receptor antagonist, tiotropium, were characterized by microenvironment localization. Intact tissue blocks were also immersed in drug solution, followed by sectioning. MALDI-MSI was then performed using a Thermo MALDI LTQ Orbitrap XL instrument to localize drug-distribution patterns. We propose three MALDI-MSI models measuring drug disposition that have been used to map the selected compounds within tissue compartments of tumors isolated from lung cancer patients. PMID:24134601

  11. The electrocardiogram in the assessment of the effect of drugs on cardiac arrhythmias.

    PubMed Central

    Reid, D S

    1978-01-01

    The search for the ideal antiarrhythmic drug continues since none of the available agents offers optimum antiarrhythmic therapy. The continuing search coupled with the interest in the mechanisms of cardiac arrhythmias has led to the development of new techniques for the study of arrhythmias and antiarrhythmic drugs. In this article it is proposed to discuss the electrocardiographic methods used in the assessment of antiarrhythmic drugs. Firstly, to discuss the electrocardiogram in the assessment of the clinical electrophysiological properties of a drug and secondly, the electrocardiogram in the assessment of the value of the drug in the management of cardiac arrhythmias in man. PMID:365208

  12. Liquid crystal nanoparticle formulation as an oral drug delivery system for liver-specific distribution

    PubMed Central

    Lee, Dong Ryeol; Park, Ji Su; Bae, Il Hak; Lee, Yan; Kim, B Moon

    2016-01-01

    Liquid crystal nanoparticles have been utilized as an efficient tool for drug delivery with enhanced bioavailability, drug stability, and targeted drug delivery. However, the high energy requirements and the high cost of the liquid crystal preparation have been obstacles to their widespread use in the pharmaceutical industry. In this study, we prepared liquid crystal nanoparticles using a phase-inversion temperature method, which is a uniquely low energy process. Particles prepared with the above method were estimated to be ~100 nm in size and exhibited a lamellar liquid crystal structure with orthorhombic lateral packing. Pharmacokinetic and tissue distribution studies of a hydrophobic peptide-based drug candidate formulated with the liquid crystal nanoparticles showed a five-fold enhancement of bioavailability, sustained release, and liver-specific drug delivery compared to a host–guest complex formulation. PMID:27042053

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

    NASA Astrophysics Data System (ADS)

    Hein, John; Jeannot, Michael

    2001-02-01

    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.

  14. Causality assessment in hepatotoxicity by drugs and dietary supplements

    PubMed Central

    Teschke, Rolf; Schwarzenboeck, Alexander; Hennermann, Karl-Heinz

    2008-01-01

    Structured causality assessment of hepatotoxicity by drugs and dietary supplements (DDS) is a major clinical challenge, since temporal associations as the sole criteria for a valid evaluation are not acceptable. Initially, a clear intuition for an ad hoc evaluation is necessary, but only provisional, and must be followed by a diagnostic algorithm using a pretest, main test and post test. The evaluation is based on a variety of items such as latency period, course of alanine aminotransferase and alkaline phosphatase after DDS discontinuation, risk factors, co-medication, previous information on hepatotoxicity of the DDS, response to rechallenge, and exclusion of other diseases. It is essential that practising and hospital physicians as well as other key health professionals, such as pharmacists, gather all information required for a sound causality assessment, obviating major discussions by expert panels, manufacturers and health agencies in face of scanty and fragmentary data. Because pharmacogenetic alterations may trigger metabolic hepatotoxicity by a few DDS, levels in plasma and urine should be measured and may be helpful for diagnosis. Concomitant genotyping of cytochrome P450 and other enzymes may also be useful in future to minimize the risk of unwanted side-effects, including toxic liver disease elicited by DDS. PMID:19032721

  15. Risk assessment of technologies for detecting illicit drugs in containers

    NASA Astrophysics Data System (ADS)

    Brandenstein, Albert E.

    1995-03-01

    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.

  16. Utility of population pharmacokinetic modeling in the assessment of therapeutic protein-drug interactions.

    PubMed

    Chow, Andrew T; Earp, Justin C; Gupta, Manish; Hanley, William; Hu, Chuanpu; Wang, Diane D; Zajic, Stefan; Zhu, Min

    2014-05-01

    Assessment of pharmacokinetic (PK) based drug-drug interactions (DDI) is essential for ensuring patient safety and drug efficacy. With the substantial increase in therapeutic proteins (TP) entering the market and drug development, evaluation of TP-drug interaction (TPDI) has become increasingly important. Unlike for small molecule (e.g., chemical-based) drugs, conducting TPDI studies often presents logistical challenges, while the population PK (PPK) modeling may be a viable approach dealing with the issues. A working group was formed with members from the pharmaceutical industry and the FDA to assess the utility of PPK-based TPDI assessment including study designs, data analysis methods, and implementation strategy. This paper summarizes key issues for consideration as well as a proposed strategy with focuses on (1) PPK approach for exploratory assessment; (2) PPK approach for confirmatory assessment; (3) importance of data quality; (4) implementation strategy; and (5) potential regulatory implications. Advantages and limitations of the approach are also discussed. PMID:24272952

  17. Modelling the Impact of Atherosclerosis on Drug Release and Distribution from Coronary Stents.

    PubMed

    McKittrick, C M; Kennedy, S; Oldroyd, K G; McGinty, S; McCormick, C

    2016-02-01

    Although drug-eluting stents (DES) are now widely used for the treatment of coronary heart disease, there remains considerable scope for the development of enhanced designs which address some of the limitations of existing devices. The drug release profile is a key element governing the overall performance of DES. The use of in vitro, in vivo, ex vivo, in silico and mathematical models has enhanced understanding of the factors which govern drug uptake and distribution from DES. Such work has identified the physical phenomena determining the transport of drug from the stent and through tissue, and has highlighted the importance of stent coatings and drug physical properties to this process. However, there is limited information regarding the precise role that the atherosclerotic lesion has in determining the uptake and distribution of drug. In this review, we start by discussing the various models that have been used in this research area, highlighting the different types of information they can provide. We then go on to describe more recent methods that incorporate the impact of atherosclerotic lesions. PMID:26384667

  18. Evaluation of optimized bronchoalveolar lavage sampling designs for characterization of pulmonary drug distribution.

    PubMed

    Clewe, Oskar; Karlsson, Mats O; Simonsson, Ulrika S H

    2015-12-01

    Bronchoalveolar lavage (BAL) is a pulmonary sampling technique for characterization of drug concentrations in epithelial lining fluid and alveolar cells. Two hypothetical drugs with different pulmonary distribution rates (fast and slow) were considered. An optimized BAL sampling design was generated assuming no previous information regarding the pulmonary distribution (rate and extent) and with a maximum of two samples per subject. Simulations were performed to evaluate the impact of the number of samples per subject (1 or 2) and the sample size on the relative bias and relative root mean square error of the parameter estimates (rate and extent of pulmonary distribution). The optimized BAL sampling design depends on a characterized plasma concentration time profile, a population plasma pharmacokinetic model, the limit of quantification (LOQ) of the BAL method and involves only two BAL sample time points, one early and one late. The early sample should be taken as early as possible, where concentrations in the BAL fluid ≥ LOQ. The second sample should be taken at a time point in the declining part of the plasma curve, where the plasma concentration is equivalent to the plasma concentration in the early sample. Using a previously described general pulmonary distribution model linked to a plasma population pharmacokinetic model, simulated data using the final BAL sampling design enabled characterization of both the rate and extent of pulmonary distribution. The optimized BAL sampling design enables characterization of both the rate and extent of the pulmonary distribution for both fast and slowly equilibrating drugs. PMID:26316105

  19. Occurrence and spatial distribution of 158 pharmaceuticals, drugs of abuse and related metabolites in offshore seawater.

    PubMed

    Alygizakis, Nikiforos A; Gago-Ferrero, Pablo; Borova, Viola L; Pavlidou, Alexandra; Hatzianestis, Ioannis; Thomaidis, Nikolaos S

    2016-01-15

    The occurrence and spatial distribution of 158 pharmaceuticals and drugs of abuse were studied in seawater of the Eastern Mediterranean Sea (Saronikos Gulf and Elefsis Bay in central Aegean Sea). This area is affected by various anthropogenic pressures as it receives the treated wastewater of the greatest Athens area and off-shore input fluxes. This study constitutes the largest one in terms of number of analytes in this environmental compartment. It provides the first evidence on the occurrence of several pharmaceuticals in marine environment including amoxicillin, lidocaine, citalopram or tramadol, among others. 22 samples were collected at three different depths in 9 sampling stations in order to assess the presence and the spatial distribution of the target compounds. A multi-residue method based on solid phase extraction and liquid chromatography coupled to tandem mass spectrometry was developed for the determination of the 158 target substances and validated for seawater sample analysis. 38 out of the 158 target compounds were detected, 15 of them with frequencies of detection equal to or higher than 50%. The highest detected values corresponded to amoxicillin, caffeine and salicylic acid, with concentrations in the range of < 5.0-127.8 ng L(-1); 5.2-78.2 ng L(-1) and < 0.4-53.3 ng L(-1), respectively. Inputs from the wastewater treatment plant (WWTP) of Athens revealed to be the main source of pollution in the Inner Saronikos Gulf, whereas, other anthropogenic pressures such as contamination from shipping activity, industrial effluents, dredging and/or inputs from land proved to be also relevant. Τhe concentrations of some compounds varied significantly with depth suggesting that currents play an important role in the dilution of the target compounds. PMID:26473711

  20. Distribution and drug resistance profile of methicillin-resistant Staphylococcus aureus after orthopaedic surgery.

    PubMed

    Song, Wen Chao; Zhang, Si Sen; Gong, Yu Hong

    2015-05-01

    This paper is aimed to comprehend clinical distribution and drug-resistance situation of methicillin-resistant Staphylococcus aureus. This study applied automatic microbe instrument Microscan W/A 96 for strain identification and drug susceptibility screening on the isolated strains. It was found that 312 MRSA strains were isolated in three years, which account for 58.1% of Staphylococcus aureus. MRSA were mainly focused in wound secretion, purulent sputum and prostatic fluid and a few of them were isolated from blood specimens; Endemic area distribution was mainly located in intensive care unit, neurosurgery, respiratory department, dermatology, orthopaedic burns and orthopaedics. MRSA strains showed high drug resistance of 82.37%~100% to most of the antibiotics including vancomycin, cotrimoxazole and rifampicin. Strain was 100% resistance towards ampicillin, amoxicillin/acid, cefalotin, cefazolin, tienam, benzylpenicillin, penicillin and tetracycline and 90% strains resisted clindamycin, cefotaxime, clarithromycin and gentamicin. PMID:26051737

  1. Comparison of equilibrium and non-equilibrium distribution coefficients for the human drug carbamazepine

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The distribution coefficient (KD) for the human drug carbamazepine was measured using a non-equilibrium technique. Repacked soil columns were prepared using an Airport silt loam (Typic Natrustalf) with an average organic matter content of 2.45%. Carbamazepine solutions were then leached through th...

  2. 10 CFR 32.21 - Radioactive drug: Manufacture, preparation, or transfer for commercial distribution of capsules...

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... 10 Energy 1 2012-01-01 2012-01-01 false Radioactive drug: Manufacture, preparation, or transfer for commercial distribution of capsules containing carbon-14 urea each for âin vivoâ diagnostic use for humans to persons exempt from licensing; Requirements for a license. 32.21 Section 32.21 Energy NUCLEAR REGULATORY COMMISSION SPECIFIC...

  3. 10 CFR 32.21 - Radioactive drug: Manufacture, preparation, or transfer for commercial distribution of capsules...

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 10 Energy 1 2014-01-01 2014-01-01 false Radioactive drug: Manufacture, preparation, or transfer for commercial distribution of capsules containing carbon-14 urea each for âin vivoâ diagnostic use for humans to persons exempt from licensing; Requirements for a license. 32.21 Section 32.21 Energy NUCLEAR REGULATORY COMMISSION SPECIFIC...

  4. Interrogating the relationship between rat in vivo tissue distribution and drug property data for >200 structurally unrelated molecules.

    PubMed

    Harrell, Andrew W; Sychterz, Caroline; Ho, May Y; Weber, Andrew; Valko, Klara; Negash, Kitaw

    2015-10-01

    The ability to explain distribution patterns from drug physicochemical properties and binding characteristics has been explored for more than 200 compounds by interrogating data from quantitative whole body autoradiography studies (QWBA). These in vivo outcomes have been compared to in silico and in vitro drug property data to determine the most influential properties governing drug distribution. Consistent with current knowledge, in vivo distribution was most influenced by ionization state and lipophilicity which in turn affected phospholipid and plasma protein binding. Basic and neutral molecules were generally better distributed than acidic counterparts demonstrating weaker plasma protein and stronger phospholipid binding. The influence of phospholipid binding was particularly evident in tissues with high phospholipid content like spleen and lung. Conversely, poorer distribution of acidic drugs was associated with stronger plasma protein and weaker phospholipid binding. The distribution of a proportion of acidic drugs was enhanced, however, in tissues known to express anionic uptake transporters such as the liver and kidney. Greatest distribution was observed into melanin containing tissues of the eye, most likely due to melanin binding. Basic molecules were consistently better distributed into parts of the eye and skin containing melanin than those without. The data, therefore, suggest that drug binding to macromolecules strongly influences the distribution of total drug for a large proportion of molecules in most tissues. Reducing lipophilicity, a strategy often used in discovery to optimize pharmacokinetic properties such as absorption and clearance, also decreased the influence of nonspecific binding on drug distribution. PMID:26516585

  5. Interrogating the relationship between rat in vivo tissue distribution and drug property data for >200 structurally unrelated molecules

    PubMed Central

    Harrell, Andrew W; Sychterz, Caroline; Ho, May Y; Weber, Andrew; Valko, Klara; Negash, Kitaw

    2015-01-01

    The ability to explain distribution patterns from drug physicochemical properties and binding characteristics has been explored for more than 200 compounds by interrogating data from quantitative whole body autoradiography studies (QWBA). These in vivo outcomes have been compared to in silico and in vitro drug property data to determine the most influential properties governing drug distribution. Consistent with current knowledge, in vivo distribution was most influenced by ionization state and lipophilicity which in turn affected phospholipid and plasma protein binding. Basic and neutral molecules were generally better distributed than acidic counterparts demonstrating weaker plasma protein and stronger phospholipid binding. The influence of phospholipid binding was particularly evident in tissues with high phospholipid content like spleen and lung. Conversely, poorer distribution of acidic drugs was associated with stronger plasma protein and weaker phospholipid binding. The distribution of a proportion of acidic drugs was enhanced, however, in tissues known to express anionic uptake transporters such as the liver and kidney. Greatest distribution was observed into melanin containing tissues of the eye, most likely due to melanin binding. Basic molecules were consistently better distributed into parts of the eye and skin containing melanin than those without. The data, therefore, suggest that drug binding to macromolecules strongly influences the distribution of total drug for a large proportion of molecules in most tissues. Reducing lipophilicity, a strategy often used in discovery to optimize pharmacokinetic properties such as absorption and clearance, also decreased the influence of nonspecific binding on drug distribution. PMID:26516585

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

    PubMed

    Jämstorp, Erik; Strømme, Maria; Bredenberg, Susanne

    2012-05-01

    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

  7. Perspectives on an NWCC/NREL Assessment of Distributed Wind

    SciTech Connect

    Parsons, B.; Cohen, J.; DeMeo, E.

    2000-09-13

    During 1998 and 1999, the National Wind Coordinating Committee (NWCC) conducted an assessment of distributed wind power. The project team was led by Princeton Economic Research, Inc., now known as Princeton Energy Resources International (PERI). Financial support was provided by the US Department of Energy (DOE) through the wind energy program at the National Renewable Energy Laboratory (NREL) and the Electric Power Research Institute (EPRI). Project oversight and review were provided by NWCC's Distributed Working Group. The overall objective for the NWCC assessment was to enhance understanding of business, policy, and technical issues associated with the deployment of wind-electric generating systems in the distributed-generation mode. In general, that mode is defined by placement of the generation close to customers-in contrast to large, distant central stations-and by electrical interconnection to the local distribution system-in contrast to higher voltage electrical transmission systems. As a follow-up to the assessment, NWCC intends to prepare a consensus-based issue brief that summarizes its findings and highlights the major results and conclusions for each stakeholder sector. This brief will also identify key action steps that could be undertaken by each stakeholder sector to facilitate the growth of distributed wind. The aim of this paper is to provide input to the NWCC for its consideration in developing the issue brief. Accordingly, this paper is in no way an NWCC consensus document. However, the authors hope to assist in the issue-brief preparation process by providing a starting point for NWCC's consideration. One of the authors, Joseph Cohen, led the team that performed the NWCC assessment. The other two were involved in management of the assessment effort on behalf of the contracting organizations and are active members of the NWCC. They feel the perspectives offered in this paper are well-grounded in the findings of the assessment research and can help in moving the consensus process forward.

  8. Methodological Issues in Assessing the Impact of Prenatal Drug Exposure

    PubMed Central

    Konijnenberg, Carolien

    2015-01-01

    Prenatal drug exposure is a common public health concern that can result in perinatal complications, birth defects, and developmental disorders. The growing literature regarding the effects of prenatal exposure to specific drugs such as tobacco, alcohol, cocaine, and heroin is often conflicting and constantly changing. This review discusses several reasons why the effects of prenatal drug exposure are so difficult to determine, including variations in dose, timing, duration of exposure, polydrug use, unreliable measures of drug exposure, latent or “sleeper” effects, genetic factors, and socioenvironmental influences. In addition to providing research guidelines, this review also aims to help clinicians and policy makers to identify the strengths and weaknesses in studies investigating the effects of prenatal drug exposure. This knowledge may be used to make better informed decisions regarding the appropriate treatment for pregnant, drug-dependent women and their children. PMID:26604776

  9. Drug interactions involving antiepileptic drugs: assessment of the consistency among three drug compendia and FDA-approved labels.

    PubMed

    Ekstein, Dana; Tirosh, Matanya; Eyal, Yonatan; Eyal, Sara

    2015-03-01

    Interactions of antiepileptic drugs (AEDs) with other substances may lead to adverse effects and treatment failure. To avoid such interactions, clinicians often rely on drug interaction compendia. Our objective was to compare the concordance for twenty-two AEDs among three drug interaction compendia (Micromedex, Lexi-Interact, and Clinical Pharmacology) and the US Food and Drug Administration-approved product labels. For each AED, the overall concordance among data sources regarding existence of interactions and their classification was poor, with less than twenty percent of interactions listed in all four sources. Concordance among the three drug compendia decreased with the fraction of the drug excreted unchanged and was greater for established inducers of hepatic drug-metabolizing enzymes than for the drugs that are not inducers (R-square=0.83, P<0.01). For interactions classified as contraindications, major, and severe, concordance among the four data sources was, in most cases, less than 30%. Prescribers should be aware of the differences between drug interaction sources of information for both older AEDs and newer AEDs, in particular for those AEDs which are not involved in hepatic enzyme-mediated interactions. PMID:25771206

  10. Condition Assessment Technologies for Water Transmission and Distribution Systems

    EPA Science Inventory

    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 transmission and distribution syst...

  11. 7 CFR 1230.73 - Uses of distributed assessments.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... PROMOTION, RESEARCH, AND CONSUMER INFORMATION Pork Promotion, Research, and Consumer Information Order... members of the Delegate Body. (b) The Council shall use its distribution of assessments pursuant to § 1230... fiscal period's budget to permit continuation of an effective promotion, research, and...

  12. 7 CFR 1230.73 - Uses of distributed assessments.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... PROMOTION, RESEARCH, AND CONSUMER INFORMATION Pork Promotion, Research, and Consumer Information Order... members of the Delegate Body. (b) The Council shall use its distribution of assessments pursuant to § 1230... fiscal period's budget to permit continuation of an effective promotion, research, and...

  13. Condition Assessment Technologies for Water Transmission and Distribution Systems

    EPA Science Inventory

    As part of the U.S. Environmental Protection Agencys (EPAs) 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 transmission and distribution syst...

  14. 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...

  15. Distribution of primaquine in human blood: Drug-binding to alpha 1-glycoprotein

    SciTech Connect

    Kennedy, E.; Frischer, H. )

    1990-12-01

    To clarify the distribution of the antimalarial primaquine in human blood, we measured the drug separately in the liquid, cellular, and ultrafiltrate phases. Washed red cells resuspended at a hematocrit of 0.4 were exposed to a submaximal therapeutic level of 250 ng/ml of carbon 14-labeled primaquine. The tracer was recovered quantitatively in separated plasma and red cells. Over 75% of the total labeled drug was found in red cells suspended in saline solution, but only 10% to 30% in red cells suspended in plasma. The plasma effect was not mediated by albumin. Studies with alpha 1-acid glycoprotein (AGP), tris(2-butoxyethyl)phosphate, an agent that displaces AGP-bound drugs, and cord blood known to have decreased AGP established that primaquine binds to physiologic amounts of the glycoprotein in plasma. Red cell primaquine concentration increased linearly as AGP level fell and as the free drug fraction rose. We suggest that clinical blood levels of primaquine include the red cell fraction or whole blood level because (1) erythrocytic primaquine is a sizable and highly variable component of the total drug in blood; (2) this component reflects directly the free drug in plasma, and inversely the extent of binding to AGP; (3) the amount of free primaquine may influence drug transport into specific tissues in vivo; and (4) fluctuations of AGP, an acute-phase reactant that increases greatly in patients with malaria and other infections, markedly affect the partition of primaquine in blood. Because AGP binds many basic drugs, unrecognized primaquine-drug interactions may exist.

  16. The association between sterilizing activity and drug distribution into tuberculosis lesions.

    PubMed

    Prideaux, Brendan; Via, Laura E; Zimmerman, Matthew D; Eum, Seokyong; Sarathy, Jansy; O'Brien, Paul; Chen, Chao; Kaya, Firat; Weiner, Danielle M; Chen, Pei-Yu; Song, Taeksun; Lee, Myungsun; Shim, Tae Sun; Cho, Jeong Su; Kim, Wooshik; Cho, Sang Nae; Olivier, Kenneth N; Barry, Clifton E; Dartois, Vronique

    2015-10-01

    Finding new treatment-shortening antibiotics to improve cure rates and curb the alarming emergence of drug resistance is the major objective of tuberculosis (TB) drug development. Using a matrix-assisted laser desorption/ionization (MALDI) mass spectrometry imaging suite in a biosafety containment facility, we show that the key sterilizing drugs rifampicin and pyrazinamide efficiently penetrate the sites of TB infection in lung lesions. Rifampicin even accumulates in necrotic caseum, a critical lesion site where persisting tubercle bacilli reside. In contrast, moxifloxacin, which is active in vitro against a subpopulation of Mycobacterium tuberculosis that persists in specific niches under drug pressure and has achieved treatment shortening in mice, does not diffuse well in caseum, concordant with its failure to shorten therapy in recent clinical trials. We suggest that such differential spatial distribution and kinetics of accumulation in lesions may create temporal and spatial windows of monotherapy in specific niches, allowing the gradual development of multidrug-resistant TB. We propose an alternative working model to prioritize new antibiotic regimens based on quantitative and spatial distribution of TB drugs in the major lesion types found in human lungs. The finding that lesion penetration may contribute to treatment outcome has wide implications for TB. PMID:26343800

  17. The association between sterilizing activity and drug distribution into tuberculosis lesions

    PubMed Central

    Prideaux, Brendan; Via, Laura E.; Zimmerman, Matthew D.; Eum, Seokyong; Sarathy, Jansy; O’Brien, Paul; Chen, Chao; Kaya, Firat; Weiner, Danielle M.; Chen, Pei-Yu; Song, Taeksun; Lee, Myungsun; Shim, TaeSun; Cho, Jeong Su; Kim, Wooshik; Cho, Sang Nae; Olivier, Kenneth N.; Barry, Clifton E.; Dartois, Véronique

    2015-01-01

    Finding new treatment-shortening antibiotics to improve cure rates and curb the alarming emergence of drug resistance is the major objective of tuberculosis (TB) drug development. Using a MALDI mass spectrometry imaging suite in a biosafety containment facility, we show that the key sterilizing drugs rifampicin and pyrazinamide efficiently penetrate the sites of TB infection in lung lesions. Rifampicin even accumulates in necrotic caseum, a critical lesion site where persisting tubercle bacilli reside1. In contrast, moxifloxacin which is active in vitro against persisters, a sub-population of Mycobacterium tuberculosis that persists in specific niches under drug pressure, and achieved treatment shortening in mice2, does not diffuse well in caseum, concordant with its failure to shorten therapy in recent clinical trials. We also suggest that such differential spatial distribution and kinetics of accumulation in lesions may create temporal and spatial windows of monotherapy in specific niches, allowing the gradual development of multidrug resistant TB. We propose an alternative working model to prioritize new antibiotic regimens based on quantitative and spatial distribution of TB drugs in the major lesion types found in human lungs. The finding that lesion penetration contributes to treatment outcome has wide implications for TB. PMID:26343800

  18. Assessment of AIDS Risk among Treatment Seeking Drug Abusers.

    ERIC Educational Resources Information Center

    Black, John L.; And Others

    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…

  19. Assessment of AIDS Risk among Treatment Seeking Drug Abusers.

    ERIC Educational Resources Information Center

    Black, John L.; And Others

    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

  20. Imaging of drug loading distributions in individual microspheres of calcium silicate hydrate - an X-ray spectromicroscopy study

    NASA Astrophysics Data System (ADS)

    Guo, Xiaoxuan; Wang, Zhiqiang; Wu, Jin; Wang, Jian; Zhu, Ying-Jie; Sham, Tsun-Kong

    2015-04-01

    Imaging is one of the most direct and ideal ways to track drug loading distributions in drug carriers on the molecular level, which will facilitate the optimization of drug carriers and drug loading capacities. Herein, we report the mapping of an individual mesoporous calcium silicate hydrate (CSH) microsphere before and after the loading of ibuprofen (IBU) and the interactions between drug carriers and drug molecules simultaneously by scanning transmission X-ray microscopy (STXM). Nanoscaled X-ray absorption near edge structure (XANES) spectroscopy clearly indicates that IBU is bonded to calcium and silicate sites via carboxylic acid groups. More importantly, STXM has been successfully used to determine the absolute thickness of IBU, revealing its distribution in the CSH microsphere.Imaging is one of the most direct and ideal ways to track drug loading distributions in drug carriers on the molecular level, which will facilitate the optimization of drug carriers and drug loading capacities. Herein, we report the mapping of an individual mesoporous calcium silicate hydrate (CSH) microsphere before and after the loading of ibuprofen (IBU) and the interactions between drug carriers and drug molecules simultaneously by scanning transmission X-ray microscopy (STXM). Nanoscaled X-ray absorption near edge structure (XANES) spectroscopy clearly indicates that IBU is bonded to calcium and silicate sites via carboxylic acid groups. More importantly, STXM has been successfully used to determine the absolute thickness of IBU, revealing its distribution in the CSH microsphere. Electronic supplementary information (ESI) available. See DOI: 10.1039/c4nr07471h

  1. Problems in distribution of scientific knowledge: intrauterine contraceptive devices and drug catalogs.

    PubMed

    Makkonen, K

    1993-01-01

    Intrauterine contraceptive devices (IUDs) are a popular method of contraception worldwide. However, some serious problems have been associated with them. Finland has developed and now manufactures and exports IUDs. Therefore, drug control and the quality of drug information existing in Finland are significant for other countries, as well. This study analyzes the information in the Finnish commercial drug catalog on copper-releasing IUDs and compares it with the scientific literature, the instructions from the licensing authority, and material in its U.S. counterpart, during the last two decades. The results indicate that the distribution of scientific knowledge to the drug catalogs has often been slow. In the early 1980s Finnish manufacturers did not give any practical information on their products, and then and later the Finnish catalog was less comprehensive than the U.S. catalog. The variations in the control system in different nations were reflected in the contents of the Finnish catalog. For practitioners, drug catalogs are important sources of medical information. The results of this study demonstrate (1) that more attention should be paid to the contents of these catalogs, and (2) the continuous need for up-to-date, unbiased drug information. PMID:8425786

  2. Health technology assessment in the Balkans: opportunities for a balanced drug assessment system

    PubMed Central

    Dankó, Dávid; Petrova, Guenka

    2014-01-01

    Countries in the Balkan region use pharmaco-economic data for decisions about the inclusion of new pharmaceuticals into their positive drug lists, but no predefined frameworks are used and resources for health technology assessment (HTA) are limited. The goal of this analysis is to investigate into possible development directions for the HTA system in the region, and provide some practical recommendations for a sustainable model. For this purpose, the main factors currently influencing HTA in Balkan countries are briefly presented, and possible development strategies are compared. A resource-saving balanced assessment approach is proposed. It is aligned with available resources and capabilities, and helps access to new pharmaceuticals while ensuring the transparency of decision-making processes and the stability of the pharmaceutical budget. PMID:26019605

  3. Drug delivery system innovation and Health Technology Assessment: Upgrading from Clinical to Technological Assessment.

    PubMed

    Panzitta, Michele; Bruno, Giorgio; Giovagnoli, Stefano; Mendicino, Francesca R; Ricci, Maurizio

    2015-11-30

    Health Technology Assessment (HTA) is a multidisciplinary health political instrument that evaluates the consequences, mainly clinical and economical, of a health care technology; the HTA aim is to produce and spread information on scientific and technological innovation for health political decision making process. Drug delivery systems (DDS), such as nanocarriers, are technologically complex but they have pivotal relevance in therapeutic innovation. The HTA process, as commonly applied to conventional drug evaluation, should upgrade to a full pharmaceutical assessment, considering the DDS complexity. This is useful to study more in depth the clinical outcome and to broaden its critical assessment toward pharmaceutical issues affecting the patient and not measured by the current clinical evidence approach. We draw out the expertise necessary to perform the pharmaceutical assessment and we propose a format to evaluate the DDS technological topics such as formulation and mechanism of action, physicochemical characteristics, manufacturing process. We integrated the above-mentioned three points in the Evidence Based Medicine approach, which is data source for any HTA process. In this regard, the introduction of a Pharmaceutics Expert figure in the HTA could be fundamental to grant a more detailed evaluation of medicine product characteristics and performances and to help optimizing DDS features to overcome R&D drawbacks. Some aspects of product development, such as manufacturing processes, should be part of the HTA as innovative manufacturing processes allow new products to reach more effectively patient bedside. HTA so upgraded may encourage resource allocating payers to invest in innovative technologies and providers to focus on innovative material properties and manufacturing processes, thus contributing to bring more medicines in therapy in a sustainable manner. PMID:26399633

  4. 41 CFR 102-41.230 - May SASPs pick up or store donated drug paraphernalia in their distribution centers?

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 41 Public Contracts and Property Management 3 2010-07-01 2010-07-01 false May SASPs pick up or store donated drug paraphernalia in their distribution centers? 102-41.230 Section 102-41.230 Public... SASPs pick up or store donated drug paraphernalia in their distribution centers? No, you must...

  5. 41 CFR 102-41.230 - May SASPs pick up or store donated drug paraphernalia in their distribution centers?

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... 41 Public Contracts and Property Management 3 2012-01-01 2012-01-01 false May SASPs pick up or store donated drug paraphernalia in their distribution centers? 102-41.230 Section 102-41.230 Public... SASPs pick up or store donated drug paraphernalia in their distribution centers? No, you must...

  6. 41 CFR 102-41.230 - May SASPs pick up or store donated drug paraphernalia in their distribution centers?

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 41 Public Contracts and Property Management 3 2013-07-01 2013-07-01 false May SASPs pick up or store donated drug paraphernalia in their distribution centers? 102-41.230 Section 102-41.230 Public... SASPs pick up or store donated drug paraphernalia in their distribution centers? No, you must...

  7. 41 CFR 102-41.230 - May SASPs pick up or store donated drug paraphernalia in their distribution centers?

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 41 Public Contracts and Property Management 3 2014-01-01 2014-01-01 false May SASPs pick up or store donated drug paraphernalia in their distribution centers? 102-41.230 Section 102-41.230 Public... SASPs pick up or store donated drug paraphernalia in their distribution centers? No, you must...

  8. 41 CFR 102-41.230 - May SASPs pick up or store donated drug paraphernalia in their distribution centers?

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 41 Public Contracts and Property Management 3 2011-01-01 2011-01-01 false May SASPs pick up or store donated drug paraphernalia in their distribution centers? 102-41.230 Section 102-41.230 Public... SASPs pick up or store donated drug paraphernalia in their distribution centers? No, you must...

  9. 41 CFR 105-74.210 - To whom must I distribute my drug-free workplace statement?

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... distribute my drug-free workplace statement? 105-74.210 Section 105-74.210 Public Contracts and Property Management Federal Property Management Regulations System (Continued) GENERAL SERVICES ADMINISTRATION... distribute my drug-free workplace statement? You must require that a copy of the statement described in §...

  10. Assessment of Drug-Drug Interactions between Daclatasvir and Methadone or Buprenorphine-Naloxone

    PubMed Central

    Wang, R.; Luo, W.-L.; Wastall, P.; Kandoussi, H.; DeMicco, M.; Bruce, R. D.; Hwang, C.; Bertz, R.; Bifano, M.

    2015-01-01

    Hepatitis C virus (HCV) infection is common among people who inject drugs, including those managed with maintenance opioids. Pharmacokinetic interactions between opioids and emerging oral HCV antivirals merit evaluation. Daclatasvir is a potent pangenotypic inhibitor of the HCV NS5A replication complex recently approved for HCV treatment in Europe and Japan in combination with other antivirals. The effect of steady-state daclatasvir (60 mg daily) on stable plasma exposure to oral opioids was assessed in non-HCV-infected subjects receiving methadone (40 to 120 mg; n = 14) or buprenorphine plus naloxone (8 to 24 mg plus 2 to 6 mg; n = 11). No relevant interaction was inferred if the 90% confidence interval (CI) of the geometric mean ratio (GMR) of opioid area under the plasma concentration-time curve over the dosing interval (AUCτ) or maximum concentration in plasma (Cmax) with versus without daclatasvir was within literature-derived ranges of 0.7 to 1.43 (R- and S-methadone) or 0.5 to 2.0 (buprenorphine and norbuprenorphine). Dose-normalized AUCτ for R-methadone (GMR, 1.08; 90% CI, 0.94 to 1.24), S-methadone (1.13; 0.99 to 1.30), and buprenorphine (GMR, 1.37; 90% CI, 1.24 to 1.52) were within the no-effect range. The norbuprenorphine AUCτ was slightly elevated in the primary analysis (GMR, 1.62; 90% CI, 1.30 to 2.02) but within the no-effect range in a supplementary analysis of all evaluable subjects. Dose-normalized Cmax for both methadone enantiomers, buprenorphine and norbuprenorphine, were within the no-effect range. Standardized assessments of opioid pharmacodynamics were unchanged throughout daclatasvir administration with methadone or buprenorphine. Daclatasvir pharmacokinetics were similar to historical data. Coadministration of daclatasvir and opioids was generally well tolerated. In conclusion, these data suggest that daclatasvir can be administered with buprenorphine or methadone without dose adjustments. PMID:26124175

  11. Assessment of Club Patrons’ Alcohol and Drug Use

    PubMed Central

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

    2014-01-01

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

  12. Assessing Combinational Drug Efficacy in Cancer Cells by Using Image-based Dynamic Response Analysis

    PubMed Central

    Sima, Chao; Hua, Jianping; Cypert, Milana; Miller, Tasha; Wilson-Robles, Heather M.; Trent, Jeffrey M.; Dougherty, Edward R.; Bittner, Michael L.

    2015-01-01

    The landscape of translational research has been shifting toward drug combination therapies. Pairing of drugs allows for more types of drug interaction with cells. In order to accurately and comprehensively assess combinational drug efficacy, analytical methods capable of recognizing these alternative reactions will be required to prioritize those drug candidates having better chances of delivering appreciable therapeutic benefits. Traditional efficacy measures are primarily based on the “extent” of drug inhibition, which is the percentage of cells being killed after drug exposure. Here, we introduce a second dimension of evaluation criterion, speed of killing, based on a live cell imaging assay. This dynamic response trajectory approach takes advantage of both “extent” and “speed” information and uncovers synergisms that would otherwise be missed, while also generating hypotheses regarding important mechanistic modes of drug action. PMID:26997864

  13. [Study of distribution of sinapine in commonly used crude drugs from cruciferous plants].

    PubMed

    Liu, Lifang; Wang, Yuxin; Li, Haiyan; Ji, Ying

    2006-01-01

    Sinapine, an important natural antioxidant, is often obtained from cruciferous plants. Many scientists are interested in it because of its great potential in the field of antiageing drugs. Thus, the distribution of sinapine in 4 commonly used crude drugs from cruciferous plants (Semen Sinapis Albae, Semen Brassicae Junceae, Semen Raphani and Semen Lepidii) was investigated. The determination was performed by reversed-phase high performance liquid chromatography (RP-HPLC) using an Alltima Phenyl column (250 mm x 4.6 mm i. d., 5 microm). A gradient elution with mobile phase consisting of (A) 3% acetic acid in water and (B) acetonitrile was used. The detection wavelength was set at 326 nm and the column temperature was kept at 25 degrees C. It is an accurate, rapid and reproducible method. The results are informative for the research of a quality control tool for these natural drugs. PMID:16827311

  14. Drug-Induced Acute Kidney Injury: A Focus on Risk Assessment for Prevention.

    PubMed

    Kane-Gill, Sandra L; Goldstein, Stuart L

    2015-10-01

    Drugs are the third to fifth leading cause of acute kidney injury (AKI) in critically ill patients following sepsis and hypotension. Susceptibilities and exposures for development of AKI have been identified, and some are modifiable allowing for the possibility of AKI prevention or mitigation of AKI severity. Using drug therapies for prevention of AKI has been attempted but with little success in human studies, so we must rely on risk-assessment strategies for prevention. The purpose of this article is to review the risk factors, risk-assessment strategies, prevention, and management of drug-induced AKI with emphasis on risk assessment. PMID:26410137

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

    NASA Astrophysics Data System (ADS)

    Boggara, Mohan; Mihailescu, Ella; Krishnamoorti, Ramanan

    2009-03-01

    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.

  16. Assessing the Potential for Drug-Nanoparticle Surface Interactions To Improve Drug Penetration into the Skin.

    PubMed

    Cai, X J; Woods, A; Mesquida, P; Jones, S A

    2016-04-01

    There is continued debate as to how nanomaterials enhance the passive diffusion of drugs through the skin. This study examined if drug-nanoparticle surface interactions, which occurred during topical application, had the capability to enhance percutaneous penetration. Atomic force microscopy force adhesion measurements were used to demonstrate that a model drug, tetracaine, strongly adsorbed to the surface of a negatively charged carboxyl-modified polystyrene nanoparticle (NanoPSCOOH) through both its methyl and amine functionalities (up to a 6- and 16-fold greater adhesion force respectively compared with the CH3-CH3 control). These drug-particle adhesion forces were significantly reduced (p < 0.05) to values that were lower than the CH3-CH3 control measurements when tetracaine interacted with a silica nanoparticle (NanoSiO2). This reduction in adhesion was attributed to the lower surface charge of the NanoSiO2 (ca. -23 mV) compared to the NanoPSCOOH (ca. -40 mV), which diminished the electrostatic interactions between positive amine of tetracaine and the negative particle. Mixing NanoPSCOOH with tetracaine on the skin retarded percutaneous drug penetration compared to the control (tetracaine saturated solution without nanoparticles), but the NanoSiO2, which still adsorbed the tetracaine, produced a 3.6-fold enhancement in percutaneous penetration compared to the same control. These data demonstrated the capability of moderate nanoparticle surface interactions that occurred within the application vehicle to promote drug percutaneous penetration. PMID:26943882

  17. Assessment of Drug Transporter Function Using Fluorescent Cell Imaging

    PubMed Central

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

    2013-01-01

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

  18. Impact of biomarker development on drug safety assessment

    SciTech Connect

    Marrer, Estelle; Dieterle, Frank

    2010-03-01

    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.

  19. Impact of biomarker development on drug safety assessment.

    PubMed

    Marrer, Estelle; Dieterle, Frank

    2010-03-01

    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. PMID:20036272

  20. The assessment and development of drug calculation skills in nurse education--a critical debate.

    PubMed

    Wright, Kerri

    2009-07-01

    The drug calculation skill of nurses continues to be a national concern. The continued concern has led to the introduction of mandatory drug calculation skills tests which students must pass in order to go on to the nursing register. However, there is little evidence to demonstrate that nurses are poor at solving drug calculation in practice. This paper argues that nurse educationalists have inadvertently created a problem that arguably does not exist in practice through use of invalid written drug assessment tests and have introduced their own pedagogical practice of solving written drug calculations. This paper will draw on literature across mathematics, philosophy, psychology and nurse education to demonstrate why written drug assessments are invalid, why learning must take place predominantly in the clinical area and why the key focus on numeracy and formal mathematical skills as essential knowledge for nurses is potentially unnecessary. PMID:19324475

  1. Interaction Potential of the Multitargeted Receptor Tyrosine Kinase Inhibitor Dovitinib with Drug Transporters and Drug Metabolising Enzymes Assessed in Vitro

    PubMed Central

    Weiss, Johanna; Theile, Dirk; Dvorak, Zdenek; Haefeli, Walter Emil

    2014-01-01

    Dovitinib (TKI-258) is under development for the treatment of diverse cancer entities. No published information on its pharmacokinetic drug interaction potential is available. Thus, we assessed its interaction with important drug metabolising enzymes and drug transporters and its efficacy in multidrug resistant cells in vitro. P-glycoprotein (P-gp, MDR1, ABCB1) inhibition was evaluated by calcein assay, inhibition of breast cancer resistance protein (BCRP, ABCG2) by pheophorbide A efflux, and inhibition of organic anion transporting polypeptides (OATPs) by 8-fluorescein-cAMP uptake. Inhibition of cytochrome P450 3A4, 2C19, and 2D6 was assessed by using commercial kits. Induction of transporters and enzymes was quantified by real-time RT-PCR. Possible aryl hydrocarbon receptor (AhR) activating properties were assessed by a reporter gene assay. Substrate characteristics were evaluated by growth inhibition assays in cells over-expressing P-gp or BCRP. Dovitinib weakly inhibited CYP2C19, CYP3A4, P-gp and OATPs. The strongest inhibition was observed for BCRP (IC50 = 10.3 ± 4.5 μM). Among the genes investigated, dovitinib only induced mRNA expression of CYP1A1, CYP1A2, ABCC3 (coding for multidrug resistance-associated protein 3), and ABCG2 and suppressed mRNA expression of some transporters and drug metabolising enzymes. AhR reporter gene assay demonstrated that dovitinib is an activator of this nuclear receptor. Dovitinib retained its efficacy in cell lines over-expressing P-gp or BCRP. Our analysis indicates that dovitinib will most likely retain its efficacy in tumours over-expressing P-gp or BCRP and gives first evidence that dovitinib might act as a perpetrator drug in pharmacokinetic drug–drug interactions. PMID:25521244

  2. Metabolic activation and drug-induced liver injury: in vitro approaches for the safety risk assessment of new drugs.

    PubMed

    Gómez-Lechón, M José; Tolosa, Laia; Donato, M Teresa

    2016-06-01

    Drug-induced liver injury (DILI) is a significant leading cause of hepatic dysfunction, drug failure during clinical trials and post-market withdrawal of approved drugs. Many cases of DILI are unexpected reactions of an idiosyncratic nature that occur in a small group of susceptible individuals. Intensive research efforts have been made to understand better the idiosyncratic DILI and to identify potential risk factors. Metabolic bioactivation of drugs to form reactive metabolites is considered an initiation mechanism for idiosyncratic DILI. Reactive species may interact irreversibly with cell macromolecules (covalent binding, oxidative damage), and alter their structure and activity. This review focuses on proposed in vitro screening strategies to predict and reduce idiosyncratic hepatotoxicity associated with drug bioactivation. Compound incubation with metabolically competent biological systems (liver-derived cells, subcellular fractions), in combination with methods to reveal the formation of reactive intermediates (e.g., formation of adducts with liver proteins, metabolite trapping or enzyme inhibition assays), are approaches commonly used to screen the reactivity of new molecules in early drug development. Several cell-based assays have also been proposed for the safety risk assessment of bioactivable compounds. Copyright © 2015 John Wiley & Sons, Ltd. PMID:26691983

  3. Strength-Based Assessment of Adolescents Who Abuse Drugs: Implications for Helping High-Risk Youth

    ERIC Educational Resources Information Center

    Cosden, Merith; Panteleakos, Frances; Gutierrez, Lisa; Barazani, Sivan; Gottheil, Elisa

    2004-01-01

    Strength-based assessments were designed to assess more completely the outcomes for youth having academic and behavioral problems in the schools. This approach has gained appeal among those working with adolescents who have serious behavior problems, such as those involved in drug use and related delinquent behavior. Traditional assessment

  4. A new approach to assess drug development performance.

    PubMed

    Rosiello, Alessandro; Dimitri, Nicola; Fiorini, Filippo

    2013-05-01

    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

  5. An informatics approach to assess pediatric pharmacotherapy: design and implementation of a hospital drug utilization system.

    PubMed

    Zuppa, Athena; Vijayakumar, Sundararajan; Jayaraman, Bhuvana; Patel, Dimple; Narayan, Mahesh; Vijayakumar, Kalpana; Mondick, John T; Barrett, Jeffrey S

    2007-09-01

    Drug utilization in the inpatient setting can provide a mechanism to assess drug prescribing trends, efficiency, and cost-effectiveness of hospital formularies and examine subpopulations for which prescribing habits may be different. Such data can be used to correlate trends with time-dependent or seasonal changes in clinical event rates or the introduction of new pharmaceuticals. It is now possible to provide a robust, dynamic analysis of drug utilization in a large pediatric inpatient setting through the creation of a Web-based hospital drug utilization system that retrieves source data from our accounting database. The production implementation provides a dynamic and historical account of drug utilization at the authors' institution. The existing application can easily be extended to accommodate a multi-institution environment. The creation of a national or even global drug utilization network would facilitate the examination of geographical and/or socioeconomic influences in drug utilization and prescribing practices in general. PMID:17656617

  6. Assessment of the Biological Effects of a Multifunctional Nano-Drug-Carrier and Its Encapsulated Drugs.

    PubMed

    Song, Yipeng; Zhao, Ruifang; Hu, Yili; Hao, Fuhua; Li, Ning; Nie, Guangjun; Tang, Huiru; Wang, Yulan

    2015-12-01

    Polymer-nanoparticle-encapsulated doxorubicin (DOX) and paclitaxel (TAX) have the potential for novel therapeutic use against cancer in the clinic. However, the systemic biological effect of the nanoparticle material, namely, methoxypoly(ethylene glycol)-poly(lactide-co-glycolide) (mPEG-PLGA), and its encapsulated drugs have not been fully studied. We have applied NMR-based metabonomics methodology to characterize and analyze the systemic metabolic changes in mice after being exposed to mPEG-PLGA, mPEG-PLGA-encapsulated DOX and TAX (NP-D/T), and their free forms. The study revealed that mPEG-PLGA exposure only induces temporary and slight metabolic alternations and that there are detoxification effects of nanoparticle packed with D/T drugs on the heart when comparing with free-form D/T drugs. Both NP-D/T and their free forms induce a shift in energy metabolism, stimulate antioxidation pathways, and disturb the gut microbial activity of the host. However, mPEG-PLGA packaging can relieve the energy metabolism inhibition and decrease the activation of antioxidation pathways caused by D/T exposure. These findings provide a holistic insight into the biological effect of polymer nanoparticle and nanoparticle-encapsulated drugs. This study also furthers our understanding of the molecular mechanisms involved in the amelioration effects of mPEG-PLGA packaging on the toxicity of the incorporated drugs. PMID:26531143

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

    PubMed

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

    2010-01-01

    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

  8. Developing and evaluating distributions for probabilistic human exposure assessments

    SciTech Connect

    Maddalena, Randy L.; McKone, Thomas E.

    2002-08-01

    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.

  9. Communication Needs Assessment for Distributed Turbine Engine Control

    NASA Technical Reports Server (NTRS)

    Culley, Dennis E.; Behbahani, Alireza R.

    2008-01-01

    Control system architecture is a major contributor to future propulsion engine performance enhancement and life cycle cost reduction. The control system architecture can be a means to effect net weight reduction in future engine systems, provide a streamlined approach to system design and implementation, and enable new opportunities for performance optimization and increased awareness about system health. The transition from a centralized, point-to-point analog control topology to a modular, networked, distributed system is paramount to extracting these system improvements. However, distributed engine control systems are only possible through the successful design and implementation of a suitable communication system. In a networked system, understanding the data flow between control elements is a fundamental requirement for specifying the communication architecture which, itself, is dependent on the functional capability of electronics in the engine environment. This paper presents an assessment of the communication needs for distributed control using strawman designs and relates how system design decisions relate to overall goals as we progress from the baseline centralized architecture, through partially distributed and fully distributed control systems.

  10. How the Probability and Potential Clinical Significance of Pharmacokinetically Mediated Drug-Drug Interactions Are Assessed in Drug Development: Desvenlafaxine as an Example

    PubMed Central

    Nichols, Alice I.; Preskorn, Sheldon H.

    2015-01-01

    Objective: The avoidance of adverse drug-drug interactions (DDIs) is a high priority in terms of both the US Food and Drug Administration (FDA) and the individual prescriber. With this perspective in mind, this article illustrates the process for assessing the risk of a drug (example here being desvenlafaxine) causing or being the victim of DDIs, in accordance with FDA guidance. Data Sources/Study Selection: DDI studies for the serotonin-norepinephrine reuptake inhibitor desvenlafaxine conducted by the sponsor and published since 2009 are used as examples of the systematic way that the FDA requires drug developers to assess whether their new drug is either capable of causing clinically meaningful DDIs or being the victim of such DDIs. In total, 8 open-label studies tested the effects of steady-state treatment with desvenlafaxine (50–400 mg/d) on the pharmacokinetics of cytochrome (CYP) 2D6 and/or CYP 3A4 substrate drugs, or the effect of CYP 3A4 inhibition on desvenlafaxine pharmacokinetics. The potential for DDIs mediated by the P-glycoprotein (P-gp) transporter was assessed in in vitro studies using Caco-2 monolayers. Data Extraction: Changes in area under the plasma concentration-time curve (AUC; CYP studies) and efflux (P-gp studies) were reviewed for potential DDIs in accordance with FDA criteria. Results: Desvenlafaxine coadministration had minimal effect on CYP 2D6 and/or 3A4 substrates per FDA criteria. Changes in AUC indicated either no interaction (90% confidence intervals for the ratio of AUC geometric least-squares means [GM] within 80%–125%) or weak inhibition (AUC GM ratio 125% to < 200%). Coadministration with ketoconazole resulted in a weak interaction with desvenlafaxine (AUC GM ratio of 143%). Desvenlafaxine was not a substrate (efflux ratio < 2) or inhibitor (50% inhibitory drug concentration values > 250 μM) of P-gp. Conclusions: A 2-step process based on FDA guidance can be used first to determine whether a pharmacokinetically mediated interaction occurs and then to assess the potential clinical significance of the DDI. In the case of the drug tested in this series of studies, the potential for clinically meaningful DDIs mediated by CYP 2D6, CYP 3A4, or P-gp was found to be low. PMID:26445693

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

    ERIC Educational Resources Information Center

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

    2012-01-01

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

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

    ERIC Educational Resources Information Center

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

    2010-01-01

    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…

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

    ERIC Educational Resources Information Center

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

    2012-01-01

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

  14. Evaluation of a procedure to assess the adverse effects of illicit drugs.

    PubMed

    van Amsterdam, J G C; Best, W; Opperhuizen, A; de Wolff, F A

    2004-02-01

    The assessment procedure of new synthetic illicit drugs that are not documented in the UN treaty on psychotropic drugs was evaluated using a modified Electre model. Drugs were evaluated by an expert panel via the open Delphi approach, where the written score was discussed on 16 items, covering medical, health, legal, and criminalistic issues of the drugs. After this face-to-face discussion the drugs were scored again. Taking the assessment of ketamine as an example, it appeared that each expert used its own scale to score, and that policymakers do not score deviant from experts trained in the medical-biological field. Of the five drugs evaluated by the panel, p-methoxy-metamphetamine (PMMA), gamma-hydroxybutyric acid (GHB), and 4-methylthio-amphetamine (MTA) were assessed as more adverse than ketamine and psilocine and psilocybine-containing mushrooms. Whereas some experts slightly adjusted during the assessment procedure their opinion on ketamine and PMMA, the opinion on mushrooms was not affected by the discussion held between the two scoring rounds. All experts rank the five drugs in a similar way on the adverse effect scale i.e., concordance scale of the Electre model, indicating unanimity in the expert panel with respect to the risk classification of these abused drugs. PMID:14746774

  15. Assessing dietary intake of drug abusing Hispanic adults with and without HIV infection

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Drug abuse is an important risk factor for Human Immunodeficiency Virus (HIV) among Hispanics in the Northeastern United States and both drug abuse and HIV are associated with nutritional deficiencies. The selection of a dietary assessment method most appropriate for Hispanic adults with/without HIV...

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

    ERIC Educational Resources Information Center

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

    2006-01-01

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

  17. Assessment of cytochrome p450 enzyme inhibition and inactivation in drug discovery and development.

    PubMed

    Nettleton, David O; Einolf, Heidi J

    2011-01-01

    Evaluation of the potential of a drug candidate to inhibit or inactivate cytochrome P450 (CYP) enzymes remains an important part of pharmaceutical drug Discovery and Development programs. CYP enzymes are considered to be one of the most important enzyme families involved in the metabolic clearance of the vast majority of prescribed drugs. Clinical drug-drug interactions (DDI) involving inhibition or time-dependent inactivation of these enzymes can result in dangerous side effects resulting from reduced clearance/increased exposure of the drug being affected (the 'victim' drug). In this regard, pharmaceutical companies have become quite vigilant in mitigating CYP inhibition/inactivation liabilities of drug candidates early in Discovery including continued risk assessment throughout Development. In this review, common strategies and decision making processes for the assessment of DDI risk in the different stages of pharmaceutical development are discussed. In addition, in vitro study designs, analysis, and interpretation of CYP inhibition and inactivation data are described in stage appropriate context. The in vitro tools and knowledge available now enable the Discovery Chemist to place the potential CYP DDI liability of a drug candidate into perspective and to aid in the optimization of chemical drug design to further mitigate this risk. PMID:21320066

  18. Nutrition and Drug/Alcohol Rehabilitation: A Needs Assessment.

    ERIC Educational Resources Information Center

    Madden, Judith; McIntosh, Elaine

    1987-01-01

    Diet histories of clients entering a drug/alcohol treatment facility showed need for improved eating habits. At least 50% had customarily low intakes of several nutrients plus calories. Nutritional adequacy improved during treatment, as did caloric excesses. Clients needed nutrition education. (Author/NB)

  19. 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...

  20. Cold air distribution in office buildings: Technology assessment for California

    SciTech Connect

    Bauman, F.S.; LaBege, P. . Center for Environmental Design Research); Borgers, T. . Dept. of Chemistry); Gadgil, A.J. )

    1992-06-01

    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.

  1. Cold Air Distribution in Office Buildings: Technology Assessment for California

    SciTech Connect

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

    1992-06-01

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

  2. Risk Assessment of Drug Management Process in Women Surgery Department of Qaem Educational Hospital (QEH) Using HFMEA Method (2013).

    PubMed

    Khani-Jazani, Reza; Molavi-Taleghani, Yasamin; Seyedin, Hesam; Vafaee-Najar, Ali; Ebrahimipour, Hossein; Pourtaleb, Arefeh

    2015-01-01

    Evaluation and improvement of drug management process are essential for patient safety. The present study was performed whit the aim of assessing risk of drug management process in Women Surgery Department of QEH using HFMEA method in 2013. A mixed method was used to analyze failure modes and their effects with HFMEA. To classify failure modes; nursing errors in clinical management model, for classifying factors affecting error; approved model by the UK National Health System, and for determining solutions for improvement; Theory of Inventive Problem Solving, were used. 48 failure modes were identified for 14 sub-process of five steps drug management process. The frequency of failure modes were as follow :35.3% in supplying step, 20.75% in prescription step, 10.4% in preparing step, 22.9% in distribution step and 10.35% in follow up and monitoring step. Seventeen failure modes (35.14%) were considered as non-acceptable risk (hazard score≥ 8) and were transferred to decision tree. Among 51 Influencing factors, the most common reasons for error were related to environmental factors (21.5%), and the less common reasons for error were related to patient factors (4.3%). HFMEA is a useful tool to evaluating, prioritization and analyzing failure modes in drug management process. Revision drug management process based focus-PDCA, assessing adverse drug reactions (ADR), USE patient identification bracelet, holding periodical pharmaceutical conferences to improve personnel knowledge, patient contribution in drug therapy; are performance solutions which were placed in work order. PMID:25901157

  3. Risk Assessment of Drug Management Process in Women Surgery Department of Qaem Educational Hospital (QEH) Using HFMEA Method (2013)

    PubMed Central

    khani-Jazani, Reza; Molavi-Taleghani, Yasamin; Seyedin, Hesam; Vafaee-Najar, Ali; Ebrahimipour, Hossein; Pourtaleb, Arefeh

    2015-01-01

    Evaluation and improvement of drug management process are essential for patient safety. The present study was performed whit the aim of assessing risk of drug management process in Women Surgery Department of QEH using HFMEA method in 2013. A mixed method was used to analyze failure modes and their effects with HFMEA. To classify failure modes; nursing errors in clinical management model, for classifying factors affecting error; approved model by the UK National Health System, and for determining solutions for improvement; Theory of Inventive Problem Solving, were used. 48 failure modes were identified for 14 sub-process of five steps drug management process. The frequency of failure modes were as follow :35.3% in supplying step, 20.75% in prescription step, 10.4% in preparing step, 22.9% in distribution step and 10.35% in follow up and monitoring step. Seventeen failure modes (35.14%) were considered as non-acceptable risk (hazard score? 8) and were transferred to decision tree. Among 51 Influencing factors, the most common reasons for error were related to environmental factors (21.5%), and the less common reasons for error were related to patient factors (4.3%). HFMEA is a useful tool to evaluating, prioritization and analyzing failure modes in drug management process. Revision drug management process based focus-PDCA, assessing adverse drug reactions (ADR), USE patient identification bracelet, holding periodical pharmaceutical conferences to improve personnel knowledge, patient contribution in drug therapy; are performance solutions which were placed in work order. PMID:25901157

  4. Evolution of the Food and Drug Administration approach to liver safety assessment for new drugs: current status and challenges.

    PubMed

    Senior, John R

    2014-11-01

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

  5. Assessing introduction risk using species’ rank-abundance distributions

    PubMed Central

    Chan, Farrah T.; Bradie, Johanna; Briski, Elizabeta; Bailey, Sarah A.; Simard, Nathalie; MacIsaac, Hugh J.

    2015-01-01

    Mixed-species assemblages are often unintentionally introduced into new ecosystems. Analysing how assemblage structure varies during transport may provide insights into how introduction risk changes before propagules are released. Characterization of introduction risk is typically based on assessments of colonization pressure (CP, the number of species transported) and total propagule pressure (total PP, the total abundance of propagules released) associated with an invasion vector. Generally, invasion potential following introduction increases with greater CP or total PP. Here, we extend these assessments using rank-abundance distributions to examine how CP : total PP relationships change temporally in ballast water of ocean-going ships. Rank-abundance distributions and CP : total PP patterns varied widely between trans-Atlantic and trans-Pacific voyages, with the latter appearing to pose a much lower risk than the former. Responses also differed by taxonomic group, with invertebrates experiencing losses mainly in total PP, while diatoms and dinoflagellates sustained losses mainly in CP. In certain cases, open-ocean ballast water exchange appeared to increase introduction risk by uptake of new species or supplementation of existing ones. Our study demonstrates that rank-abundance distributions provide new insights into the utility of CP and PP in characterizing introduction risk. PMID:25473007

  6. In silico assessment of kinetics and state dependent binding properties of drugs causing acquired LQTS.

    PubMed

    Lee, William; Mann, Stefan A; Windley, Monique J; Imtiaz, Mohammad S; Vandenberg, Jamie I; Hill, Adam P

    2016-01-01

    The Kv11.1 or hERG potassium channel is responsible for one of the major repolarising currents (IKr) in cardiac myocytes. Drug binding to hERG can result in reduction in IKr, action potential prolongation, acquired long QT syndrome and fatal cardiac arrhythmias. The current guidelines for pre-clinical assessment of drugs in development is based on the measurement of the drug concentration that causes 50% current block, i.e., IC50. However, drugs with the same apparent IC50 may have very different kinetics of binding and unbinding, as well as different affinities for the open and inactivated states of Kv11.1. Therefore, IC50 measurements may not reflect the true risk of drug induced arrhythmias. Here we have used an in silico approach to test the hypothesis that drug binding kinetics and differences in state-dependent affinity will influence the extent of cardiac action potential prolongation independent of apparent IC50 values. We found, in general that drugs with faster overall kinetics and drugs with higher affinity for the open state relative to the inactivated state cause more action potential prolongation. These characteristics of drug-hERG interaction are likely to be more arrhythmogenic but cannot be predicted by IC50 measurement alone. Our results suggest that the pre-clinical assessment of Kv11.1-drug interactions should include descriptions of the kinetics and state dependence of drug binding. Further, incorporation of this information into sophisticated in silico models should be able to better predict arrhythmia risk and therefore more accurately assess safety of new drugs in development. PMID:26713558

  7. Causality assessment for suspected DILI during clinical phases of drug development.

    PubMed

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

    2014-11-01

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

  8. Predicting Drug Extraction in the Human Gut Wall: Assessing Contributions from Drug Metabolizing Enzymes and Transporter Proteins using Preclinical Models.

    PubMed

    Peters, Sheila Annie; Jones, Christopher R; Ungell, Anna-Lena; Hatley, Oliver J D

    2016-06-01

    Intestinal metabolism can limit oral bioavailability of drugs and increase the risk of drug interactions. It is therefore important to be able to predict and quantify it in drug discovery and early development. In recent years, a plethora of models-in vivo, in situ and in vitro-have been discussed in the literature. The primary objective of this review is to summarize the current knowledge in the quantitative prediction of gut-wall metabolism. As well as discussing the successes of current models for intestinal metabolism, the challenges in the establishment of good preclinical models are highlighted, including species differences in the isoforms; regional abundances and activities of drug metabolizing enzymes; the interplay of enzyme-transporter proteins; and lack of knowledge on enzyme abundances and availability of empirical scaling factors. Due to its broad specificity and high abundance in the intestine, CYP3A is the enzyme that is frequently implicated in human gut metabolism and is therefore the major focus of this review. A strategy to assess the impact of gut wall metabolism on oral bioavailability during drug discovery and early development phases is presented. Current gaps in the mechanistic understanding and the prediction of gut metabolism are highlighted, with suggestions on how they can be overcome in the future. PMID:26895020

  9. Industrial Power Distribution System Reliability Assessment utilizing Markov Approach

    NASA Astrophysics Data System (ADS)

    Guzman-Rivera, Oscar R.

    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.

  10. In Vivo Assessment of Drug Efficacy against Mycobacterium abscessus Using the Embryonic Zebrafish Test System

    PubMed Central

    Bernut, Audrey; Le Moigne, Vincent; Lesne, Tiffany; Lutfalla, Georges; Herrmann, Jean-Louis

    2014-01-01

    Mycobacterium abscessus is responsible for a wide spectrum of clinical syndromes and is one of the most intrinsically drug-resistant mycobacterial species. Recent evaluation of the in vivo therapeutic efficacy of the few potentially active antibiotics against M. abscessus was essentially performed using immunocompromised mice. Herein, we assessed the feasibility and sensitivity of fluorescence imaging for monitoring the in vivo activity of drugs against acute M. abscessus infection using zebrafish embryos. A protocol was developed where clarithromycin and imipenem were directly added to water containing fluorescent M. abscessus-infected embryos in a 96-well plate format. The status of the infection with increasing drug concentrations was visualized on a spatiotemporal level. Drug efficacy was assessed quantitatively by measuring the index of protection, the bacterial burden (CFU), and the number of abscesses through fluorescence measurements. Both drugs were active in infected embryos and were capable of significantly increasing embryo survival in a dose-dependent manner. Protection from bacterial killing correlated with restricted mycobacterial growth in the drug-treated larvae and with reduced pathophysiological symptoms, such as the number of abscesses within the brain. In conclusion, we present here a new and efficient method for testing and compare the in vivo activity of two clinically relevant drugs based on a fluorescent reporter strain in zebrafish embryos. This approach could be used for rapid determination of the in vivo drug susceptibility profile of clinical isolates and to assess the preclinical efficacy of new compounds against M. abscessus. PMID:24798271

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

    PubMed Central

    Rawlings, Neil D.

    2006-01-01

    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. PMID:17173540

  12. Assessing the distribution of the Argentine ant using physiological data

    NASA Astrophysics Data System (ADS)

    Abril, Sílvia; Roura-Pascual, Núria; Oliveras, Jordi; Gómez, Crisanto

    2009-09-01

    To address the lack of physiological approaches in current models assessing the potential distribution of the Argentine ant, we used data on brood development from distinct sources to evaluate a series of degree-day models for Catalonia (NE Iberian Peninsula), and data on the brood survival and oviposition rates to develop a worker production model. The degree-day model generated using data from Newell and Barber (1913) and Benois (1973) indicated that the number of degree-days required for the complete development from egg to adult worker was 445.4 degree-days above a threshold of 15.9 °C, while the model calibrated using data from Abril et al. (2008, in press) suggested 599.5 degree-days above 18.4 °C. Comparisons between the degree-day model predictions and the currently known distribution of the Argentine ant suggested that the one generated using data from Newell and Barber (1913) and Benois (1973) overestimated the presence of the species, while the one calibrated using data from Abril et al. (2008; in press) underestimated it. On the other hand, the predicted daily net production of Argentine ant workers generated by the worker production model predicted more accurately the distribution of the Argentine ant than the degree-day models. Our results show the utility of incorporating physiological data in models to assess the distribution limits of the Argentine ant, which up to date have taken little account of the physiological needs of the species in terms of its establishment and dispersion in its introduced ranges.

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

    PubMed Central

    Isbister, Geoffrey K; Page, Colin B

    2013-01-01

    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

  14. Clinical assessment of drug-drug interactions of tasimelteon, a novel dual melatonin receptor agonist.

    PubMed

    Ogilvie, Brian W; Torres, Rosarelis; Dressman, Marlene A; Kramer, William G; Baroldi, Paolo

    2015-09-01

    Tasimelteon ([1R-trans]-N-[(2-[2,3-dihydro-4-benzofuranyl] cyclopropyl) methyl] propanamide), a novel dual melatonin receptor agonist that demonstrates specificity and high affinity for melatonin receptor types 1 and 2 (MT1 and MT2 receptors), is the first treatment approved by the US Food and Drug Administration for Non-24-Hour Sleep-Wake Disorder. Tasimelteon is rapidly absorbed, with a mean absolute bioavailability of approximately 38%, and is extensively metabolized primarily by oxidation at multiple sites, mainly by cytochrome P450 (CYP) 1A2 and CYP3A4/5, as initially demonstrated by in vitro studies and confirmed by the results of clinical drug-drug interactions presented here. The effects of strong inhibitors and moderate or strong inducers of CYP1A2 and CYP3A4/5 on the pharmacokinetics of tasimelteon were evaluated in humans. Coadministration with fluvoxamine resulted in an approximately 6.5-fold increase in tasimelteon's area under the curve (AUC), whereas cigarette smoking decreased tasimelteon's exposure by approximately 40%. Coadministration with ketoconazole resulted in an approximately 54% increase in tasimelteon's AUC, whereas rifampin pretreatment resulted in a decrease in tasimelteon's exposure of approximately 89%. PMID:25851638

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

    PubMed

    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

    2013-03-01

    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

  16. Informed toxicity assessment in drug discovery: systems-based toxicology.

    PubMed

    Mayne, James T; Ku, Warren W; Kennedy, Scott P

    2006-01-01

    Technological advances in the biological, chemical and in silico sciences have transformed many scientific disciplines, including toxicology. A vast new palate of toxicity testing tools is now available to investigators, enabling the generation of enormous amounts of data using only small amounts of test sample and at relatively low cost. In addition to these tools, the pharmaceutical industry has an urgent need for toxicity testing earlier in the process, based on the recognition that safety issues are the single largest cause of drug candidate attrition from development portfolios and the marketplace. However, along with the opportunity provided by new testing tools comes the dilemma of deciding which tools to use and, equally as important, when and why to use them. It may well be unwise to apply a new toxicity test or screening system simply because one can, as both false positive and false negative outcomes can quickly negate the value of a toxicity test system and may even have a net negative impact on drug discovery productivity. This can be true even of test systems that are considered to be 'validated' in the traditional sense. How then is an investigator or drug discovery organization to decide which of the new tools to use, and when to use them? Proposed herein is a strategy for identifying high-value toxicity testing systems and strategies based on program knowledge and informed decision-making. The decision to apply a certain toxicity testing system in this strategy is informed by knowledge of the pharmacological target, the chemical features of molecules active at the pharmacological target, and existing public domain or institutional learning. This 'fit-for-purpose' approach limits non-targeted or 'uninformed' toxicity screening to only those few test systems with high specificity, strong outcome concordance and molecular relevance to frequently encountered toxicity risks (eg, genotoxicity). Additional toxicity testing and screening is then conducted to address specific known or potential toxicity risks, based on existing knowledge of the target pharmacology and secondary pharmacology or chemical attributes with known or suspect risk, and by active 'interrogation' of both the target and active chemical moieties during the drug discovery process. This model for toxicity testing decision-making is illustrated by two case studies from recent experience. PMID:16445119

  17. Genetic diversity of Plasmodium falciparum and distribution of drug resistance haplotypes in Yemen

    PubMed Central

    2013-01-01

    Background Despite evident success of malaria control in many sites in the Arabian Peninsula, malaria remains endemic in a few spots, in Yemen and south-west of Saudi Arabia. In addition to local transmission, imported malaria sustains an extra source of parasites that can challenge the strengths of local control strategies. This study examined the genetic diversity of Plasmodium falciparum in Yemen and mutations of drug resistant genes, to elucidate parasite structure and distribution of drug resistance genotypes in the region. Methods Five polymorphic loci (MSP-2, Pfg377 and three microsatellites on chromosome 8) not involved in anti-malarial drug resistance, and four drug resistant genes (pfcrt, pfmdr1, dhfr and dhps) were genotyped in 108 P. falciparum isolates collected in three sites in Yemen: Dhamar, Hodeidah and Taiz. Results High diversity was seen in non-drug genes, pfg377 (He = 0.66), msp-2 (He = 0.80) and three microsatellites on chr 8, 7.7 kb (He = 0.88), 4.3 kb (He = 0.77) and 0.8 kb (He = 0.71). There was a high level of mixed-genotype infections (57%), with an average 1.8 genotypes per patient. No linkage disequilibrium was seen between drug resistant genes and the non-drug markers (p < 0.05). Genetic differentiation between populations was low (most pair-wise FST values <0.03), indicating extensive gene flow between the parasites in the three sites. There was a high prevalence of mutations in pfmdr1, pfcrt and dhfr; with four mutant pfmdr1 genotypes (NFCDD[57%], NFSND[21%], YFCDD[13%] and YFSND[8% ]), two mutant pfcrt genotypes (CVIET[89%] and SVMNT[4%]) and one mutant dhfr genotype (ICNI[53.7%]). However, no dhps mutations were detected. Conclusion The high diversity of P. falciparum in Yemen is indicative of a large parasite reservoir, which represents a challenge to control efforts. The presence of two distinct pfcrt genotype, CVIET and SVMNT, suggests that chloroquine resistance can possibly be related to a migratory path from Africa and Asia. The absence of the triple mutant dhfr genotype (IRN) and dhps mutations supports the use of artesunate + sulphadoxine-pyrimethamine as first-line therapy. However, the prevalent pfmdr1 genotype NFSND [21%] has previously been associated with tolerance/resistance response to artemisinin combination therapy (ACT). Regular surveys are, therefore, important to monitor spread of pfmdr1 and dhfr mutations and response to ACT. PMID:23855834

  18. Assessment of simvastatin niosomes for pediatric transdermal drug delivery.

    PubMed

    Zidan, Ahmed S; Hosny, Khaled M; Ahmed, Osama A A; Fahmy, Usama A

    2016-06-01

    The prevalence of childhood dyslipidemia increases and is considered as an important risk factor for the incidence of cardiovascular disease in the adulthood. To improve dosing accuracy and facilitate the determination of dosing regimens in function of the body weight, the proposed study aims at preparing transdermal niosomal gels of simvastatin as possible transdermal drug delivery system for pediatric applications. Twelve formulations were prepared to screen the influence of formulation and processing variables on critical niosomal characteristics. Nano-sized niosomes with 0.31 μm number-weighted size displayed highest simvastatin release rate with 8.5% entrapment capacity. The niosomal surface coverage by negative charges was calculated according to Langmuir isotherm with n = 0.42 to suggest that the surface association was site-independent, probably producing surface rearrangements. Hypolipidemic activities after transdermal administration of niosomal gels to rats showed significant reduction in cholesterol and triglyceride levels while increasing plasma high-density lipoproteins concentration. Bioavailability estimation in rats revealed an augmentation in simvastatin bioavailability by 3.35 and 2.9 folds from formulation F3 and F10, respectively, compared with oral drug suspension. Hence, this transdermal simvastatin niosomes not only exhibited remarkable potential to enhance its bioavailability and hypolipidemic activity but also considered a promising pediatric antihyperlipidemic formulation. PMID:25386740

  19. Drug Abuse Assessment, Program Planning and Resource Development in the Black Community.

    ERIC Educational Resources Information Center

    Gunn, Karen S.

    This paper presents a needs assessment project developed to establish drug-related services in a small black community. A literature review reveals the influence of social issues relevant to the population on research methodology, program planning, and social action. The convergent analysis approach used in the needs assessment is explained and…

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

    ERIC Educational Resources Information Center

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

    2007-01-01

    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

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

    ERIC Educational Resources Information Center

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

    2011-01-01

    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

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

    ERIC Educational Resources Information Center

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

    2011-01-01

    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…

  3. Modifying the intensity distribution by assessing the reliability

    NASA Astrophysics Data System (ADS)

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

    2013-12-01

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

  4. Assessment of Web-Based Consumer Reviews as a Resource for Drug Performance

    PubMed Central

    Adusumalli, Swarnaseetha; Lee, HueyTyng; Hoi, Qiangze; Koo, Si-Lin; Tan, Iain Beehuat

    2015-01-01

    Background Some health websites provide a public forum for consumers to post ratings and reviews on drugs. Drug reviews are easily accessible and comprehensible, unlike clinical trials and published literature. Because the public increasingly uses the Internet as a source of medical information, it is important to know whether such information is reliable. Objective We aim to examine whether Web-based consumer drug ratings and reviews can be used as a resource to compare drug performance. Methods We analyzed 103,411 consumer-generated reviews on 615 drugs used to treat 249 disease conditions from the health website WebMD. Statistical analysis identified 427 drug pairs from 24 conditions for which two drugs treating the same condition had significantly and substantially different satisfaction ratings (with at least a half-point difference between Web-based ratings and P<.01). PubMed and Google Scholar were searched for publications that were assessed for concordance with findings online. Results Scientific literature was found for 77 out of the 427 drug pairs and compared to findings online. Nearly two-thirds (48/77, 62%) of the online drug trends with at least a half-point difference in online ratings were supported by published literature (P=.02). For a 1-point online rating difference, the concordance rate increased to 68% (15/22) (P=.07). The discrepancies between scientific literature and findings online were further examined to obtain more insights into the usability of Web-based consumer-generated reviews. We discovered that (1) drugs with FDA black box warnings or used off-label were rated poorly in Web-based reviews, (2) drugs with addictive properties were rated higher than their counterparts in Web-based reviews, and (3) second-line or alternative drugs were rated higher. In addition, Web-based ratings indicated drug delivery problems. If FDA black box warning labels are used to resolve disagreements between publications and online trends, the concordance rate increases to 71% (55/77) (P<.001) for a half-point rating difference and 82% (18/22) for a 1-point rating difference (P=.002). Our results suggest that Web-based reviews can be used to inform patients’ drug choices, with certain caveats. Conclusions Web-based reviews can be viewed as an orthogonal source of information for consumers, physicians, and drug manufacturers to assess the performance of a drug. However, one should be cautious to rely solely on consumer reviews as ratings can be strongly influenced by the consumer experience. PMID:26319108

  5. The feasibility of pharmacy-based naloxone distribution interventions: a qualitative study with injection drug users and pharmacy staff in Rhode Island.

    PubMed

    Zaller, Nickolas D; Yokell, Michael A; Green, Traci Craig; Gaggin, Julia; Case, Patricia

    2013-06-01

    This study analyzed qualitative data from a Rapid Policy Assessment and Response project to assess the feasibility of a potential pharmacy-based naloxone intervention to reduce opioid overdose mortality among injection drug users (IDUs). We conducted in-depth, semistructured interviews with 21 IDUs and 21 pharmacy staff (pharmacists and technicians). Although most participants supported the idea of a pharmacy-based naloxone intervention, several barriers were identified, including misinformation about naloxone, interpersonal relationships between IDUs and pharmacy staff, and costs of such an intervention. Implications for future pharmacy-based overdose prevention interventions for IDUs, including pharmacy-based naloxone distribution, are considered. The study's limitations are noted. PMID:23750660

  6. Anti-angiogenesis or pro-angiogenesis for cancer treatment: focus on drug distribution

    PubMed Central

    Huang, Dongsheng; Lan, Huanrong; Liu, Fanlong; Wang, Shibing; Chen, Xiaoyi; Jin, Ketao; Mou, Xiaozhou

    2015-01-01

    Enhancing chemotherapy delivery to tumors, improving tumor growth control, reducing metastasis, and increasing survival are all critical objectives of improved cancer therapy. One of the obstacles to the success of anticancer therapies is related to the inefficient distribution of drugs to tumor cells. To be effective, chemotherapeutics must reach a concentration in cancer cells that is sufficient to inhibit its targets. In the past years, the vascular normalization theory has gained widespread acceptance for explaining additional antitumor effects of inhibitors of vascular endothelial growth factor (VEGF) signaling, when combined with chemotherapeutics. Vascular normalization is a strategy to enhance the antitumor effects of chemotherapeutics, but this is time and dose dependent and therefore difficult to implement clinically. Thus, alternative strategies that overcome these issues are needed. Accumulating scientific data demonstrate an alternative approach called “vascular promotion therapy” can increase chemotherapeutics delivery and intracellular uptake of the drug and reduces hypoxia by increasing tumor blood vessel density, blood flow, leakiness, and dilation, which leads to reduced cancer growth and metastasis. In this article, we first summarize the structural and functional abnormalities of the tumor microvasculature to highlight the importance of this phenomenon for chemotherapeutics distribution. Next, we summarize the limitations of anti-angiogenic strategy in cancer treatment, discuss some key prototypical underlying mechanisms of vascular normalization and initial clinical evidence of vascular promotion therapy, and speculate on the clinical potential of anticoagulation as a novel paradigm to improve cancer treatment. PMID:26309490

  7. Drug Use Prevention Data, Missed Assessments and Survival Analysis.

    ERIC Educational Resources Information Center

    Bacik, Jennifer M.; Murphy, Susan A.; Anthony, James C.

    1998-01-01

    Two missing data procedures, both of which allow the subsequent use of discrete time survival analysis, are compared, and each is applied to each of two data sets. Results illustrate the advantages of multiple imputation over artificial censoring as an approach when there are intermittent missed assessments (missing data). (SLD)

  8. Multivariate Generalized Beta Distributions with Applications to Utility Assessment.

    ERIC Educational Resources Information Center

    Libby, David L.; Novick, Melvin R.

    1982-01-01

    Two multivariate probability distributions, a generalized beta distribution and a generalized F distribution, are derived. Formulas for the moments of these distributions are given and an example of the bivariate generalized beta is presented. (Author/JKS)

  9. Drugs.

    ERIC Educational Resources Information Center

    Hurst, Hunter, Ed.; And Others

    1984-01-01

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

  10. Assessment of Adverse Drug Reactions Based on Spontaneous Signals at Secondary Care Public Hospital

    PubMed Central

    Ponnusankar, S.; Tejaswini, M.; Chaitanya, M.

    2015-01-01

    Adverse drug reactions are considered to be among the leading causes of morbidity and mortality. Approximately 5-25% of hospital admissions are due to adverse drug reactions and 6-15% of hospitalized patients experience serious adverse drug reactions, causing significant prolongation of hospital stay. Thus this study was aimed at determining adverse drug reactions by conducting spontaneous reporting in secondary care Govt. District Head Quarters Hospital at Ooty. A prospective Spontaneous Adverse Drug Reaction reporting study was conducted over a period of 12 months from July 2012 to June 2013. The assessment, categorization, causality, severity and preventability were assessed using standard criteria. A total of 47 suspected adverse drug reactions were reported during the study period. Over all incidences was 1.29% among the study population. Antibiotics (31.91%) were the class of drug most commonly involved, while ciprofloxacin (14.89%) was the most frequently reported. Type H (Hypersensitivity) reactions (51.06%) accounted for majority of the reports and a greater share of the adverse drug reactions are probable (89.36%) based on causality assessment. Mild reactions accounted 82.97% based on modified Hartwig and Siegel severity scale. In 76.59% of the reports, the reaction was considered to be preventable based on Schumock and Thornton preventability scale. The implementation of monitoring based on spontaneous reporting will be useful for the detection and evaluation is associated with increase in morbidity and duration of hospitalization. This study also has established the vital role of clinical pharmacist in the adverse drug reaction monitoring program. PMID:26664067

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

    ERIC Educational Resources Information Center

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

    2006-01-01

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

  12. Performance Assessment of OVERFLOW on Distributed Computing Environment

    NASA Technical Reports Server (NTRS)

    Djomehri, M. Jahed; Rizk, Yehia M.

    2000-01-01

    The aerodynamic computer code, OVERFLOW, with a multi-zone overset grid feature, has been parallelized to enhance its performance on distributed and shared memory paradigms. Practical application benchmarks have been set to assess the efficiency of code's parallelism on high-performance architectures. The code's performance has also been experimented with in the context of the distributed computing paradigm on distant computer resources using the Information Power Grid (IPG) toolkit, Globus. Two parallel versions of the code, namely OVERFLOW-MPI and -MLP, have developed around the natural coarse grained parallelism inherent in a multi-zonal domain decomposition paradigm. The algorithm invokes a strategy that forms a number of groups, each consisting of a zone, a cluster of zones and/or a partition of a large zone. Each group can be thought of as a process with one or multithreads assigned to it and that all groups run in parallel. The -MPI version of the code uses explicit message-passing based on the standard MPI library for sending and receiving interzonal boundary data across processors. The -MLP version employs no message-passing paradigm; the boundary data is transferred through the shared memory. The -MPI code is suited for both distributed and shared memory architectures, while the -MLP code can only be used on shared memory platforms. The IPG applications are implemented by the -MPI code using the Globus toolkit. While a computational task is distributed across multiple computer resources, the parallelism can be explored on each resource alone. Performance studies are achieved with some practical aerodynamic problems with complex geometries, consisting of 2.5 up to 33 million grid points and a large number of zonal blocks. The computations were executed primarily on SGI Origin 2000 multiprocessors and on the Cray T3E. OVERFLOW's IPG applications are carried out on NASA homogeneous metacomputing machines located at three sites, Ames, Langley and Glenn. Plans for the future will exploit the distributed parallel computing capability on various homogeneous and heterogeneous resources and large scale benchmarks. Alternative IPG toolkits will be used along with sophisticated zonal grouping strategies to minimize the communication time across the computer resources.

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

    PubMed Central

    Bruce-Chwatt, L. J.

    1959-01-01

    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. PMID:13805135

  14. Development and psychometric evaluation of scales that assess stigma associated with illicit drug users.

    PubMed

    Palamar, Joseph J; Kiang, Mathew V; Halkitis, Perry N

    2011-01-01

    This study established validity evidence for scales that assess perceived public stigma and stigmatization of illicit drug use. These concepts were measured with respect to five commonly used drugs: marijuana, powder cocaine, ecstasy, and nonmedical use of opioids and amphetamine. Data were collected from a diverse sample of 1,048 emerging adults in New York City in 2009. Exploratory and confirmatory factor analyses suggested two distinct factors, which were inversely related to exposure to users and recent use of each drug. These measures demonstrated good criterion, construct, and incremental validity and effectiveness in analyzing predictors of use. Study limitations were discussed. PMID:21767076

  15. Dual isotope technique for in vivo quantitative assessment of intra-arterial(IA) drug delivery to hepatic metastases

    SciTech Connect

    Line, B.R.; Harper, G.; Armstrong, M.; Ruckdeschel, J.

    1984-01-01

    Qualitative Tc-99m macro-aggregated albumin (MAA) scans can evaluate both IA catheter placement and regional hepatic perfusion. The authors report a new, dual isotope technique for the quantitative assessment of IA drug delivery to hepatic metastases (mets). Four patients (pts) with colon cancer metastatic to liver were treated for two week cycles with continuous IA 5-fluoro-2'-deoxyuridine (FUDR) infusion via an implantable pump (INFUSAID) at a dose of 0.1 to 0.3 mg/kg/d. At four week intervals each patient had quantitative hepatic imaging studies with Tc-99m SC to estimate met volume followed immediately by Tc-99m MAA through the pump to map drug distribution. MAA was distinguished from SC by computer subtraction and a distribution index (DI) expressed as the ratio of MAA in tumor vs normal tissues was determined. The lesion volume and DI were used to calculate the amount of FUDR delivered to tumor during treatment. Marked variability was found in the DI and chemotherapy delivered to tumor tissue between and within different pts. Pretreatment DIs were estimated to be 54%, 20%, 15%, and 1%. One pt demonstrated a drop in relative blood flow from a pretreatment DI of 54% to 49% at 4 weeks, and 37% at 8 weeks. The pt with the least DI (1.1%-5.0%) had the largest tumor burden (900 gm) and the smallest FUDR tumor delivery (0.2-1.1 ng/gm/min). The pt with the smallest tumor burden (80 gm) had the greatest FUDR delivery (14.8-22.1 ng/gm/min). This imaging technique provides quantitative estimates of tumor size and relative perfusion which can evaluate drug delivery to tumor and refine the assessment of both antitumor drug activity and toxicity of IA hepatic chemotherapy.

  16. Assessment of inhibition of porcine hepatic cytochrome P450 enzymes by 48 commercial drugs.

    PubMed

    Hu, Steven X; Mazur, Chase A; Feenstra, Kenneth L; Lorenz, Julie K; Merritt, Dawn A

    2016-05-01

    Drug interactions due to inhibition of hepatic cytochrome P450 (CYP450) enzymes are not well understood in veterinary medicine. Forty-eight commercial porcine medicines were selected to evaluate their potential inhibition on porcine hepatic CYP450 enzymes at their commercial doses and administration routes. Those drugs were first assessed through a single point inhibitory assay at 3 µM in porcine liver microsomes for six specific CYP450 metabolisms (phenacetin o-deethylation, coumarin 7-hydroxylation, tolbutamide 4-hydroxylation, bufuralol 1-hydroxylation, chlorozoxazone 6-hydroxylation and midazolam 1'-hydroxylation). When the inhibition was > 10% in the single point inhibitory assay, IC50 values (inhibitory concentrations that decrease biotransformation of selected substrate by 50%) were determined. Overall, 17 drugs showed in vitro inhibition on one or more porcine hepatic CYP450 metabolisms with different IC50 values. The potential in vivo porcine hepatic CYP450 inhibition by those drugs was assessed by combining the in vitro data and in vivo Cmax (maximum plasma concentrations from pharmacokinetic studies of the porcine medicines at their commercial doses and administration routes). Three drugs showed high potential inhibition to one or two porcine hepatic CYP450 isoforms at their commercial doses and administration routes, while seven drugs had medium risk and seven had low risk of such in vivo inhibition. These data are useful to prevent potential drug interactions in veterinary medical practice. PMID:27053015

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

    PubMed

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

    2014-11-01

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

  18. [Requirements for drug approval and additional benefits assessment : Regulatory aspects and experiences].

    PubMed

    Broich, K; Löbker, W; Schulte, A; Beinlich, P; Müller, T

    2016-04-01

    The early assessment of benefits of newly approved drugs with novel active substances or new applications, which came into force on 1 January 2011 still represents a challenge to all parties involved. This article highlights the definitions, regulatory requirements and interaction between drug marketing approval and early assessment of benefits in Germany. The constellation of an extensively harmonized European and even international drug authorization process with a predominantly national regulation of drug reimbursement situation inevitably causes friction, which could be markedly reduced through early joint advisory discussions during the planning phase for pivotal clinical trials. During the year 2015 the Federal Institute for Drugs and Medical Devices (BfArM) carried out 300 scientific advice procedures of which 34 were concerned with applications in the field of indications for the central nervous system (CNS). In comparison 98 advisory meetings were held by the Federal Joint Committee (G-BA) of which the BfArM provided advice in 12 instances and in 2 cases on CNS indications. Study design, endpoints and appropriate comparative therapies are the key issues in exchanges and discussions between the BfArM, the G‑BA and applicants. Under these aspects the BfArM and G‑BA promote an early and consistent involvement in early advice procedures regarding the prerequisites for drug approval and assessment of additional benefits. PMID:27003322

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

    PubMed

    Agrawal, M; Calantone, R J

    1995-01-01

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

  20. Distributed Energy Resources and Dynamic Microgrid: An Integrated Assessment

    NASA Astrophysics Data System (ADS)

    Shang, Duo Rick

    The overall goal of this thesis is to improve understanding in terms of the benefit of DERs to both utility and to electricity end-users when integrated in power distribution system. To achieve this goal, a series of two studies was conducted to assess the value of DERs when integrated with new power paradigms. First, the arbitrage value of DERs was examined in markets with time-variant electricity pricing rates (e.g., time of use, real time pricing) under a smart grid distribution paradigm. This study uses a stochastic optimization model to estimate the potential profit from electricity price arbitrage over a five-year period. The optimization process involves two types of PHEVs (PHEV-10, and PHEV-40) under three scenarios with different assumptions on technology performance, electricity market and PHEV owner types. The simulation results indicate that expected arbitrage profit is not a viable option to engage PHEVs in dispatching and in providing ancillary services without more favorable policy and PHEV battery technologies. Subsidy or change in electricity tariff or both are needed. Second, it examined the concept of dynamic microgrid as a measure to improve distribution resilience, and estimates the prices of this emerging service. An economic load dispatch (ELD) model is developed to estimate the market-clearing price in a hypothetical community with single bid auction electricity market. The results show that the electricity market clearing price on the dynamic microgrid is predominantly decided by power output and cost of electricity of each type of DGs. At circumstances where CHP is the only source, the electricity market clearing price in the island is even cheaper than the on-grid electricity price at normal times. Integration of PHEVs in the dynamic microgrid will increase electricity market clearing prices. It demonstrates that dynamic microgrid is an economically viable alternative to enhance grid resilience.

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

    NASA Astrophysics Data System (ADS)

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

    2011-03-01

    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.

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

    PubMed Central

    2013-01-01

    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. PMID:23763856

  3. Role of transporters in the distribution of platinum-based drugs

    PubMed Central

    Harrach, Saliha; Ciarimboli, Giuliano

    2015-01-01

    Platinum derivatives used as chemotherapeutic drugs such as cisplatin and oxaliplatin have a potent antitumor activity. However, severe side effects such as nephro-, oto-, and neurotoxicity are associated with their use. Effects and side effects of platinum-based drugs are in part caused by their transporter-mediated uptake in target and non target cells. In this mini review, the transport systems involved in cellular handling of platinum derivatives are illustrated, focusing on transporters for cisplatin. The copper transporter 1 seems to be of particular importance for cisplatin uptake in tumor cells, while the organic cation transporter (OCT) 2, due to its specific organ distribution, may play a major role in the development of undesired cisplatin side effects. In polarized cells, e.g., in renal proximal tubule cells, apically expressed transporters, such as multidrug and toxin extrusion protein 1, mediate secretion of cisplatin and in this way contribute to the control of its toxic effects. Specific inhibition of cisplatin uptake transporters such as the OCTs may be an attractive therapeutic option to reduce its toxicity, without impairing its antitumor efficacy. PMID:25964760

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

    SciTech Connect

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

    1981-06-01

    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.

  5. Myocardial Drug Distribution Generated from Local Epicardial Application: Potential Impact of Cardiac Capillary Perfusion in a Swine Model Using Epinephrine

    PubMed Central

    Maslov, Mikhail Y.; Edelman, Elazer R.; Pezone, Matthew J.; Wei, Abraham E.; Wakim, Matthew G.; Murray, Michael R.; Tsukada, Hisashi; Gerogiannis, Iraklis S.; Groothuis, Adam; Lovich, Mark A.

    2014-01-01

    Prior studies in small mammals have shown that local epicardial application of inotropic compounds drives myocardial contractility without systemic side effects. Myocardial capillary blood flow, however, may be more significant in larger species than in small animals. We hypothesized that bulk perfusion in capillary beds of the large mammalian heart enhances drug distribution after local release, but also clears more drug from the tissue target than in small animals. Epicardial (EC) drug releasing systems were used to apply epinephrine to the anterior surface of the left heart of swine in either point-sourced or distributed configurations. Following local application or intravenous (IV) infusion at the same dose rates, hemodynamic responses, epinephrine levels in the coronary sinus and systemic circulation, and drug deposition across the ventricular wall, around the circumference and down the axis, were measured. EC delivery via point-source release generated transmural epinephrine gradients directly beneath the site of application extending into the middle third of the myocardial thickness. Gradients in drug deposition were also observed down the length of the heart and around the circumference toward the lateral wall, but not the interventricular septum. These gradients extended further than might be predicted from simple diffusion. The circumferential distribution following local epinephrine delivery from a distributed source to the entire anterior wall drove drug toward the inferior wall, further than with point-source release, but again, not to the septum. This augmented drug distribution away from the release source, down the axis of the left ventricle, and selectively towards the left heart follows the direction of capillary perfusion away from the anterior descending and circumflex arteries, suggesting a role for the coronary circulation in determining local drug deposition and clearance. The dominant role of the coronary vasculature is further suggested by the elevated drug levels in the coronary sinus effluent. Indeed, plasma levels, hemodynamic responses, and myocardial deposition remote from the point of release were similar following local EC or IV delivery. Therefore, the coronary vasculature shapes the pharmacokinetics of local myocardial delivery of small catecholamine drugs in large animal models. Optimal design of epicardial drug delivery systems must consider the underlying bulk capillary perfusion currents within the tissue to deliver drug to tissue targets and may favor therapeutic molecules with better potential retention in myocardial tissue. PMID:25234821

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

    SciTech Connect

    Not Available

    1981-04-01

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

  7. A framework for assessing the consistency of drug classes across sources

    PubMed Central

    2014-01-01

    Background The objective of this study is to develop a framework for assessing the consistency of drug classes across sources, such as MeSH and ATC. Our framework integrates and contrasts lexical and instance-based ontology alignment techniques. Moreover, we propose metrics for assessing not only equivalence relations, but also inclusion relations among drug classes. Results We identified 226 equivalence relations between MeSH and ATC classes through the lexical alignment, and 223 through the instance-based alignment, with limited overlap between the two (36). We also identified 6,257 inclusion relations. Discrepancies between lexical and instance-based alignments are illustrated and discussed. Conclusions Our work is the first attempt to align drug classes with sophisticated instance-based techniques, while also distinguishing between equivalence and inclusion relations. Additionally, it is the first application of aligning drug classes in ATC and MeSH. By providing a detailed account of similarities and differences between drug classes across sources, our framework has the prospect of effectively supporting the creation of a mapping of drug classes between ATC and MeSH by domain experts. PMID:25101165

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

    PubMed Central

    2011-01-01

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

  9. Incidence and Geographic Distribution of Extensively Drug-Resistant Tuberculosis in KwaZulu-Natal Province, South Africa

    PubMed Central

    Lim, Jennifer R.; Gandhi, Neel R.; Mthiyane, Thuli; Mlisana, Koleka; Moodley, Julie; Jaglal, Prenika; Ramdin, Neeshan; Brust, James C. M.; Ismail, Nazir; Rustomjee, Roxana; Shah, N. Sarita

    2015-01-01

    South Africa is experiencing a widespread drug-resistant tuberculosis epidemic, although data are limited regarding the current situation. This study finds that the extensively drug-resistant tuberculosis (XDR-TB) incidence in KwaZulu-Natal increased to 3.5 cases/100,000 (776 cases) in 2011-2012. XDR-TB cases are widely distributed geographically, with the majority of districts experiencing a rise in incidence. PMID:26147963

  10. In Vitro Assessment of Dual Drug Combinations To Inhibit Growth of Neisseria gonorrhoeae

    PubMed Central

    Pettus, Kevin; Sharpe, Samera

    2015-01-01

    The development of resistance to first-line antimicrobial therapies has led to recommendations for combination therapies for the treatment of gonorrhea infection. Recent studies have shown the success of combination therapies in treating patients, but few have reported on the in vitro activities of these drug combinations. An in vitro assessment of azithromycin in combination with gentamicin demonstrated inhibition of growth and suggests that clinical trials may be warranted to assess the utility of this combination in treating gonorrhea infections. PMID:25624328

  11. Health education and knowledge assessment of HTLV-III diseases among intravenous drug users.

    PubMed

    Ginzburg, H M; French, J; Jackson, J; Hartsock, P I; MacDonald, M G; Weiss, S H

    1986-01-01

    The human T-cell lymphotropic virus, type III (HTLV-III) is the causative agent of acquired immunodeficiency syndrome (AIDS). Since AIDS is not curable, public health efforts must be focused on decreasing AIDS transmission. 72% of all AIDS cases are male homosexuals; 17% are intravenous (IV) drug users; and 3% are hemophiliacs, blood recipients, and infants of these groups. The gay community is sufficiently organized to provide the necessary infrastructure for AIDS education and treatment; the drug users are not, and at least 1/3 of IV drug users share needles and syringes. In 1984 a cooperative study was undertaken in New Jersey by the New Jersey State Department of Health, the National Cancer Institute (NCI), and the National Institute on Drug Abuse (NIDA) to determine the seroprevalence of HTLV-III among IV drug users and to assess their knowledge about AIDS. Over 95% knew the severer symptoms of AIDS; 76% knew that most AIDS patients die within 2 years of diagnosis; but 9% thought AIDS could be treated. A year later in 1985 a similar knowledge assessment survey was done among 577 clients entering drug treatment programs in New Jersey. 90% of these respondents knew that homosexuals and IV drug users were the primary risk groups, but 11% thought alcoholics were also at risk, and 43% did not know that the infants of drug users were at risk. 84% knew that sex and shared needles were the major modes of transmission, but 1/3 thought that an infected person would immediately show visible signs of illness, and many did not know how rapidly AIDS killed. Also, many did not know how to adequately clean syringes. They thought boiling would damage the syringes, and only 1/3 knew that a dilute solution of household bleach kills the virus. New Jersey decided to use indigenous health workers, recruited from rehabilitated drug users, to educate the drug community. The core message was: get treatment; don't share needles; and if you must share needles, clean them. The same message reaches drug users on late-night television and radio and English language newspapers. Drug users are educable; whether education and peer pressure will effect behavior modification remains to be seen. PMID:3781861

  12. Simulated Drug Discovery Process to Conduct a Synoptic Assessment of Pharmacy Students

    PubMed Central

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

    2014-01-01

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

  13. Applications of Genetically Modified Tools to Safety Assessment in Drug Development

    PubMed Central

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

    2010-01-01

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

  14. Intrathecal Drug Delivery Systems for Noncancer Pain: A Health Technology Assessment

    PubMed Central

    2016-01-01

    Background Intrathecal drug delivery systems can be used to manage refractory or persistent chronic nonmalignant (noncancer) pain. We investigated the benefits, harms, cost-effectiveness, and budget impact of these systems compared with current standards of care for adult patients with chronic pain owing to nonmalignant conditions. Methods We searched Ovid MEDLINE, Ovid Embase, the Cochrane Library, and the National Health Service's Economic Evaluation Database and Tufts Cost-Effectiveness Analysis Registry from January 1994 to April 2014 for evidence of effectiveness, harms, and cost-effectiveness. We used existing systematic reviews that had employed reliable search and screen methods and also searched for studies published after the search date reported in the latest systematic review to identify studies. Two reviewers screened records and assessed study validity. Results We found comparative evidence of effectiveness and harms in one cohort study at high risk of bias (≥ 3-year follow-up, N = 130). Four economic evaluations of low to very low quality were also included. Compared with oral opioid analgesia alone or a program of analgesia plus rehabilitation, intrathecal drug delivery systems significantly reduced pain (27% additional improvement) and morphine consumption. Despite these reductions, intrathecal drug delivery systems were not superior in patient-reported well-being or quality of life. There is no evidence of superiority of intrathecal drug delivery systems over oral opioids in global pain improvement and global treatment satisfaction. Comparative evidence of harms was not found. Cost-effectiveness evidence is of insufficient quality to assess the appropriateness of funding intrathecal drug delivery systems. Evidence comparing intrathecal drug delivery systems with standard care was of very low quality. Conclusions Current evidence does not establish (or rule out) superiority or cost-effectiveness of intrathecal drug delivery systems for managing chronic refractory nonmalignant pain. The budget impact of funding intrathecal drug delivery systems would be between $1.5 and $5.0 million per year. PMID:27026797

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

    PubMed

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

    2013-05-01

    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

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

    ERIC Educational Resources Information Center

    Primmerman, William

    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…

  17. 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...

  18. Use of the "Personal Delivery" System for Assessment of Drug and Alcohol Attitudes and Usage Patterns.

    ERIC Educational Resources Information Center

    Crabtree, J. Michael; Myers, Stanley B.

    Community data concerning drug and alcohol usage patterns was assessed via a unique "personal delivery" system. The system, which can be used for collecting other community data produced a return rate of 45% and was very economical. This system largely overcomes the main drawback of the mailed questionnaire (low return rate) by (1) having…

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

    EPA Science Inventory

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

  20. The Distributive Impact Assessment Model (DIAM): Technology share component

    SciTech Connect

    Poyer, D.A.; Earl, E.; Bonner, B.

    1995-03-01

    The models described in this report are used to allocate total energy consumption in an energy end-use service area by fuel type (including electricity) within the Distributive Impact Assessment Model (DIAM) framework. The primary objective of the DIAM is to provide energy consumption and expenditure forecasts for different population categories that are consistent with the US Department of Energy (DOE) Energy Information Administration`s (EIA`s) National Energy Modeling System (NEMS) forecast, which is produced annually in the Annual Energy Outlook and periodically in support of DOE policy formulation and analysis. The models are multinominal logit models that have been estimated using EIA`s 1990 Residential Energy Consumption Survey. Three models were estimated: space heating share, water heating share, and cooking share. These models are used to allocate total end-use service consumption over different technologies defined by fuel type characteristics. For each of the end-use service categories, consumption shares are estimated for a subset of six fuel types: natural gas, electricity, liquid petroleum gas, fuel oil/kerosene, wood, and other fuel.

  1. Assessing Distributional Impacts of Forest Policies and Projects: An Integrated Approach.

    ERIC Educational Resources Information Center

    Xu, Zhi

    1994-01-01

    Identifies the demand for distributional impact assessment related to forest policies and projects and the linkages between distributional impacts and sustainable development. An integrated model is developed to assess the distributional impact of forest policies and projects. Studying the impact of the introduction of structural particleboard…

  2. Investigation of drug-cyclodextrin complexes by a phase-distribution method: some theoretical and practical considerations.

    PubMed

    Másson, Már; Sigurdardóttir, Birna Vigdís; Matthíasson, Kristján; Loftsson, Thorsteinn

    2005-08-01

    The purpose of the study was to evaluate an octanol-water phase distribution method for investigation of drug/cyclodextrin (D/CD) complexes and to compare stability constant values obtained by this method to values obtained by the phase solubility method. A general equation for determination of 1 : 1 D/CD complex stability constant (K1 : 1) from the slope of a phase-distribution diagram (a diagram of the reciprocal of the apparent partition coefficient vs. the total CD concentration) was derived. The equation accounted for the possible inclusion of the organic solvent in the CD cavity and the gradual saturation of the CD binding with increasing concentration of the guest compound. This method was used to determine K1 : 1 for 2-hydroxypropyl-beta-cyclodextrin (HPbetaCD) complexes of hydrocortisone, prednisolone, diazepam, beta-estradiol and diethylstilbestrol. These values were comparable to K1 : 1 values determined by the phase-solubility method. The phase-distribution method could also be applied to determine stability constants for the neutral and ionic forms of the weakly acidic drugs, naproxen and triclosan and the weakly basic drug lidocaine. The phase-distribution method is a very versatile and fast method and has the advantage, compared to the phase-solubility method, that it only requires very small drug samples. Thus, this method would be suitable for screening of new drug candidates. PMID:16079528

  3. Distribution of animal drugs between skim milk and milk fat fractions in spiked whole milk: Understanding the potential impact on commercial milk products

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Seven animal drugs [penicillin G (PENG), sulfadimethoxine (SDMX), oxytetracycline (OTET), erythromycin (ERY), ketoprofen (KETO), thiabendazole (THIA) and ivermectin (IVR)] were used to evaluate drug distribution between milk fat and skim milk fractions of cow milk. Greater than 90% of radioactivity...

  4. Spatial distribution of theobromine--a low MW drug--in tissues via matrix-free NALDI-MS imaging.

    PubMed

    Tata, Alessandra; Montemurro, Chiara; Porcari, Andreia M; Silva, Kamila C; Lopes de Faria, José B; Eberlin, Marcos N

    2014-09-01

    The ability of nano-assisted laser desorption-ionization mass spectrometry imaging (NALDI-IMS) to provide selective chemical monitoring with appropriate spatial distribution of a low molecular drug in a biological tissue was investigated. NALDI-IMS is a matrix-free laser desorption ionization (LDI) protocol based on imprinting of tissue constituents on a nanostructured surface. Using the accumulation of theobromine in rat kidney as a model, NALDI-IMS was found to provide well-resolved images of the special distribution of this low molecular weight (MW) drug in tissue. PMID:25066957

  5. Hepatocyte-based in vitro model for assessment of drug-induced cholestasis

    SciTech Connect

    Chatterjee, Sagnik; Richert, Lysiane; Augustijns, Patrick; Annaert, Pieter

    2014-01-01

    Early detection of drug-induced cholestasis remains a challenge during drug development. We have developed and validated a biorelevant sandwich-cultured hepatocytes- (SCH) based model that can identify compounds causing cholestasis by altering bile acid disposition. Human and rat SCH were exposed (24–48 h) to known cholestatic and/or hepatotoxic compounds, in the presence or in the absence of a concentrated mixture of bile acids (BAs). Urea assay was used to assess (compromised) hepatocyte functionality at the end of the incubations. The cholestatic potential of the compounds was expressed by calculating a drug-induced cholestasis index (DICI), reflecting the relative residual urea formation by hepatocytes co-incubated with BAs and test compound as compared to hepatocytes treated with test compound alone. Compounds with clinical reports of cholestasis, including cyclosporin A, troglitazone, chlorpromazine, bosentan, ticlopidine, ritonavir, and midecamycin showed enhanced toxicity in the presence of BAs (DICI ≤ 0.8) for at least one of the tested concentrations. In contrast, the in vitro toxicity of compounds causing hepatotoxicity by other mechanisms (including diclofenac, valproic acid, amiodarone and acetaminophen), remained unchanged in the presence of BAs. A safety margin (SM) for drug-induced cholestasis was calculated as the ratio of lowest in vitro concentration for which was DICI ≤ 0.8, to the reported mean peak therapeutic plasma concentration. SM values obtained in human SCH correlated well with reported % incidence of clinical drug-induced cholestasis, while no correlation was observed in rat SCH. This in vitro model enables early identification of drug candidates causing cholestasis by disturbed BA handling. - Highlights: • Novel in vitro assay to detect drug-induced cholestasis • Rat and human sandwich-cultured hepatocytes (SCH) as in vitro models • Cholestatic compounds sensitize SCH to toxic effects of accumulating bile acids • Drug-induced cholestasis index (DICI) as measure of a drug's cholestatic signature • In vitro findings correlate well with clinical reports on cholestasis.

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

    SciTech Connect

    Sakane, T.; Nakatsu, M.; Yamamoto, A.; Hashida, M.; Sezaki, H.; Yamashita, S.; Nadai, T. )

    1991-06-01

    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.

  7. Landslide Probability Assessment by the Derived Distributions Technique

    NASA Astrophysics Data System (ADS)

    Muñoz, E.; Ochoa, A.; Martínez, H.

    2012-12-01

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

  8. Assessing Natural Product-Drug Interactions: An End-to-End Safety Framework.

    PubMed

    Roe, Amy L; Paine, Mary F; Gurley, Bill J; Brouwer, Kenneth R; Jordan, Scott; Griffiths, James C

    2016-04-01

    The use of natural products (NPs), including herbal medicines and other dietary supplements, by North Americans continues to increase across all age groups. This population has access to conventional medications, with significant polypharmacy observed in older adults. Thus, the safety of the interactions between multi-ingredient NPs and drugs is a topic of paramount importance. Considerations such as history of safe use, literature data from animal toxicity and human clinical studies, and NP constituent characterization would provide guidance on whether to assess NP-drug interactions experimentally. The literature is replete with reports of various NP extracts and constituents as potent inhibitors of drug metabolizing enzymes, and transporters. However, without standard methods for NP characterization or in vitro testing, extrapolating these reports to clinically-relevant NP-drug interactions is difficult. This lack of a clear definition of risk precludes clinicians and consumers from making informed decisions about the safety of taking NPs with conventional medications. A framework is needed that describes an integrated robust approach for assessing NP-drug interactions; and, translation of the data into formulation alterations, dose adjustment, labelling, and/or post-marketing surveillance strategies. A session was held at the 41st Annual Summer Meeting of the Toxicology Forum in Colorado Springs, CO, to highlight the challenges and critical components that should be included in a framework approach. PMID:26776752

  9. Molecular Analysis of Terminalia spp. Distributed in Thailand and Authentication of Crude Drugs from Terminalia Plants.

    PubMed

    Intharuksa, Aekkhaluck; Ando, Hirokazu; Miyake, Katsunori; Sirisa-Ard, Panee; Mikage, Masayuki; Sasaki, Yohei

    2016-01-01

    Terminalia, a large genus of Combretaceae, is distributed in Tropical Asia, Africa, and America. Some Terminalia plants are used in folk medicine because they possess powerful medicinal properties. Dried fruits of Terminalia bellirica and Terminalia chebula are used as the main ingredient in Triphala, a famous polyherbal formulation in Ayurvedic medicine and Thai folk medicine, because of their laxative, detoxifying, and rejuvenating effects. To clarify the phylogenetic relationships of medicinal Terminalia species (T. bellirica, T. chebula, and T. catappa) and authenticate their crude drugs, "Samo" and Triphala, nucleotide sequencing alignments in the internal transcribed spacer one-two (ITS 1-2) regions of Terminalia plants collected in Thailand were performed. The amplified fragments of Terminalia species were approximately 800 bp in length. To compare these sequences and DDBJ registered data, a molecular phylogenetic tree was constructed. Phylogenetic analysis clearly separated the sequences into two groups: Asian Terminalia and African Terminalia with some exceptions. In the analyzed sequences, the length of the ITS1-5.8S-ITS2 region was 674 bp in T. chebula, and 677 bp in T. bellirica and T. catappa. Eighty-one single nucleotide polymorphisms (SNPs) and nine insertion-deletions (indels) were observed, and the nucleotide sequences of this region showed species-specific sequences. Based on these differences, polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and amplification refractory mutation system (ARMS) were applied to identify medicinal Terminalia species. Moreover, the ARMS method was chosen for fingerprinting analysis of Samo crude drugs and Triphala formulations because it was a fast, cost-effective, and reproducible approach. PMID:27040622

  10. Distribution of Animal Drugs between Skim Milk and Milk Fat Fractions in Spiked Whole Milk: Understanding the Potential Impact on Commercial Milk Products.

    PubMed

    Hakk, Heldur; Shappell, Nancy W; Lupton, Sara J; Shelver, Weilin L; Fanaselle, Wendy; Oryang, David; Yeung, Chi Yuen; Hoelzer, Karin; Ma, Yinqing; Gaalswyk, Dennis; Pouillot, Régis; Van Doren, Jane M

    2016-01-13

    Seven animal drugs [penicillin G (PENG), sulfadimethoxine (SDMX), oxytetracycline (OTET), erythromycin (ERY), ketoprofen (KETO), thiabendazole (THIA), and ivermectin (IVR)] were used to evaluate the drug distribution between milk fat and skim milk fractions of cow milk. More than 90% of the radioactivity was distributed into the skim milk fraction for ERY, KETO, OTET, PENG, and SDMX, approximately 80% for THIA, and 13% for IVR. The distribution of drug between milk fat and skim milk fractions was significantly correlated to the drug's lipophilicity (partition coefficient, log P, or distribution coefficient, log D, which includes ionization). Data were fit with linear mixed effects models; the best fit was obtained within this data set with log D versus observed drug distribution ratios. These candidate empirical models serve for assisting to predict the distribution and concentration of these drugs in a variety of milk and milk products. PMID:26652058

  11. COMPARATIVE ASSESSMENT OF TWO DISTRIBUTED WATERSHED MODELS WITH APPLICATION TO A SMALL WATERSHED

    EPA Science Inventory

    Distributed watershed models are beneficial tools for assessment of management practices on runoff and water-induced erosion. This paper evaluates, by application to an experimental watershed, two promising distributed watershed-scale sediment models in detail: The Kinematic Runo...

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

    PubMed Central

    2014-01-01

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

  13. Ecological Momentary Assessment of Illicit Drug Use Compared to Biological and Self-Reported Methods

    PubMed Central

    Genz, Andrew; Westergaard, Ryan P; Chang, Larry W; Bollinger, Robert C; Latkin, Carl; Kirk, Gregory D

    2016-01-01

    Background The use of mHealth methods for capturing illicit drug use and associated behaviors have become more widely used in research settings, yet there is little research as to how valid these methods are compared to known measures of capturing and quantifying drug use. Objective We examined the concordance of ecological momentary assessment (EMA) of drug use to previously validated biological and audio-computer assisted self-interview (ACASI) methods. Methods The Exposure Assessment in Current Time (EXACT) study utilized EMA methods to assess drug use in real-time in participants’ natural environments. Utilizing mobile devices, participants self-reported each time they used heroin or cocaine over a 4-week period. Each week, PharmChek sweat patch samples were collected for measurement of heroin and cocaine and participants answered an ACASI-based questionnaire to report behaviors and drug using events during the prior week. Reports of cocaine and heroin use captured through EMA were compared to weekly biological or self-report measures through percent agreement and concordance correlation coefficients to account for repeated measures. Correlates of discordance were obtained from logistic regression models. Results A total of 109 participants were a median of 48.5 years old, 90% African American, and 52% male. During 436 person-weeks of observation, we recorded 212 (49%) cocaine and 103 (24%) heroin sweat patches, 192 (44%) cocaine and 161 (37%) heroin ACASI surveys, and 163 (37%) cocaine and 145 (33%) heroin EMA reports. The percent agreement between EMA and sweat patch methods was 70% for cocaine use and 72% for heroin use, while the percent agreement between EMA and ACASI methods was 77% for cocaine use and 79% for heroin use. Misreporting of drug use by EMA compared to sweat patch and ACASI methods were different by illicit drug type. Conclusions Our work demonstrates moderate to good agreement of EMA to biological and standard self-report methods in capturing illicit drug use. Limitations occur with each method and accuracy may differ by type of illicit drugs used. PMID:26980400

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

    PubMed Central

    2012-01-01

    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 μm and 121 minutes for micro bubbles with an average diameter of 73.74 μm, 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. PMID:22995578

  15. 10 CFR 32.72 - Manufacture, preparation, or transfer for commercial distribution of radioactive drugs containing...

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... requirements specified in 10 CFR 30.33; (2) The applicant submits evidence that the applicant is at least one... processing of a drug under 21 CFR 207.20(a); (ii) Registered or licensed with a state agency as a drug... prepare radioactive drugs for medical use, as defined in 10 CFR 35.2, provided that the radioactive...

  16. 10 CFR 32.72 - Manufacture, preparation, or transfer for commercial distribution of radioactive drugs containing...

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... requirements specified in 10 CFR 30.33; (2) The applicant submits evidence that the applicant is at least one... processing of a drug under 21 CFR 207.20(a); (ii) Registered or licensed with a state agency as a drug... prepare radioactive drugs for medical use, as defined in 10 CFR 35.2, provided that the radioactive...

  17. 10 CFR 32.72 - Manufacture, preparation, or transfer for commercial distribution of radioactive drugs containing...

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... requirements specified in 10 CFR 30.33; (2) The applicant submits evidence that the applicant is at least one... processing of a drug under 21 CFR 207.20(a); (ii) Registered or licensed with a state agency as a drug... prepare radioactive drugs for medical use, as defined in 10 CFR 35.2, provided that the radioactive...

  18. 10 CFR 32.72 - Manufacture, preparation, or transfer for commercial distribution of radioactive drugs containing...

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... requirements specified in 10 CFR 30.33; (2) The applicant submits evidence that the applicant is at least one... processing of a drug under 21 CFR 207.20(a); (ii) Registered or licensed with a state agency as a drug... prepare radioactive drugs for medical use, as defined in 10 CFR 35.2, provided that the radioactive...

  19. 10 CFR 32.72 - Manufacture, preparation, or transfer for commercial distribution of radioactive drugs containing...

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... requirements specified in 10 CFR 30.33; (2) The applicant submits evidence that the applicant is at least one... processing of a drug under 21 CFR 207.20(a); (ii) Registered or licensed with a state agency as a drug... prepare radioactive drugs for medical use, as defined in 10 CFR 35.2, provided that the radioactive...

  20. Development and Distribution of Drugs for NTDs: Efforts of One Pharmaceutical Company.

    PubMed

    Asada, Makoto

    2016-01-01

      The Pharmaceutical Industry is expected to play a proactive global role in combatting neglected tropical diseases (NTDs) and other tropical diseases affecting low-income countries. Such a role would include novel medicine R&D, manufacturing and distribution. In order to succeed in this role, several challenges need to be overcome: a) the economic challenge or cost benefit balance for the development of these medicines, and b) sparse in-house experience with these diseases within the Industry. During the last decade, the Product Development Partnership (PDP) model has become an effective strategy to address such challenges. Organizations such as the Medicines for Malaria Venture (MMV), Drugs for Neglected Diseases initiative (DNDi), TB alliance, PATH (formerly the Program for Appropriate Technology in Health), and others have linked pharmaceutical companies, funding organizations, academic researchers and others, and have thus been able to successfully populate treatment pipelines directed at NTDs, Malaria, tuberculosis (TB), and human immunodeficiency virus (HIV)/AIDS. In this paper, our experience working with one of these organizations, DNDi, is described. We have been collaborating with DNDi in evaluating the actions of Eisai's antifungal compound, E1224, in a clinical study for treating Chagas Disease. In addition, other Eisai initiatives directed at NTDs and improving patients' access to medicines are introduced. PMID:26831797

  1. Latent class analysis of discordance between results of drug use assessments in the CATIE data

    PubMed Central

    Johnson, Kiersten L.; Desmarais, Sarah L.; Swartz, Marvin S.; Van Dorn, Richard A.

    2016-01-01

    Objective The primary aim is to examine concordant/discordant results of drug use assessments in adults with schizophrenia. Methods Latent class analysis and multinomial logistic regression were used to examine concordance/discordance between drug use measures and identify characteristics differentiating participants across classes. Results Four classes – non-users, users, probable users, and RIA discordant –fit best. Age, sex, race/ethnicity, and psychiatric symptoms differed significantly across classes. Conclusions Findings showed that discordance between results occurs at non-trivial rates and is, in part, attributable to individual characteristics. Results suggest the need for strategies to limit discordance and improve detection of drug use in adults with schizophrenia. PMID:25476120

  2. A community effort to assess and improve drug sensitivity prediction algorithms

    PubMed Central

    Costello, James C; Heiser, Laura M; Georgii, Elisabeth; Gönen, Mehmet; Menden, Michael P; Wang, Nicholas J; Bansal, Mukesh; Ammad-ud-din, Muhammad; Hintsanen, Petteri; Khan, Suleiman A; Mpindi, John-Patrick; Kallioniemi, Olli; Honkela, Antti; Aittokallio, Tero; Wennerberg, Krister; Collins, James J; Gallahan, Dan; Singer, Dinah; Saez-Rodriguez, Julio; Kaski, Samuel; Gray, Joe W; Stolovitzky, Gustavo

    2015-01-01

    Predicting the best treatment strategy from genomic information is a core goal of precision medicine. Here we focus on predicting drug response based on a cohort of genomic, epigenomic and proteomic profiling data sets measured in human breast cancer cell lines. Through a collaborative effort between the National Cancer Institute (NCI) and the Dialogue on Reverse Engineering Assessment and Methods (DREAM) project, we analyzed a total of 44 drug sensitivity prediction algorithms. The top-performing approaches modeled nonlinear relationships and incorporated biological pathway information. We found that gene expression microarrays consistently provided the best predictive power of the individual profiling data sets; however, performance was increased by including multiple, independent data sets. We discuss the innovations underlying the top-performing methodology, Bayesian multitask MKL, and we provide detailed descriptions of all methods. This study establishes benchmarks for drug sensitivity prediction and identifies approaches that can be leveraged for the development of new methods. PMID:24880487

  3. Differences in T cell distribution and CCR5 expression in HIV-positive and HIV-exposed seronegative persons who inject drugs.

    PubMed

    Kallas, Eveli; Huik, Kristi; Türk, Silver; Pauskar, Merit; Jõgeda, Ene-Ly; Šunina, Marina; Karki, Tõnis; Des Jarlais, Don; Uusküla, Anneli; Avi, Radko; Lutsar, Irja

    2016-06-01

    Some individuals remain uninfected despite repeated exposure to HIV. This protection against HIV has been partly associated with altered T cell subset distributions and CCR5 expression levels. However, the majority of studies have been conducted in sexually exposed subjects. We aimed to assess whether HIV infection and intravenous drug use were associated with differences in CCR5 expression, immune activation on the CD4+ and CD8+ T cells and T cell distribution among Caucasian persons who inject drugs (PWIDs). Analyses of the data from 41 HIV-positive PWIDs, 47 HIV-exposed seronegative PWIDs (ESNs) and 47 age- and gender-matched HIV-negative non-drug users are presented. Of all of the study subjects, 111 (82 %) were male, and the median age was 29 years. T cell phenotyping was performed in peripheral blood mononuclear cells with multicolour flow cytometry using anti-CD3, CD4, CD8, CD45RA, CD45RO, HLA-DR and CCR5 antibodies. The ESNs exhibited greater levels of immune activation and higher percentages of CD4+ CD45RA+RO+ and CD8+ CD45RA+RO+ cells compared to the controls but not the HIV-positive people. The CCR5 expression on the CD4+ T cell subsets in the ESNs was lower than that in the controls but similar to that the HIV positives. The percentages of CCR5+ T cells were similar in all study groups and in most of the studied cell populations. Intravenous drug use was similarly associated with differences in T cell subset distributions and CCR5 expression among both the HIV-positive and HIV-negative PWIDs compared with the controls. PMID:26696529

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

    PubMed Central

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

    2013-01-01

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

  5. Intrathecal Drug Delivery Systems for Cancer Pain: A Health Technology Assessment

    PubMed Central

    2016-01-01

    Background Intrathecal drug delivery systems can be used to manage refractory or persistent cancer pain. We investigated the benefits, harms, cost-effectiveness, and budget impact of these systems compared with current standards of care for adult patients with chronic pain due owing to cancer. Methods We searched Ovid MEDLINE, Ovid Embase, the Cochrane Library databases, National Health Service's Economic Evaluation Database, and Tufts Cost-Effectiveness Analysis Registry from January 1994 to April 2014 for evidence of effectiveness, harms, and cost-effectiveness. We used existing systematic reviews that had employed reliable search and screen methods and searched for studies published after the search date reported in the latest systematic review to identify studies. Two reviewers screened records and assessed study validity. The cost burden of publicly funding intrathecal drug delivery systems for cancer pain was estimated for a 5-year timeframe using a combination of published literature, information from the device manufacturer, administrative data, and expert opinion for the inputs. Results We included one randomized trial that examined effectiveness and harms, and one case series that reported an eligible economic evaluation. We found very low quality evidence that intrathecal drug delivery systems added to comprehensive pain management reduce overall drug toxicity; no significant reduction in pain scores was observed. Weak conclusions from economic evidence suggested that intrathecal drug delivery systems had the potential to be more cost-effective than high-cost oral therapy if administered for 7 months or longer. The cost burden of publicly funding this therapy is estimated to be $100,000 in the first year, increasing to $500,000 by the fifth year. Conclusions Current evidence could not establish the benefit, harm, or cost-effectiveness of intrathecal drug delivery systems compared with current standards of care for managing refractory cancer pain in adults. Publicly funding intrathecal drug delivery systems for cancer pain would result in a budget impact of several hundred thousand dollars per year. PMID:27026796

  6. Assessment of PLGA-PEG-PLGA Copolymer Hydrogel for Sustained Drug Delivery in the Ear

    PubMed Central

    Feng, Liang; Ward, Jonette A.; Li, S. Kevin; Tolia, Gaurav; Hao, Jinsong; Choo, Daniel I.

    2014-01-01

    Temperature sensitive copolymer systems were previously studied using modified diffusion cells in vitro for intratympanic injection, and the PLGA-PEG-PLGA copolymer systems were found to provide sustained drug delivery for several days. The objectives of the present study were to assess the safety of PLGA-PEG-PLGA copolymers in intratympanic injection in guinea pigs in vivo and to determine the effects of additives glycerol and poloxamer in PLGA-PEG-PLGA upon drug release in the diffusion cells in vitro for sustained inner ear drug delivery. In the experiments, the safety of PLGA-PEG-PLGA copolymers to inner ear was evaluated using auditory brainstem response (ABR). The effects of the additives upon drug release from PLGA-PEG-PLGA hydrogel were investigated in the modified Franz diffusion cells in vitro with cidofovir as the model drug. The phase transition temperatures of the PLGA-PEG-PLGA copolymers in the presence of the additives were also determined. In the ABR safety study, the PLGA-PEG-PLGA copolymer alone did not affect hearing when delivered at 0.05-mL dose but caused hearing loss after 0.1-mL injection. In the drug release study, the incorporation of the bioadhesive additive, poloxamer, in the PLGA-PEG-PLGA formulations was found to decrease the rate of drug release whereas the increase in the concentration of the humectant additive, glycerol, provided the opposite effect. In summary, the PLGA-PEG-PLGA copolymer did not show toxicity to the inner ear at the 0.05-mL dose and could provide sustained release that could be controlled by using the additives for inner ear applications. PMID:24438444

  7. Laser-evoked potentials as a tool for assessing the efficacy of antinociceptive drugs

    PubMed Central

    Truini, A.; Panuccio, G.; Galeotti, F.; Maluccio, M.R.; Sartucci, F.; Avoli, M.; Cruccu, G.

    2016-01-01

    Laser-evoked potentials (LEPs) are brain responses to laser radiant heat pulses and reflect the activation of Aδ nociceptors. LEPs are to date the reference standard technique for studying nociceptive pathway function in patients with neuropathic pain. To find out whether LEPs also provide a useful neurophysiological tool for assessing antinociceptive drug efficacy, in this double-blind placebo-controlled study we measured changes induced by the analgesic tramadol on LEPs in 12 healthy subjects. We found that tramadol decreased the amplitude of LEPs, whereas placebo left LEPs unchanged. The opioid antagonist naloxone partially reversed the tramadol-induced LEP amplitude decrease. We conclude that LEPs may be reliably used in clinical practice and research for assessing the efficacy of antinociceptive drugs. PMID:19477145

  8. Digital technologies for cognitive assessment to accelerate drug development in Alzheimer's disease.

    PubMed

    Leurent, C; Ehlers, M D

    2015-11-01

    For many neurological and psychiatric diseases, novel therapeutics have been elusive for decades. By focusing on attention interference in Alzheimer's disease (AD), we provide a future vision on how emerging mobile, computer, and device-based cognitive tools are converting classically noisy, subjective, data-poor clinical endpoints associated with neuropsychiatric disease assessment into a richer, scalable, and objective set of measurements. Incorporation of such endpoints into clinical drug trials holds promise for more quickly and efficiently developing new medicines. PMID:26272508

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

    PubMed Central

    2013-01-01

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

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

    PubMed Central

    2010-01-01

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

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

    PubMed

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

    2010-01-01

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

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

    NASA Technical Reports Server (NTRS)

    Schmeckpeper, K. R.

    1988-01-01

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

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

    NASA Technical Reports Server (NTRS)

    Schmeckpeper, K. R.

    1988-01-01

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

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

    NASA Astrophysics Data System (ADS)

    Valussi, Silvia; Underhill, Mark

    2006-09-01

    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.

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

    PubMed

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

    2014-08-01

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

  16. 7 CFR 1230.72 - Distribution of assessments.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... AGREEMENTS AND ORDERS; MISCELLANEOUS COMMODITIES), DEPARTMENT OF AGRICULTURE PORK PROMOTION, RESEARCH, AND CONSUMER INFORMATION Pork Promotion, Research, and Consumer Information Order Expenses and Assessments... Body or 16.5 percent, whichever is higher, of the net assessments attributable to that State. The...

  17. 7 CFR 1230.72 - Distribution of assessments.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... AGREEMENTS AND ORDERS; MISCELLANEOUS COMMODITIES), DEPARTMENT OF AGRICULTURE PORK PROMOTION, RESEARCH, AND CONSUMER INFORMATION Pork Promotion, Research, and Consumer Information Order Expenses and Assessments... Body or 16.5 percent, whichever is higher, of the net assessments attributable to that State. The...

  18. Research Techniques Made Simple: Drug Delivery Techniques, Part 2: Commonly Used Techniques to Assess Topical Drug Bioavailability.

    PubMed

    Patel, Parth; Schmieder, Shawn; Krishnamurthy, Karthik

    2016-05-01

    Assessing the extent of absorption of topical drugs into the various skin layers has been one of the biggest challenges of recent dermatological research. Although skin biopsy samples can be used to directly measure topical drug absorption, biopsies are invasive and not practical for obtaining kinetic data. Common alternative techniques used to assess the bioavailability of topical drugs include in vitro (Franz cell chamber), ex vivo (isolated perfused skin models), and in vivo (vasoconstrictor assay, tape stripping/dermatopharmacokinetics, and microdialysis) techniques. Despite the popularity of these techniques, each technique has its own advantages and disadvantages that limit its use. Consideration of each technique requires that there is a rational linkage to the drug's clinical endpoint and/or site of action. In this article, we review these in vitro, ex vivo, and in vivo techniques, focusing on the basic concepts and the advantages and disadvantages of each technique. PMID:27107377

  19. Site of drug absorption after oral administration: assessment of membrane permeability and luminal concentration of drugs in each segment of gastrointestinal tract.

    PubMed

    Masaoka, Yoshie; Tanaka, Yusuke; Kataoka, Makoto; Sakuma, Shinji; Yamashita, Shinji

    2006-11-01

    This study was conducted to assess the site of drug absorption in the gastrointestinal (GI) tract after oral administration. Drug permeability to different regions of rat intestine, jejunum, ileum and colon, was measured by in situ single-pass perfusion method. It was revealed that the epithelial surface area should not be a determinant of the regional difference in the intestinal permeability of highly permeable drugs. Effects of the mucus layer at the surface of the epithelium and the fluidity of the epithelial cell membrane on the drug permeability were investigated. These factors are demonstrated to contribute to the regional differences in intestinal drug permeability. The luminal drug concentration in each segment of the GI tract after oral administration was measured directly in fasted rats. Water ingested orally was absorbed quickly in the jejunum and the luminal fluid volume was diminished in the middle to lower part of the small intestine. According to the absorption of water luminal concentration of atenolol, a drug with low permeability, was elevated and exceeded the initial dose concentration. In contrast, the concentration of highly permeable drugs, antipyrine and metoprolol, decreased quickly in the upper part of the intestine and a significant amount of drugs was not detected in the lower jejunum and the ileum. From the time-profiles of luminal drug concentration, fraction of dose absorbed from each segment of the GI tract was calculated. Both antipyrine and metoprolol were found to be absorbed quickly at the upper part of the small intestine. In addition, the possible contribution of gastric absorption was demonstrated for these drugs. The pattern of site-dependent absorption of atenolol showed the higher absorbability in the middle and lower portion of the jejunum. These informations on site-dependent absorption of drugs are considered to be important for effective oral delivery systems. PMID:16876987

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

    PubMed

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

    2013-12-01

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

  1. Comparison of equilibrium and non-equilibrium distribution coefficients for the human drug carbamazepine in soil.

    PubMed

    Williams, C F; Watson, J E; Nelson, S D

    2014-01-01

    The distribution coefficient (KD) for the human drug carbamazepine was measured using a non-equilibrium technique. Repacked soil columns were prepared using an Airport silt loam (Typic Natrustalf) with an average organic matter content of 2.45%. Carbamazepine solutions were then leached through the columns at 0.5, 1.0 and 1.5 mL min(-1) representing average linear velocities of 1.8, 3.5 and 5.3 cm h(-1) respectively. Each flow rate was replicated three times and three carbamazepine pulses were applied to each column resulting in a total of 9 columns with 27 total carbamazepine pulses. Breakthrough curves were used to determine KD using the parameter fitting software CXTFIT. Results indicate that as flow rate decreased from 5.3 to 1.8 cm h(-1), KD increased an average of 21%. Additionally, KD determined by column leaching (14.7-22.7 L kg(-1)) was greater than KD determined by a 2h batch equilibrium adsorption (12.6 L kg(-1)). Based on these KD's carbamazepine would be generally characterized as non-mobile in the soil investigated. However, repeated carbamazepine applications resulted in an average 22% decrease in KD between the first and third applications. Decreasing KD is attributed to differences in sorption site kinetics and carbamazepine residence time in contact with the soil. This would indicate that the repeated use of reclaimed wastewater at high application rates for long-term irrigation or groundwater recharge has the potential to lead to greater transport of carbamazepine than KD determined by batch equilibrium would predict. PMID:24050717

  2. Hepatocyte-based in vitro model for assessment of drug-induced cholestasis.

    PubMed

    Chatterjee, Sagnik; Richert, Lysiane; Augustijns, Patrick; Annaert, Pieter

    2014-01-01

    Early detection of drug-induced cholestasis remains a challenge during drug development. We have developed and validated a biorelevant sandwich-cultured hepatocytes- (SCH) based model that can identify compounds causing cholestasis by altering bile acid disposition. Human and rat SCH were exposed (24-48h) to known cholestatic and/or hepatotoxic compounds, in the presence or in the absence of a concentrated mixture of bile acids (BAs). Urea assay was used to assess (compromised) hepatocyte functionality at the end of the incubations. The cholestatic potential of the compounds was expressed by calculating a drug-induced cholestasis index (DICI), reflecting the relative residual urea formation by hepatocytes co-incubated with BAs and test compound as compared to hepatocytes treated with test compound alone. Compounds with clinical reports of cholestasis, including cyclosporin A, troglitazone, chlorpromazine, bosentan, ticlopidine, ritonavir, and midecamycin showed enhanced toxicity in the presence of BAs (DICI≤0.8) for at least one of the tested concentrations. In contrast, the in vitro toxicity of compounds causing hepatotoxicity by other mechanisms (including diclofenac, valproic acid, amiodarone and acetaminophen), remained unchanged in the presence of BAs. A safety margin (SM) for drug-induced cholestasis was calculated as the ratio of lowest in vitro concentration for which was DICI≤0.8, to the reported mean peak therapeutic plasma concentration. SM values obtained in human SCH correlated well with reported % incidence of clinical drug-induced cholestasis, while no correlation was observed in rat SCH. This in vitro model enables early identification of drug candidates causing cholestasis by disturbed BA handling. PMID:24211272

  3. Comparative Dynamics and Distribution of Influenza Drug Resistance Acquisition to Protein M2 and Neuraminidase Inhibitors

    PubMed Central

    Garcia, Vanessa; Aris-Brosou, Stéphane

    2014-01-01

    Although efficient influenza vaccines are designed on a regular basis, the only protection of human populations against an unforeseen virus such as during the H1N1 pandemic in 2009 might be antiviral drugs. Adamantanes and neuraminidase inhibitors (Oseltamivir) represent two classes of such drugs that target the viral matrix protein 2 and neuraminidase, respectively. Although the emergence of resistance to both drugs has been described, the timing and spread of the acquisition of either single or dual resistances by different hosts is still unclear. Using a multilayered phylogenetic approach based on relaxed molecular clocks and large-scale maximum likelihood approaches, we show that Adamantane resistance evolved multiple times in various subtypes and hosts, possibly in breeding contexts (swine); and Oseltamivir resistance was also found in different subtypes and hosts, but its transmission is only sustained in humans. Furthermore, the dynamics of the emergence of antiviral resistance were examined for each drug. This showed that although the first mutations conferring resistance to Adamantanes precede US Food and Drug Administration (FDA) approval, general resistance emerged 15–38 years post-drug approval. This is in contrast to Oseltamivir resistance mutations that emerged at most 7 years after FDA approval of the drug. This study demonstrates the power of large-scale analyses to uncover and monitor the emergence dynamics of drug resistance. PMID:24214415

  4. 10 CFR 32.21 - Radioactive drug: Manufacture, preparation, or transfer for commercial distribution of capsules...

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... 10 Energy 1 2013-01-01 2013-01-01 false Radioactive drug: Manufacture, preparation, or transfer... CONTAINING BYPRODUCT MATERIAL Exempt Concentrations and Items § 32.21 Radioactive drug: Manufacture... application to, a human being; (5) The carbon-14 urea is in the form of a capsule, identified as...

  5. 10 CFR 32.21 - Radioactive drug: Manufacture, preparation, or transfer for commercial distribution of capsules...

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 10 Energy 1 2011-01-01 2011-01-01 false Radioactive drug: Manufacture, preparation, or transfer... CONTAINING BYPRODUCT MATERIAL Exempt Concentrations and Items § 32.21 Radioactive drug: Manufacture... application to, a human being; (5) The carbon-14 urea is in the form of a capsule, identified as...

  6. 38 CFR 48.210 - To whom must I distribute my drug-free workplace statement?

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... my drug-free workplace statement? 48.210 Section 48.210 Pensions, Bonuses, and Veterans' Relief DEPARTMENT OF VETERANS AFFAIRS (CONTINUED) GOVERNMENTWIDE REQUIREMENTS FOR DRUG-FREE WORKPLACE (FINANCIAL...-free workplace statement? You must require that a copy of the statement described in § 48.205 be...

  7. Comparative dynamics and distribution of influenza drug resistance acquisition to protein m2 and neuraminidase inhibitors.

    PubMed

    Garcia, Vanessa; Aris-Brosou, Stéphane

    2014-02-01

    Although efficient influenza vaccines are designed on a regular basis, the only protection of human populations against an unforeseen virus such as during the H1N1 pandemic in 2009 might be antiviral drugs. Adamantanes and neuraminidase inhibitors (Oseltamivir) represent two classes of such drugs that target the viral matrix protein 2 and neuraminidase, respectively. Although the emergence of resistance to both drugs has been described, the timing and spread of the acquisition of either single or dual resistances by different hosts is still unclear. Using a multilayered phylogenetic approach based on relaxed molecular clocks and large-scale maximum likelihood approaches, we show that Adamantane resistance evolved multiple times in various subtypes and hosts, possibly in breeding contexts (swine); and Oseltamivir resistance was also found in different subtypes and hosts, but its transmission is only sustained in humans. Furthermore, the dynamics of the emergence of antiviral resistance were examined for each drug. This showed that although the first mutations conferring resistance to Adamantanes precede US Food and Drug Administration (FDA) approval, general resistance emerged 15-38 years post-drug approval. This is in contrast to Oseltamivir resistance mutations that emerged at most 7 years after FDA approval of the drug. This study demonstrates the power of large-scale analyses to uncover and monitor the emergence dynamics of drug resistance. PMID:24214415

  8. Genome-wide assessment of the carriers involved in the cellular uptake of drugs: a model system in yeast

    PubMed Central

    2011-01-01

    Background The uptake of drugs into cells has traditionally been considered to be predominantly via passive diffusion through the bilayer portion of the cell membrane. The recent recognition that drug uptake is mostly carrier-mediated raises the question of which drugs use which carriers. Results To answer this, we have constructed a chemical genomics platform built upon the yeast gene deletion collection, using competition experiments in batch fermenters and robotic automation of cytotoxicity screens, including protection by 'natural' substrates. Using these, we tested 26 different drugs and identified the carriers required for 18 of the drugs to gain entry into yeast cells. Conclusions As well as providing a useful platform technology, these results further substantiate the notion that the cellular uptake of pharmaceutical drugs normally occurs via carrier-mediated transport and indicates that establishing the identity and tissue distribution of such carriers should be a major consideration in the design of safe and effective drugs. PMID:22023736

  9. Risk assessment of distribution coefficient from 137Cs measurements.

    PubMed

    Külahci, Fatih; Sen, Zekai

    2009-02-01

    Classically distribution coefficient is defined as the ratio of solid total element concentration to surface water total concentration. This coefficient is obtained from the ion measurements in the Keban Dam, Turkey, which supplies water for domestic, irrigation and hydroelectric energy generation purposes. The measurements of 137Cs are carried out in 40 different sites and the general risk formulation and application is achieved for the distribution coefficient. The models are of exponential type and the spatial independence of the data is considered. Various charts are prepared for a set of risk levels as 5%, 10%, 20%, 25%, and 50%. PMID:18274870

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

    PubMed Central

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

    2013-01-01

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

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

    PubMed

    Chuang-Stein, Christy; Xia, H Amy

    2013-01-01

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

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

    PubMed Central

    Carter, Lawrence P.; Griffiths, Roland R.

    2009-01-01

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

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

    PubMed Central

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

    2007-01-01

    Background Fatal heroin overdose is a significant cause of mortality for injection drug users (IDUs). Many of these deaths are preventable because opiate overdoses can be quickly and safely reversed through the injection of Naloxone [brand name Narcan], a prescription drug used to revive persons who have overdosed on heroin or other opioids. Currently, in several cities in the United States, drug users are being trained in naloxone administration and given naloxone for immediate and successful reversals of opiate overdoses. There has been very little formal description of the challenges faced in the development and implementation of large-scale IDU naloxone administration training and distribution programs and the lessons learned during this process. Methods During a one year period, over 1,000 participants were trained in SKOOP (Skills and Knowledge on Opiate Prevention) and received a prescription for naloxone by a medical doctor on site at a syringe exchange program (SEP) in New York City. Participants in SKOOP were over the age of 18, current participants of SEPs, and current or former drug users. We present details about program design and lessons learned during the development and implementation of SKOOP. Lessons learned described in the manuscript are collectively articulated by the evaluators and implementers of the project. Results There were six primary challenges and lessons learned in developing, implementing, and evaluating SKOOP. These include a) political climate surrounding naloxone distribution; b) extant prescription drug laws; c) initial low levels of recruitment into the program; d) development of participant appropriate training methodology; e) challenges in the design of a suitable formal evaluation; and f) evolution of program response to naloxone. Conclusion Other naloxone distribution programs may anticipate similar challenges to SKOOP and we identify mechanisms to address them. Strategies include being flexible in program planning and implementation, developing evaluation instruments for feasibility and simplicity, and responding to and incorporating feedback from participants. PMID:17254345

  14. Assessment of potential drug–drug interactions and its associated factors in the hospitalized cardiac patients

    PubMed Central

    Murtaza, Ghulam; Khan, Muhammad Yasir Ghani; Azhar, Saira; Khan, Shujaat Ali; Khan, Tahir M.

    2015-01-01

    Drug–drug interactions (DDIs) may result in the alteration of therapeutic response. Sometimes they may increase the untoward effects of many drugs. Hospitalized cardiac patients need more attention regarding drug–drug interactions due to complexity of their disease and therapeutic regimen. This research was performed to find out types, prevalence and association between various predictors of potential drug–drug interactions (pDDIs) in the Department of Cardiology and to report common interactions. This study was performed in the hospitalized cardiac patients at Ayub Teaching Hospital, Abbottabad, Pakistan. Patient charts of 2342 patients were assessed for pDDIs using Micromedex® Drug Information. Logistic regression was applied to find predictors of pDDIs. The main outcome measure in the study was the association of the potential drug–drug interactions with various factors such as age, gender, polypharmacy, and hospital stay of the patients. We identified 53 interacting-combinations that were present in total 5109 pDDIs with median number of 02 pDDIs per patient. Overall, 91.6% patients had at least one pDDI; 86.3% were having at least one major pDDI, and 84.5% patients had at least one moderate pDDI. Among 5109 identified pDDIs, most were of moderate (55%) or major severity (45%); established (24.2%), theoretical (18.8%) or probable (57%) type of scientific evidence. Top 10 common pDDIs included 3 major and 7 moderate interactions. Results obtained by multivariate logistic regression revealed a significant association of the occurrence of pDDIs in patient with age of 60 years or more (p < 0.001), hospital stay of 7 days or longer (p < 0.001) and taking 7 or more drugs (p < 0.001). We found a high prevalence for pDDIs in the Department of Cardiology, most of which were of moderate severity. Older patients, patients with longer hospital stay and with elevated number of prescribed drugs were at higher risk of pDDIs. PMID:27013915

  15. Comparision of the different probability distributions for earthquake hazard assessment in the North Anatolian Fault Zone

    NASA Astrophysics Data System (ADS)

    Yilmaz, Şeyda; Bayrak, Erdem; Bayrak, Yusuf

    2016-04-01

    In this study we examined and compared the three different probabilistic distribution methods for determining the best suitable model in probabilistic assessment of earthquake hazards. We analyzed a reliable homogeneous earthquake catalogue between a time period 1900-2015 for magnitude M ≥ 6.0 and estimated the probabilistic seismic hazard in the North Anatolian Fault zone (39°-41° N 30°-40° E) using three distribution methods namely Weibull distribution, Frechet distribution and three-parameter Weibull distribution. The distribution parameters suitability was evaluated Kolmogorov-Smirnov (K-S) goodness-of-fit test. We also compared the estimated cumulative probability and the conditional probabilities of occurrence of earthquakes for different elapsed time using these three distribution methods. We used Easyfit and Matlab software to calculate these distribution parameters and plotted the conditional probability curves. We concluded that the Weibull distribution method was the most suitable than other distribution methods in this region.

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

    ERIC Educational Resources Information Center

    Hughes, Shannon; Cohen, David

    2010-01-01

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

  17. 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...

  18. Assessment of Distributed Generation Potential in JapaneseBuildings

    SciTech Connect

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

    2005-05-25

    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.

  19. Assessment of distributed solar power systems: Issues and impacts

    NASA Astrophysics Data System (ADS)

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

    1982-11-01

    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 interactive computer program that allows easy calculation of allowable system prices and allowable generation-equipment prices was developed as part of this project. It is concluded that the technical problems raised by distributed solar systems are surmountable, but their resolution may be costly. The stringent purchase criteria likely to be imposed by many potential system users and the economies of large-scale systems make small systems (less than 10 to 20 kW) less attractive than larger systems. Utilities that consider life-cycle costs in making investment decisions and third-party investors who have tax and financial advantages are likely to place the highest value on solar-power systems.

  20. Assessing the HIV-1 Epidemic in Brazilian Drug Users: A Molecular Epidemiology Approach

    PubMed Central

    Guimarães, Monick Lindenmeyer; Marques, Bianca Cristina Leires; Bertoni, Neilane; Teixeira, Sylvia Lopes Maia; Morgado, Mariza Gonçalves; Bastos, Francisco Inácio

    2015-01-01

    Person who inject illicit substances have an important role in HIV-1 blood and sexual transmission and together with person who uses heavy non-injecting drugs may have less than optimal adherence to anti-retroviral treatment and eventually could transmit resistant HIV variants. Unfortunately, molecular biology data on such key population remain fragmentary in most low and middle-income countries. The aim of the present study was to assess HIV infection rates, evaluate HIV-1 genetic diversity, drug resistance, and to identify HIV transmission clusters in heavy drug users (DUs). For this purpose, DUs were recruited in the context of a Respondent-Driven Sampling (RDS) study in different Brazilian cities during 2009. Overall, 2,812 individuals were tested for HIV, and 168 (6%) of them were positive, of which 19 (11.3%) were classified as recent seroconverters, corresponding to an estimated incidence rate of 1.58%/year (95% CI 0.92–2.43%). Neighbor joining phylogenetic trees from env and pol regions and bootscan analyses were employed to subtype the virus from132 HIV-1-infected individuals. HIV-1 subtype B was prevalent in most of the cities under analysis, followed by BF recombinants (9%-35%). HIV-1 subtype C was the most prevalent in Curitiba (46%) and Itajaí (86%) and was also detected in Brasília (9%) and Campo Grande (20%). Pure HIV-1F infections were detected in Rio de Janeiro (9%), Recife (6%), Salvador (6%) and Brasília (9%). Clusters of HIV transmission were assessed by Maximum likelihood analyses and were cross-compared with the RDS network structure. Drug resistance mutations were verified in 12.2% of DUs. Our findings reinforce the importance of the permanent HIV-1 surveillance in distinct Brazilian cities due to viral resistance and increasing subtype heterogeneity all over Brazil, with relevant implications in terms of treatment monitoring, prophylaxis and vaccine development. PMID:26536040

  1. Assessing the HIV-1 Epidemic in Brazilian Drug Users: A Molecular Epidemiology Approach.

    PubMed

    Guimares, Monick Lindenmeyer; Marques, Bianca Cristina Leires; Bertoni, Neilane; Teixeira, Sylvia Lopes Maia; Morgado, Mariza Gonalves; Bastos, Francisco Incio

    2015-01-01

    Person who inject illicit substances have an important role in HIV-1 blood and sexual transmission and together with person who uses heavy non-injecting drugs may have less than optimal adherence to anti-retroviral treatment and eventually could transmit resistant HIV variants. Unfortunately, molecular biology data on such key population remain fragmentary in most low and middle-income countries. The aim of the present study was to assess HIV infection rates, evaluate HIV-1 genetic diversity, drug resistance, and to identify HIV transmission clusters in heavy drug users (DUs). For this purpose, DUs were recruited in the context of a Respondent-Driven Sampling (RDS) study in different Brazilian cities during 2009. Overall, 2,812 individuals were tested for HIV, and 168 (6%) of them were positive, of which 19 (11.3%) were classified as recent seroconverters, corresponding to an estimated incidence rate of 1.58%/year (95% CI 0.92-2.43%). Neighbor joining phylogenetic trees from env and pol regions and bootscan analyses were employed to subtype the virus from132 HIV-1-infected individuals. HIV-1 subtype B was prevalent in most of the cities under analysis, followed by BF recombinants (9%-35%). HIV-1 subtype C was the most prevalent in Curitiba (46%) and Itaja (86%) and was also detected in Braslia (9%) and Campo Grande (20%). Pure HIV-1F infections were detected in Rio de Janeiro (9%), Recife (6%), Salvador (6%) and Braslia (9%). Clusters of HIV transmission were assessed by Maximum likelihood analyses and were cross-compared with the RDS network structure. Drug resistance mutations were verified in 12.2% of DUs. Our findings reinforce the importance of the permanent HIV-1 surveillance in distinct Brazilian cities due to viral resistance and increasing subtype heterogeneity all over Brazil, with relevant implications in terms of treatment monitoring, prophylaxis and vaccine development. PMID:26536040

  2. Causality assessment of adverse drug reaction in Pulmonology Department of a Tertiary Care Hospital

    PubMed Central

    Khan, Amer; Adil, Mir S.; Nematullah, K.; Ihtisham, S.; Aamer, K.; Aamir, Syed

    2015-01-01

    Background: Adverse drug reaction (ADR) is considered to be the sixth leading cause of death. The incidence rate estimates approximately 2% of hospital admissions are due to ADRs. Objective: To monitor ADRs in Pulmonology department of a tertiary care hospital patient with pulmonary diseases in an inpatient department of pulmonology. Materials and Methods: A prospective, single centered, observational and open labeled study was carried out in Princess Esra Hospital. The patient population was broadly divided into four categories based on diagnosis - chronic obstructive pulmonary disease, Infections, Asthma and Others. Suspected ADRs were reported, analyzed, and causality assessment was carried out using Naranjo's algorithm scale. Results: A total of 302 patients were observed, of which 98 patients experienced ADRs, which accounted for 32.23% of the incidence and totally 160 ADEs were observed. Adult Patients were found to have higher incidence (32.09%) while the incidence rate was slightly greater in geriatric patients (32.39%). The highest incidence of ADEs were found in others group (78.57%). Majority of ADRs were suspected to be due to theophylline (19.39%). Gastrointestinal system (38.75%) was the most common organ system affected due to ADRs. Drug was withdrawn in 12 patients, and specific treatment was administered to 32 patients in view of clinical status. Specific treatment for the management of suspected reaction was administered in 32.65% of ADR reports. Conclusion: A relatively high incidence of adverse drug events (32.2%) have been recorded which shows that not only Geriatric patients, but also adults are more susceptible to adverse drug effects. A number of drugs in combination were used, and ADEs often get multiplied. Careful therapeutic monitoring and dose individualization is necessary. PMID:26229344

  3. A Challenge for Diagnosing Acute Liver Injury with Concomitant/Sequential Exposure to Multiple Drugs: Can Causality Assessment Scales Be Utilized to Identify the Offending Drug?

    PubMed Central

    Lim, Roxanne; Conner, Kim; Karnsakul, Wikrom

    2014-01-01

    Drug-induced hepatotoxicity most commonly manifests as an acute hepatitis syndrome and remains the leading cause of drug-induced death/mortality and the primary reason for withdrawal of drugs from the pharmaceutical market. We report a case of acute liver injury in a 12-year-old Hispanic boy, who received a series of five antibiotics (amoxicillin, ceftriaxone, vancomycin, ampicillin/sulbactam, and clindamycin) for cervical lymphadenitis/retropharyngeal cellulitis. Histopathology of the liver biopsy specimen revealed acute cholestatic hepatitis. All known causes of acute liver injury were appropriately excluded and (only) drug-induced liver injury was left as a cause of his cholestasis. Liver-specific causality assessment scales such as Council for the International Organization of Medical Sciences/Roussel Uclaf Causality Assessment Method scoring system (CIOMS/RUCAM), Maria and Victorino scale, and Digestive Disease Week-Japan were applied to seek the most likely offending drug. Although clindamycin is the most likely cause by clinical diagnosis, none of causality assessment scales aid in the diagnosis. PMID:25506455

  4. Independent Orbiter Assessment (IOA): Assessment of the electrical power distribution and control subsystem, volume 1

    NASA Technical Reports Server (NTRS)

    Schmeckpeper, K. R.

    1988-01-01

    The results of the Independent Orbiter Assessment (IOA) of the Failure Modes and Effects Analysis (FMEA) and Critical Items List (CIL) are presented. The IOA first completed an analysis of the Electrical Power Distribution and Control (EPD and C) hardware, generating draft failure modes and potential critical items. To preserve independence, this analysis was accomplished without reliance upon the results contained within the NASA FMEA/CIL documentation. The IOA results were then compared to the NASA FMEA/CIL baseline with proposed Post 51-L updates included. A resolution of each discrepancy from the comparison is provided through additional analysis as required. This report documents the results of that comparison for the Orbiter EPD and C hardware. The IOA product for the EPD and C analysis consisted of 1671 failure mode analysis worksheets that resulted in 468 potential critical items being identified. Comparison was made to the proposed NASA Post 51-L baseline which consisted of FMEAs and 158 CIL items. Volume 1 contains the EPD and C subsystem description, analysis results, ground rules and assumptions, and some of the IOA worksheets.

  5. Assessment and prevention of gastrointestinal toxicity of non-steroidal anti-inflammatory drugs.

    PubMed

    Lane, Majella E; Kim, Mi-Jeong

    2006-10-01

    Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used for analgesic, anti-inflammatory and, in the case of aspirin, for anti-thrombotic actions. The serious gastrointestinal side-effects associated with these drugs are of concern and pose a significant obstacle to their use. This review discusses the pathogenic mechanisms by which the conventional acidic NSAIDs induce gastrointestinal toxicity, with particular emphasis on non-prostaglandin effects. Methods of assessment of NSAID-induced enteropathy are reviewed, with particular emphasis on the use of functional measurement of NSAID-induced changes in the gastrointestinal tract. The advances in our knowledge of the pathogenesis of these effects have resulted in the development of a range of novel NSAIDs. Where functional assessment of the effects of NSAIDs has been employed, it appears to be more useful as an indicator of early-stage changes rather than a predictor of the effects of long-term NSAID exposure. Successful pharmaceutical strategies now offer considerable promise for reducing the severity of NSAID damage to the gastrointestinal tract. The utility of intestinal permeability measurements for selection and assessment of these strategies is discussed. PMID:17034651

  6. Application of distribution coefficients to radiological assessment models

    SciTech Connect

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

    1985-01-01

    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.

  7. Assessing human vulnerability: Daytime residential distribution as a vulnerability indicator

    NASA Astrophysics Data System (ADS)

    Gokesch, Karin; Promper, Catrin; Papathoma-Köhle, Maria; Glade, Thomas

    2014-05-01

    Natural hazard risk management is based on detailed information on potential impacts of natural hazards. Especially concerning fast onset hazards such as flash floods, earthquakes but also debris flows and landslides, knowing potential hotspots of impact to both, assets and human lives is essential. This information is important for emergency management and decision making in the response phase of the disaster management cycle. Emergency managers are in need of information regarding not only the number of humans being potentially affected but also the respective vulnerability of the group affected based on characteristics such as age, income, health condition, mobility, etc. regarding a certain hazard. The analysis presented focuses on the distribution of the population, assuming a certain pattern of people in a certain radius of action. The method applied is based on a regular pattern of movement of different groups of people and a pattern of presence in certain units, e.g. schools, businesses or residential buildings. The distribution is calculated on a minimum of available data including the average household size, as well as information on building types. The study area is located in the Southwest of Lower Austria, Austria. The city of Waidhofen/Ybbs can be regarded as a regional center providing basic infrastructure, shops and schools. The high concentration of buildings combining shops and residential units leads to a high damage potential throughout the whole study area. The presented results indicate the population distribution within the study area on an average working day. It is clear that explicitly high numbers of people are located in specific buildings (e.g. schools and hospitals) which also include highly vulnerable groups especially to fast onset hazards. The results provide emergency services with the information that they need in order to intervene directly where large numbers of victims or people that need to be evacuated are located. In this way, emergency services can focus and prioritize their actions in order to save lives and reduce the number of potential victims.

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

    PubMed Central

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

    2012-01-01

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

  9. Assessing cognitive improvement in people with Down syndrome: important considerations for drug-efficacy trials.

    PubMed

    Fernandez, Fabian; Reeves, Roger H

    2015-01-01

    Experimental research over just the past decade has raised the possibility that learning deficits connected to Down syndrome (DS) might be effectively managed by medication. In the current chapter, we touch on some of the work that paved the way for these advances and discuss the challenges associated with translating them. In particular, we highlight sources of phenotypic variability in the DS population that are likely to impact performance assessments. Throughout, suggestions are made on how to detect meaningful changes in cognitive-adaptive function in people with DS during drug treatment. The importance of within-subjects evaluation is emphasized. PMID:25977089

  10. Pharmacoepidemiology in the postmarketing assessment of the safety and efficacy of drugs in older adults.

    PubMed

    Hilmer, Sarah N; Gnjidic, Danijela; Abernethy, Darrell R

    2012-02-01

    Much of the information on safety and efficacy of drugs in older people is obtained after marketing. Pharmacoepidemiologic studies play an increasing role in obtaining this information. Pharmacoepidemiologic studies contribute significantly to knowledge of risks associated with medicines in older people and less so to that of benefits. Recent improvements in methodology in both pharmacoepidemiology and geriatric medicine have improved the validity and reduced the bias of these studies. Pharmacoepidemiologic studies are a critical component of assessing the risks of medicines in older people. Where possible, findings of pharmacoepidemiologic studies should be tested with well-conducted interventional randomized trials in relevant populations of older people. PMID:21653991

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

    PubMed Central

    Swanton, R H; Coltart, D J

    1978-01-01

    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. PMID:359015

  12. Initial volume of a drug before it reaches the volume of distribution: pharmacokinetics of F(ab')2 antivenoms and other drugs.

    PubMed

    Sevcik, Carlos; Salazar, Victor; Díaz, Patricia; D'Suze, Gina

    2007-10-01

    Fast disappearance of F(ab')2 antivenoms from the plasma compartment [Sevcik et al., 2004. Modelling Tityus scorpion venom and antivenom pharmacokinetics. Evidence of active immunoglobulin G's F(ab')2 extrusion mechanism from blood to tissues. Toxicon 44, 731-734; Vazquez et al., 2005. Pharmacokinetics of a F(ab')2 scorpion antivenom in healthy human volunteers. Toxicon 46, 797-805] suggests a quick time course to reach its final distribution volume. An equation was developed to describe how the volume occupied by a drug in the body grows with time. As discussed in the paper this equation is free of some shortcomings of an equation developed for the same purpose by Niazi [1976. Volume of distribution as a function of time. J. Pharm. Sci. 65, 452-454]. Fluorescence microscopy showed that the rapid initial decay in plasmatic F(ab')2 concentration may be related to uptake of F(ab')2 by vascular endothelium which, in combination with accumulation in the vascular wall connective tissue, may produce an intermediate plateau in F(ab')2 V(sl)(t), which reached its final value after 10 h. The V(sl)(t) equation predicts that the plasma concentration half-time of decay has little use to estimate how a drug distributes through the body to exert its action, and predicts that, in some instances, intermediate plateaus in the time course of V(sl)(t) exist. Data from the literature showed that the kinetic considerations for V(sl)(t) also apply to clevidipine, digoxin, digitoxin, lidocaine and thiopentone. PMID:17689580

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

    PubMed

    Cauwels, Vanessa; Vanhavere, Filip; Reginatto, Marcel

    2014-10-01

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

  14. Assessing mechanical vulnerability in water distribution networks under multiple failures

    NASA Astrophysics Data System (ADS)

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

    2014-03-01

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

  15. Assessing the Impact of Drug Use and Drug Selling on Violent Offending in a Panel of Delinquent Youth

    PubMed Central

    Phillips, Matthew D.

    2016-01-01

    Despite a vast number of empirical studies arguing for or against a causal relationship between illegal drug use and selling and violent behavior, the debate continues. In part this is due to methodological weaknesses of previous research. Using data from the Rochester Youth Development Study, the current study seeks to improve on prior research designs to allow for a more precise examination of the mechanisms that lead from an individual’s drug use (chiefly, marijuana use in the current sample) and drug selling to violent action. Results will allow for greater confidence in making causal inference regarding a long-standing concern in the discipline. PMID:26889079

  16. Capturing illicit drug use where and when it happens: an ecological momentary assessment of the social, physical and activity environment of using versus craving illicit drugs

    PubMed Central

    Linas, Beth S.; Latkin, Carl; Westergaard, Ryan P.; Chang, Larry W.; Bollinger, Robert C.; Genz, Andrew; Kirk, Gregory D.

    2015-01-01

    Aims To understand the environmental and contextual influences of illicit cocaine and heroin use and craving using mobile health (mHealth) methods. Design Interactive mHealth methods of ecological momentary assessment (EMA) were utilized in the Exposure Assessment in Current Time (EXACT) study to assess drug use and craving among urban drug users in real time. Participants were provided with mobile devices and asked to self-report every time they either craved (without using) or used heroin or cocaine for 30 days from November 2008 through May 2013. Setting Baltimore, MD, USA. Participants A total of 109 participants from the AIDS Linked to the IntraVenous Experience (ALIVE) study. Measurements For each drug use or craving event, participants answered questions concerning their drug use, current mood and their social, physical and activity environments. Odds ratios (OR) of drug use versus craving were obtained from logistic regression models with generalized estimating equations of all reported events. Findings Participants were a median of 48.5 years old, 90% African American, 52% male and 59% HIV-infected. Participants were significantly more likely to report use rather than craving drugs if they were with someone who was using drugs [adjusted odds ratio (aOR) = 1.45, 95% confidence interval (CI) = 1.13, 1.86), in an abandoned space (aOR = 6.65, 95% CI = 1.78, 24.84) or walking/wandering (aOR = 1.68, 95% CI = 1.11, 2.54). Craving drugs was associated with being with a child (aOR = 0.26, 95% CI = 0.12, 0.59), eating (aOR = 0.54, 95% CI = 0.34, 0.85) or being at the doctor’s office (aOR = 0.31, 95% CI = 0.12, 0.80). Conclusions There are distinct drug using and craving environments among urban drug users, which may provide a framework for developing real-time context-sensitive interventions. PMID:25311241

  17. Assessing the spectral distribution on different tracking confederations

    NASA Astrophysics Data System (ADS)

    Gaspar, G.; Pó, J. M.; Magarreiro, C.; Los, A.; Brito, M. C.

    2012-10-01

    In this paper we evaluate the local spectral resource of different tracking configurations for low CPV applications, under clear sky conditions. The Spectral Model for Atmospheric Transmission of Sunshine (SMARTS) is employed to compute the solar spectrum of cloud free weather conditions, together with a model that describes the performance of different tracking configurations. The required input data to run the models are gathered for one specific clear sky day at Cabauw, The Netherlans, where the measured radiative fluxes showed a good agreement. We also calculate the spectral indicator Average Photon Energy (APE) of the SMARTS output for the different tracking configurations, to study the spectral variation during the day. Results show that the spectral distribution of a tracking system varies more than a horizontal fixed surface, and also, that the different tracking configurations can have different shifts in the incident spectrum, which provides interesting information for a low CPV systems design.

  18. Assessment of a model for measuring drug diffusion through implant-generated fibrous capsule membranes.

    PubMed

    Wood, R C; LeCluyse, E L; Fix, J A

    1995-08-01

    Fibrous tissue, which encapsulates subcutaneously implanted silastic, vinyl, polyurethane and Teflon discs in rats, has been isolated, characterized and tested for drug permeability in order to develop an in vitro model for determining the effect of this tissue on drug disposition from implant sites. With all materials, capsule tissue thickness and collagen content (approximately 59%) was consistent from 2 to 4 months after implantation. Silastic implants afforded the most consistent and usable tissue in terms of thickness and lack of vascularity, and these capsule membranes were used for determining the transport of three model compounds in an in vitro diffusion cell model. The rank ordering of permeability through these membranes was estrone (60.2 x 10(-6) cm s-1) > 3-O-methylglucose (18.7 x 10(-6) cm s-1) > dextran of molecular weight 70 000 (5.6 x 10(-6) cm s-1), which is consistent with expectations based on the molecular weights and partitioning behaviour of the model compounds. The results of these studies indicate that implant-generated encapsulating membranes can be successfully isolated and employed to study drug diffusion in an in vitro model, providing a direct assessment of the barrier properties of encapsulating membranes. PMID:8562786

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

    PubMed

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

    2010-03-01

    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 1.0mg/kg/inj of histamine was effective in moving responding to the alternate lever, whereas saline, 0.1, or 0.3mg/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

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

    PubMed Central

    Gruskin, Sofia; Raad, Zyde

    2010-01-01

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

  1. Neonatal drug exposure: assessing a specific population and services provided by visiting nurses.

    PubMed

    Mahony, D L; Murphy, J M

    1999-01-01

    Historically, community health nurses have provided nursing services to infants who were exposed to licit and illicit drugs in utero and their mothers. The charts of 145 infants whose mothers had a history of drug and alcohol abuse and who were referred to a visiting nurse agency between 1988 and 1994 were reviewed for this study. Of the infants who were reported to have been exposed to drugs in utero, 69% were exposed to cocaine, 11% to heroin, and 6% to marijuana. The average age of the mothers was 26 years; 83.4% were single; 82.1% received Aid for Families of Dependent Children (AFDC); 92.4% were on Medicaid; and 95.9% were involved with child protective services. The most frequent nursing problems identified were (a) maternal-child attachment, (b) sleep patterns, (c) infant feeding, and (d) infant development. Nursing interventions included nutritional management, physical assessment, monitoring growth and development, and education in parenting skills. Fifty percent of the infants increased their weight by at least one percentile and 31% increased two percentiles. Resolution of nursing problems occurred in 50% of the cases. PMID:10335247

  2. Independent assessment of Mass Drug Administration in filariasis affected Surat city.

    PubMed

    Vaishnav, K G; Patel, I C

    2006-03-01

    The Mass Drug Administration (MDA) done in Surat city (Gujarat) during 2005, revealed good impact on infection and infectivity in mosquitoes and also on microfilaria rate & mean infection density. The overall impact seen was 23% on mf rate, 28% on mean mf density, 65% on infection rate and 50% on infectivity rate in vectors. Indigenous population contribution to microfilaria cases was 9.7%, whereas migratory population contributed 72.2%; predominant 51.9% from Orissa and 20.3% from U.P. Of the total 3640 persons interviewed for MDA compliance in seven zones of the Surat city revealed that actual drug consumption was 76.7% (2792/3640). Another 11.9% although took the drug but did not consume and 11.4% refused. Important reasons for consuming was fear to get the disease (40.7%) and for not consuming; 'will consume after meal' (6.9%), too many tablets (1.7%), seek consent from doctor (1.5%), lack of awareness (1.4%) etc. Refusal was mainly due to the reason as respondents felt apparently healthy. Assessment of IEC activities suggested that main awareness was created by media (local or national TV, banners or handbills, local news papers or mike announcement) alongwith some impact made through NGO's. These observations clearly indicated the utility of effective health education for optimum community participation and shown that it was crucial for successful community based elimination campaign. However some gray areas also suggest the scope for further improvements. PMID:17370677

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

    ERIC Educational Resources Information Center

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

    2013-01-01

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

  4. Assessment of the use of oral fluid as a matrix for drug monitoring in patients undergoing treatment for opioid addiction.

    PubMed

    Kunkel, Frank; Fey, Elizabeth; Borg, Damon; Stripp, Richard; Getto, Christine

    2015-01-01

    Drug testing is an important clinical tool that is available to physicians who are assessing the effectiveness of drug treatment as well as patient compliance to the administered program. While urine has traditionally been the matrix of choice for drug monitoring, oral fluid, a filtrate of the blood, has shown great promise as an alternative matrix for such applications. Oral fluid collection can be accomplished without the need for highly trained medical staff through the use of a simple, noninvasive oral fluid collection device, which obtains an adequate sample in only a few minutes. There has been a significant amount of research performed on the use of oral fluid for forensic toxicology application; however, more studies assessing the use of oral fluid drug testing are required to validate its ability to achieve clinical drug monitoring goals. Testing for various drugs in oral fluid may yield a different result when compared to the same drugs in urine, requiring an assessment of the utility of oral fluid for such practices. The purpose of this study was to examine the application of oral fluid drug testing in patients undergoing buprenorphine treatment for opioid dependence. A retrospective analysis of drug testing results obtained from 6,928 patients (4,560 unobserved urine collections and 2,368 observed oral fluid collections) monitored for heroin metabolite, amphetamine, benzodiazepines, buprenorphine, tetrahydrocannabinol, cocaine, codeine, hydrocodone, hydromorphone, methadone, morphine, oxycodone, and oxymorphone was completed. Results of this statistical exercise indicated that patients undergoing observed oral fluid collection tested positive more frequently than those unobserved urine collections for several illicit drugs and prescription medications targeted. Oral fluid was shown to detect illicit drug use as well as noncompliance in this patient population under the studied conditions more often than the urine specimens. PMID:26535971

  5. The effect of the drying temperature on the properties of wet-extruded calcium stearate pellets: pellet microstructure, drug distribution, solid state and drug dissolution.

    PubMed

    Schrank, S; Kann, B; Saurugger, E; Hainschitz, M; Windbergs, M; Glasser, B J; Khinast, J; Roblegg, E

    2015-01-30

    Although drying is widely applied during the manufacturing of solid dosage forms, its potential effect on the product's (key) properties is often underestimated. Hence, the present study addresses drying related modifications of wet-extruded pellets comprising calcium stearate (CaSt, matrix former) and ibuprofen (model drug). After spheronization, the pellets were tray dried at different temperatures. The dried pellets were evaluated regarding their microstructure, the ibuprofen distribution, solid state modifications and the resulting in-vitro dissolution profiles. The ibuprofen distribution profiles along the pellets' cross-sections varied for the different drying conditions. The profiles turned from inhomogeneous to uniform with increasing drying temperature. Temperatures above 20°C yielded solid state modifications, including ibuprofen transition into the amorphous state and the formation of eutectic compositions. As none of the batches exhibited a high specific surface area associated with an open, well-interconnected pore system, the dissolution profiles were a function of the ibuprofen distribution. Differences in the solid state did not contribute to the dissolution behavior, since the CaSt matrix did not swell or dissolve in the dissolution medium. These findings show that drying may considerably affect the final product properties even for moderate drying conditions. PMID:25526671

  6. Drug-induced QT interval prolongation and torsades de pointes: Role of the pharmacist in risk assessment, prevention and management.

    PubMed

    Tisdale, James E

    2016-05-01

    Torsades de pointes (TdP) is a life-threatening arrhythmia associated with prolongation of the corrected QT (QTc) interval on the electrocardiogram. More than 100 drugs available in Canada, including widely used antibiotics, antidepressants, cardiovascular drugs and many others, may cause QTc interval prolongation and TdP. Risk factors for TdP include QTc interval >500 ms, increase in QTc interval ≥60 ms from the pretreatment value, advanced age, female sex, acute myocardial infarction, heart failure with reduced ejection fraction, hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, treatment with diuretics and elevated plasma concentrations of QTc interval-prolonging drugs due to drug interactions, inadequate dose adjustment of renally eliminated drugs in patients with kidney disease and rapid intravenous administration. Pharmacokinetic drug interactions associated with the highest risk of TdP include antifungal agents, macrolide antibiotics (except azithromycin) and drugs to treat human immunodeficiency virus interacting with amiodarone, disopyramide, dofetilide or pimozide. Other important pharmacokinetic interactions include antidepressants (bupropion, duloxetine, fluoxetine, paroxetine) interacting with flecainide, quinidine or thioridazine. Pharmacists play an important role in minimizing the risk of drug-induced QTc interval prolongation and TdP through knowledge of drugs that are associated with a known or possible risk of TdP, individualized assessment of risk of drug-induced QTc interval prolongation, awareness of drug interactions most likely to result in TdP and attention to dose reduction of renally eliminated QTc interval-prolonging drugs in patients with kidney disease. Treatment of hemodynamically stable TdP consists of discontinuation of the offending drug(s), correction of electrolyte abnormalities and administration of intravenous magnesium sulfate 1 to 2 g. PMID:27212965

  7. Assessing the Essentiality of Leishmania donovani Nitroreductase and Its Role in Nitro Drug Activation

    PubMed Central

    Patterson, Stephen; Fairlamb, Alan H.

    2013-01-01

    The nitroimidazole fexinidazole has potential as a safe and effective oral drug therapy for the treatment of visceral leishmaniasis. To date, nitroheterocyclics have not been used in the treatment of leishmaniasis, and relatively little is known about their mechanism of action. In African trypanosomes, nitro drugs are reductively activated by a type I nitroreductase (NTR), absent in mammalian cells. Modulation of nitroreductase levels in Trypanosoma brucei directly affected sensitivity to nitro compounds, with reduced concentrations of the enzyme leading to moderate nitro drug resistance. In view of the progression of fexinidazole into clinical development for visceral leishmaniasis, here we assess the essentiality of the nitroreductase in Leishmania donovani and the effect of modulating nitroreductase levels on susceptibility to fexinidazole. The failure to directly replace both endogenous copies of the NTR gene, except in the presence of an ectopic copy of the gene, suggests that the NTR gene is essential for the growth and survival of L. donovani promastigotes. Loss of a single chromosomal copy of the L. donovani NTR gene resulted in parasites that were mildly resistant (<2-fold) to the predominant in vivo metabolite of fexinidazole, while parasites overexpressing NTR were 18-fold more susceptible. These data confirm that Leishmania NTR plays a pivotal role in fexinidazole activation. Reliance on a single enzyme for prodrug activation may leave fexinidazole vulnerable to the emergence of drug resistance. However, the essentiality of the NTR in L. donovani promastigotes, combined with the limited resistance shown by NTR single knockout cells, suggests that the potential for the spread of NTR-based resistance to fexinidazole may be limited. PMID:23208716

  8. Can vesicle size distributions assess eruption intensity during volcanic activity?

    NASA Astrophysics Data System (ADS)

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

    2013-10-01

    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 Eyjafjallajkull 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 Eyjafjallajkull 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 Eyjafjallajkull 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 Eyjafjallajkull 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 Eyjafjallajkull 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.

  9. Comparative assessment of two indices of drug induced permeability changes in the perfused rat intestine.

    PubMed

    Lane, Majella E; Levis, Karl; McDonald, George S A; Corrigan, Owen I

    2006-04-01

    In the present study, two indices of acute intestinal permeability changes were investigated as measurements of drug induced intestinal damage. The first method was based on 14C-polyethylene glycol (PEG) 4000 permeability assessment and the second was based on histological evaluation of the intestine. The test compounds were ibuprofen, ketoprofen and naproxen and the alanine, glycine and phenylalanine amide derivatives of ibuprofen. Perfusion studies were carried out using a rat model. Post-perfusion, the gut was fixed and tissue changes were assessed and scored. Ibuprofen, ketoprofen and naproxen altered the barrier properties of the intestine to PEG 4000 with significantly higher scores (p<0.05) for gastrointestinal toxicity relative to blank buffer. For ketoprofen, PEG 4000 permeability and intestinal damage scores increased with increasing ketoprofen concentration. Ibuprofen amide derivatives did not induce significant histological damage or PEG 4000 permeability when compared with ibuprofen. A correlation coefficient of 0.91 is obtained when intestinal damage scores are plotted against PEG 4000 permeability for all compounds. Both indices are proposed as rapid and useful measures of drug induced acute intestinal damage. PMID:16476530

  10. Using ICR and SCID mice as animal models for smallpox to assess antiviral drug efficacy.

    PubMed

    Titova, Ksenya A; Sergeev, Alexander A; Zamedyanskaya, Alena S; Galahova, Darya O; Kabanov, Alexey S; Morozova, Anastasia A; Bulychev, Leonid E; Sergeev, Artemiy A; Glotova, Tanyana I; Shishkina, Larisa N; Taranov, Oleg S; Omigov, Vladimir V; Zavjalov, Evgenii L; Agafonov, Alexander P; Sergeev, Alexander N

    2015-09-01

    The possibility of using immunocompetent ICR mice and immunodeficient SCID mice as model animals for smallpox to assess antiviral drug efficacy was investigated. Clinical signs of the disease did not appear following intranasal (i.n.) challenge of mice with strain Ind-3a of variola virus (VARV), even when using the highest possible dose of the virus (5.2 log10 p.f.u.). The 50 % infective doses (ID50) of VARV, estimated by the virus presence or absence in the lungs 3 and 4 days post-infection, were 2.7 ± 0.4 log10 p.f.u. for ICR mice and 3.5 ± 0.7 log10 p.f.u. for SCID mice. After i.n. challenge of ICR and SCID mice with VARV 30 and 50 ID50, respectively, steady reproduction of the virus occurred only in the respiratory tract (lungs and nose). Pathological inflammatory destructive changes were revealed in the respiratory tract and the primary target cells for VARV (macrophages and epithelial cells) in mice, similar to those in humans and cynomolgus macaques. The use of mice to assess antiviral efficacies of NIOCH-14 and ST-246 demonstrated the compliance of results with those described in scientific literature, which opens up the prospect of their use as an animal model for smallpox to develop anti-smallpox drugs intended for humans. PMID:26067292

  11. The "other diseases" of the Millennium Development Goals: rhetoric and reality of free drug distribution to cure the poor's parasites.

    PubMed

    Allen, Tim; Parker, Melissa

    2011-01-01

    The sixth MDG aims 'to combat HIV/AIDS, TB, malaria and other diseases'. The residual category of 'other diseases' has become the focus of intense interest, partly because it has provided an opportunity to increase resources for the control of the mostly parasitic 'neglected tropical diseases' (NTDs). Intense lobbying has secured large amounts of funding from donors, as well as generous donations of medicines from the major drug companies. A massive programme is now underway to treat the parasites of the poor in Africa via integrated vertical interventions of mass drug administration in endemic areas. The approach has been hailed as remarkably effective, with claims that there is now a real prospect of complete control and, for some NTDs, even elimination. However, a closer look at evaluation and research data reveals that much less is known about what is being achieved than is suggested. Competition between implementing organisations is leading to potentially counterproductive exaggerations about treatment coverage. Detailed local-level research in Uganda and Tanzania shows that actual rates of drug take-up among target populations are often lower than is necessary to effectively control the diseases, and that methods of drug distribution may even lead to active resistance to treatment. If current trends are not corrected, declining rates of NTD infection will not be sustained. Much more rigorous and effective monitoring is essential. PMID:21591302

  12. Intravitreal clearance and volume of distribution of compounds in rabbits: In silico prediction and pharmacokinetic simulations for drug development.

    PubMed

    del Amo, Eva M; Vellonen, Kati-Sisko; Kidron, Heidi; Urtti, Arto

    2015-09-01

    The aims of this research were to (1) create a curated universal database of intravitreal volumes of distribution (Vss, ivt) and clearances (CL ivt) of small molecular weight compounds and macromolecules and (2) to develop quantitative structure property relationship (QSPR) and pharmacokinetic models for the estimation of vitreal drug concentrations based on the compound structure. Vss, ivt and CL ivt values were determined from the available literature on intravitreal drug administration using compartmental models and curve fitting. A simple QSPR model for CL ivt of small molecular weight compounds was obtained with two descriptors: Log D7.4 and hydrogen bond donor capacity. The model predicted the internal and external test sets reliably with a mean fold error of 1.50 and 1.33, respectively (Q(2)Y=0.62). For 80% of the compounds the Vss, ivt was 1.18-2.28 ml; too narrow range for QSPR model building. Integration of the estimated Vss, ivt and predicted CL ivt parameters into pharmacokinetic simulation models allows prediction of vitreous drug concentrations after intravitreal administration. The present work presents for the first time a database of CL ivt and Vss, ivt values and the dependence of the CL ivt values on the molecular structure. The study provides also useful in silico tools to investigate a priori the intravitreal pharmacokinetic profiles for intravitreally injected candidate compounds and drug delivery systems. PMID:25603198

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

    NASA Astrophysics Data System (ADS)

    Zhang, Xianjun

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

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

    PubMed

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

    2014-07-10

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

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

    EPA Science Inventory

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

  16. 45 CFR 156.295 - Prescription drug distribution and cost reporting.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... prescriptions that were provided under the QHP through retail pharmacies compared to mail order pharmacies, and... drugs dispensed, broken down by pharmacy type, which includes an independent pharmacy, supermarket pharmacy, or mass merchandiser pharmacy that is licensed as a pharmacy by the State and that...

  17. 45 CFR 156.295 - Prescription drug distribution and cost reporting.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... prescriptions that were provided under the QHP through retail pharmacies compared to mail order pharmacies, and... drugs dispensed, broken down by pharmacy type, which includes an independent pharmacy, supermarket pharmacy, or mass merchandiser pharmacy that is licensed as a pharmacy by the State and that...

  18. 45 CFR 156.295 - Prescription drug distribution and cost reporting.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... prescriptions that were provided under the QHP through retail pharmacies compared to mail order pharmacies, and... drugs dispensed, broken down by pharmacy type, which includes an independent pharmacy, supermarket pharmacy, or mass merchandiser pharmacy that is licensed as a pharmacy by the State and that...

  19. 77 FR 59156 - Antimicrobial Animal Drug Sales and Distribution Reporting; Extension of Comment Period

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-09-26

    ... notice of proposed rulemaking that published July 27, 2012 (77 FR 44177) is extended. Submit written or... . SUPPLEMENTARY INFORMATION: I. Background In the Federal Register of July 27, 2012 (77 FR 44177), FDA published...), Food and Drug Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852. Instructions:...

  20. 78 FR 59308 - Antimicrobial Animal Drug Sales and Distribution Annual Summary Report Data Tables

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-09-26

    ... security and confidential business information. In the Federal Register of July 27, 2012 (77 FR 44177), FDA... response to the July 27, 2012, ANPRM (77 FR 44177) commonly included suggestions for further reporting of..., Center for Veterinary Medicine (HFV-210), Food and Drug Administration, 7519 Standish Pl., ]...

  1. A method for the assessment of specific energy distribution in a model tumor system

    SciTech Connect

    Noska, M.A.

    1996-12-31

    Due to the short range of alpha particles in tissue, the calculation of dose from internally deposited alpha emitters requires a detailed analysis of the microscopic distribution of the radionuclide in order to determine the spatial distribution of energy emission events and, from this, the spatial distribution of dose. In the present study, the authors used quantitative autoradiography (QAR) to assess the microdistribution of a radiolabeled monoclonal antibody (MAb) fragment in human glioma xenografts in mice.

  2. A mixture of exponentials distribution for a simple and precise assessment of the volcanic hazard

    NASA Astrophysics Data System (ADS)

    Mendoza-Rosas, A. T.; de La Cruz-Reyna, S.

    2009-03-01

    The assessment of volcanic hazard is the first step for disaster mitigation. The distribution of repose periods between eruptions provides important information about the probability of new eruptions occurring within given time intervals. The quality of the probability estimate, i.e., of the hazard assessment, depends on the capacity of the chosen statistical model to describe the actual distribution of the repose times. In this work, we use a mixture of exponentials distribution, namely the sum of exponential distributions characterized by the different eruption occurrence rates that may be recognized inspecting the cumulative number of eruptions with time in specific VEI (Volcanic Explosivity Index) categories. The most striking property of an exponential mixture density is that the shape of the density function is flexible in a way similar to the frequently used Weibull distribution, matching long-tailed distributions and allowing clustering and time dependence of the eruption sequence, with distribution parameters that can be readily obtained from the observed occurrence rates. Thus, the mixture of exponentials turns out to be more precise and much easier to apply than the Weibull distribution. We recommended the use of a mixture of exponentials distribution when regimes with well-defined eruption rates can be identified in the cumulative series of events. As an example, we apply the mixture of exponential distributions to the repose-time sequences between explosive eruptions of the Colima and Popocatépetl volcanoes, México, and compare the results obtained with the Weibull and other distributions.

  3. A Distributed, Collaborative Intelligent Agent System Approach for Proactive Postmarketing Drug Safety Surveillance

    PubMed Central

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

    2014-01-01

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

  4. Structure-Based Prediction of Drug Distribution Across the Headgroup and Core Strata of a Phospholipid Bilayer Using Surrogate Phases

    PubMed Central

    2015-01-01

    Solvation of drugs in the core (C) and headgroup (H) strata of phospholipid bilayers affects their physiological transport rates and accumulation. These characteristics, especially a complete drug distribution profile across the bilayer strata, are tedious to obtain experimentally, to the point that even simplified preferred locations are only available for a few dozen compounds. Recently, we showed that the partition coefficient (P) values in the system of hydrated diacetyl phosphatidylcholine (DAcPC) and n-hexadecane (C16), as surrogates of the H- and C-strata of the bilayer composed of the most abundant mammalian phospholipid, PC, agree well with the preferred bilayer location of compounds. High P values are typical for lipophiles accumulating in the core, and low P values are characteristic of cephalophiles preferring the headgroups. This simple pattern does not hold for most compounds, which usually have more even distribution and may also accumulate at the H/C interface. To model complete distribution, the correlates of solvation energies are needed for each drug state in the bilayer: (1) for the H-stratum it is the DAcPC/W P value, calculated as the ratio of the C16/W and C16/DAcPC (W for water) P values; (2) for the C-stratum, the C16/W P value; (3) for the H/C interface, the P values for all plausible molecular poses are characterized using the fragment DAcPC/W and C16/W solvation parameters for the parts of the molecule embedded in the H- and C-strata, respectively. The correlates, each scaled by two Collander coefficients, were used in a nonlinear, mass-balance based model of intrabilayer distribution, which was applied to the easily measurable overall P values of compounds in the DMPC (M = myristoyl) bilayers and monolayers as the dependent variables. The calibrated model for 107 neutral compounds explains 94% of experimental variance, achieves similar cross-validation levels, and agrees well with the nontrivial, experimentally determined bilayer locations for 27 compounds. The resulting structure-based prediction system for intrabilayer distribution will facilitate more realistic modeling of passive transport and drug interactions with those integral membrane proteins, which have the binding sites located in the bilayer, such as some enzymes, influx and efflux transporters, and receptors. If only overall bilayer accumulation is of interest, the 1-octanol/W P values suffice to model the studied set. PMID:25179490

  5. Incorporating the assessment of abuse liability into the drug discovery and development process.

    PubMed

    Mansbach, Robert S; Feltner, Douglas E; Gold, Lisa H; Schnoll, Sidney H

    2003-06-01

    Evaluation of abuse liability is one of many obligations incurred by industrial sponsors in the development of medications acting on substrates in the central nervous system. In addition to providing the information necessary for a scheduling recommendation in the marketing application, the abuse liability assessment allows sponsors to estimate safety and commercial risks associated with scheduling, as well as to tailor their pre- and post-approval programs to collect information relevant to product misuse, illicit diversion and physical dependence. There are several important factors to consider before embarking on an abuse liability assessment, including the compound's primary and secondary biochemical activities, its absorption and metabolism, its final formulation, and its intended clinical population. Each of these factors will temper the timing and extent of the abuse liability program in animals and humans. Although every drug development program is unique in some way, a decision-making process may be applied to abuse liability assessment that will serve to better utilize limited resources and inform decisions regarding subsequent steps in the process. The emerging properties of the product will define the unique procedures best applied to assess it. PMID:12759198

  6. Current Approaches for Absorption, Distribution, Metabolism, and Excretion Characterization of Antibody-Drug Conjugates: An Industry White Paper.

    PubMed

    Kraynov, Eugenia; Kamath, Amrita V; Walles, Markus; Tarcsa, Edit; Deslandes, Antoine; Iyer, Ramaswamy A; Datta-Mannan, Amita; Sriraman, Priya; Bairlein, Michaela; Yang, Johnny J; Barfield, Matthew; Xiao, Guangqing; Escandon, Enrique; Wang, Weirong; Rock, Dan A; Chemuturi, Nagendra V; Moore, David J

    2016-05-01

    An antibody-drug conjugate (ADC) is a unique therapeutic modality composed of a highly potent drug molecule conjugated to a monoclonal antibody. As the number of ADCs in various stages of nonclinical and clinical development has been increasing, pharmaceutical companies have been exploring diverse approaches to understanding the disposition of ADCs. To identify the key absorption, distribution, metabolism, and excretion (ADME) issues worth examining when developing an ADC and to find optimal scientifically based approaches to evaluate ADC ADME, the International Consortium for Innovation and Quality in Pharmaceutical Development launched an ADC ADME working group in early 2014. This white paper contains observations from the working group and provides an initial framework on issues and approaches to consider when evaluating the ADME of ADCs. PMID:26669328

  7. Distributional consequences of the transition from age-based to income-based prescription drug coverage in British Columbia, Canada.

    PubMed

    Hanley, Gillian E; Morgan, Steve; Hurley, Jeremiah; van Doorslaer, Eddy

    2008-12-01

    In May, 2003, British Columbia transitioned from an age-based public drug program, with public subsidy primarily based on age, to an age-irrelevant income-based drug program, in which public subsidy is based primarily on household income. As one of the specific aims of the policy change was to improve fairness by increasing the extent to which payment for drugs is based on ability to pay, we measure the progressivity of pharmaceutical financing before and after the policy change in BC using Kakwani indices. Our results suggest that pharmaceutical financing became less regressive after the policy change. However, this decrease in regressivity arose primarily because high-income seniors were making greater direct contributions to pharmaceutical financing and not because low-income households were making smaller direct contributions. Our results also suggest that if the public financing of pharmaceuticals were maintained or increased, a change from age-based to income-based eligibility can unambiguously improve equity in finance. As populations in developed countries age, governments will increasingly consider reforms to publicly financed health-care programs with age-based eligibility. In assessing policy options, financial equity is likely to be a key consideration. These results suggest that income-based pharmacare can improve financial equity especially when implemented with a commitment to maintain or increase public funding for prescription drugs. PMID:18189226

  8. The use of 2D fingerprint methods to support the assessment of structural similarity in orphan drug legislation

    PubMed Central

    2014-01-01

    Background In the European Union, medicines are authorised for some rare disease only if they are judged to be dissimilar to authorised orphan drugs for that disease. This paper describes the use of 2D fingerprints to show the extent of the relationship between computed levels of structural similarity for pairs of molecules and expert judgments of the similarities of those pairs. The resulting relationship can be used to provide input to the assessment of new active compounds for which orphan drug authorisation is being sought. Results 143 experts provided judgments of the similarity or dissimilarity of 100 pairs of drug-like molecules from the DrugBank 3.0 database. The similarities of these pairs were also computed using BCI, Daylight, ECFC4, ECFP4, MDL and Unity 2D fingerprints. Logistic regression analyses demonstrated a strong relationship between the human and computed similarity assessments, with the resulting regression models having significant predictive power in experiments using data from submissions of orphan drug medicines to the European Medicines Agency. The BCI fingerprints performed best overall on the DrugBank dataset while the BCI, Daylight, ECFP4 and Unity fingerprints performed comparably on the European Medicines Agency dataset. Conclusions Measures of structural similarity based on 2D fingerprints can provide a useful source of information for the assessment of orphan drug status by regulatory authorities. PMID:24485002

  9. On the Use of the Beta Distribution in Probabilistic Resource Assessments

    SciTech Connect

    Olea, Ricardo A.

    2011-12-15

    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.

  10. On the Use of the Beta Distribution in Probabilistic Resource Assessments

    USGS Publications Warehouse

    Olea, R.A.

    2011-01-01

    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. ?? 2011 International Association for Mathematical Geology (outside the USA).

  11. Evolution of health technology assessment: best practices of the pan-Canadian Oncology Drug Review

    PubMed Central

    Rocchi, Angela; Chabot, Isabelle; Glennie, Judith

    2015-01-01

    Background In 2007, Canada chose to develop a separate and distinct path for oncology drug health technology assessment (HTA). In 2013, the decision was made to transfer the pan-Canadian Oncology Drug Review (pCODR) to the Canadian Agency for Drugs and Technologies in Health (CADTH), to align the pCODR and CADTH Common Drug Review processes while building on the best practices of both. The objective of this research was to conduct an examination of the best practices established by the pCODR. Methods A qualitative research approach was taken to assess the policies, processes, and practices of the pCODR, based on internationally accepted best practice “principles” in HTA, with a particular focus on stakeholder engagement. Publicly available information regarding the approach of the pCODR was used to gauge the agency’s performance against these principles. In addition, stakeholder observations and real-world experiences were gathered through key informant interviews to be inclusive of perspectives from patient advocacy groups, provincial and/or cancer agency decision-makers, community and academic oncologists, industry, expert committee members, and health economists. Results This analysis indicated that, through the pCODR, oncology stakeholders have had a voice in and have come to trust the quality and relevance of oncology HTA as a vital tool to ensure the best decisions for Canadians with cancer and their health care system. It could be expected that adoption of the principles and processes of the pCODR would bring a similar level of engagement and trust to other HTA organizations in Canada and elsewhere. Conclusion The results of this research led to recommendations for improvement and potential extrapolation of these best practices to other HTA organizations worldwide, along with suggestions for continued evolution of the pCODR in conjunction with its integration into the CADTH. It is clear that the transition of the pCODR to CADTH provides an opportunity for practices initiated by the pCODR to become the standard for these newly amalgamated HTA agencies in Canada. PMID:26082654

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

    NASA Astrophysics Data System (ADS)

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

    2009-12-01

    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.

  13. Assessing the prevalence distribution of abnormal laboratory tests in patients with simple febrile seizure

    PubMed Central

    Yousefichaijan, Parsa; Dorreh, Fatemeh; Abbasian, Ladan; Pakniyat, Abdol Ghader

    2015-01-01

    Introduction: Febrile seizure is an important issue in pediatric practice. Even some pediatricians do not have a proper approach to febrile seizure, making the sick child undergo complex laboratory tests or invasive procedures or even long-term treatment with anticonvulsant drugs. In spite of multiple studies, many controversies have still remained about the significance of febrile seizure. The goal of this study is to assess the prevalence distribution of routinely requested laboratory tests results in simple febrile seizure. Materials and Methods: In a descriptive study, 549 patients with simple febrile seizure were studied. The routine lab tests including complete blood count, electrolyte, urine analysis, and cerebrospinal fluid (CSF) analysis had already been performed for all patients and the results had been recorded in their medical data. These results were collected and statistically analyzed through SPSS software. Results: About 58.7% of our cases were male. Most of the cases were 12–24 months old and the mean body temperature of them was 38.2°C. 99.3% of blood sugar tests, 98% of blood calcium tests, 100% and 99.5% of sodium, and potassium tests, respectively, 100% of blood creatinine, 96.9% of blood urea nitrogen, and 99.1% of urine analysis tests were normal. CSF analysis was done in only 49 cases and the results were normal in all of them. Conclusion: The percentage of abnormal laboratory test results was not statistically significant in febrile seizure and shows that performing all these tests in all patients with simple febrile seizure as routine is not necessary. PMID:26167207

  14. 10 CFR 32.21 - Radioactive drug: Manufacture, preparation, or transfer for commercial distribution of capsules...

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... commercial distribution capsules containing 37 kBq (1 µCi) carbon-14 urea (allowing for nominal variation... 37 kBq (1 µCi) carbon-14 urea (allowing for nominal variation that may occur during the...

  15. Subtraction CT with Low-Flow-Rate Arterial Contrast Injection to Estimate Drug Distribution During Balloon-Occluded Arterial Chemotherapy Infusion for Bladder Cancer

    SciTech Connect

    Mori, Kensaku; Yoshioka, Hiroshi; Nakajima, Kotaro; Irie, Toshiyuki; Sugahara, Shinji; Nozawa, Kumiko; Saida, Yukihisa; Itai, Yuji; Ishikawa, Satoru; Hayashi, Hitoshi

    2000-03-15

    Purpose: To simulate drug distribution during balloon-occluded arterial chemotherapy infusion (BOAI) for urinary bladder cancer using subtraction computed tomography (CT) with low-flow-rate arterial contrast injection (S-CTLA).Methods: Ten patients with bladder cancer underwent S-CTLA, and the distribution of contrast agent during BOAI into both internal iliac arteries simultaneously was evaluated in nine pairs of internal iliac arteries and one single artery. For S-CTLA, spiral CT data were acquired before and after 0.2 ml/sec intraarterial injection of contrast material. The enhancement of the urinary bladder wall, the gluteal muscles, and the pelvic bones was categorized using a 4-grade scale. The grades were compared in each of the three pelvic components and differences were tested for significance using the Wilcoxon test for paired groups.Results: S-CTLA revealed the distribution of the contrast agent clearly. Gluteal muscles grades were significantly higher than those of the other two assessed components.Conclusion: BOAI does not improve the concentration of contrast agent to the bladder wall over neighboring structures, suggesting that the balloon occlusion technique does not achieve its desired goal for chemotherapy targeting.

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

    SciTech Connect

    Walker, Gordon

    2010-09-15

    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.

  17. Polypharmacy as commonly defined is an indicator of limited value in the assessment of drug-related problems

    PubMed Central

    Viktil, Kirsten K; Blix, Hege S; Moger, Tron A; Reikvam, Aasmund

    2007-01-01

    What is already known about this subject Polypharmacy has been linked to heightened risk of occurrence of drug-related problems (DRPs) and a detrimental health outcome. Polypharmacy has been variously defined; in research studies a commonly applied definition has been the concomitant use of five or more drugs. The value of using a definite number of drugs as a cut-off to describe polypharmacy as a risk factor for the occurrence of DRPs has not been validated. What this study adds Nearly half of the patients admitted to general hospitals used five or more drugs; during the hospital stay these patients were prescribed as many new drugs as those admitted with fewer drugs. The presence of DRPs increased approximately linearly with the number of drugs used, for the range of one to >11 drugs. To set a strict cut-off to identify polypharmacy and declare that using more than this number of drugs represents a potential risk for occurrence of DRPs, is of limited value in clinical practice. Aim To investigate whether polypharmacy defined as a definite number of drugs is a suitable indicator for describing the risk of occurrence of drug-related problems (DRPs) in a hospital setting. Methods Patients admitted to six internal medicine and two rheumatology departments in five hospitals were consecutively included and followed during the hospital stay, with particular attention to medication and DRPs. Comparisons were made between patients admitted with five or more drugs and with less than five drugs. Clinical pharmacists assessed DRPs by reviewing medical records and by participating in multidisciplinary team discussions. Results Of a total of 827 patients, 391 (47%) used five or more drugs on admission. Patients admitted with five or more and less than five drugs were prescribed the same number of drugs after admission: 4.1 vs. 3.9 drugs [P = 0.4, 95% confidence interval (CI) − 0.57, 0.23], respectively. The proportion of drugs used on admission which was associated with DRPs was similar in the patient group admitted with five or more drugs and in those admitted with less than five drugs. The number of DRPs per patient increased approximately linearly with the increase in number of drugs used; one unit increase in number of drugs yielded a 8.6% increase in the number of DRPs (95% CI 1.07, 1.10). Conclusion The number of DRPs per patient was linearly related to the number of drugs used on admission. To set a strict cut-off to identify polypharmacy and declare that using more than this number of drugs represents a potential risk for occurrence of DRPs, is of limited value when assessing DRPs in a clinical setting. PMID:16939529

  18. Use of a multistaged time-dependent inhibition assay to assess the impact of intestinal metabolism on drug-drug interaction potential.

    PubMed

    Zientek, Michael; Dalvie, Deepak

    2012-03-01

    In early discovery, compounds are often eliminated because of their potential to undergo metabolic activation and/or cytochrome P450 time-dependent inactivation (TDI). The blockbuster drug raloxifene is an example of a compound that would have been eliminated in the current paradigm. Despite raloxifene's in vitro bioactivation and TDI of CYP3A4, it is well tolerated in patients with no drug-drug interactions. This discordance is attributed to its presystemic glucuronidation, thereby decreasing the amount of unchanged raloxifene available for CYP3A inactivation. The current study used raloxifene as a model to assess the effect of hepatic and intestinal glucuronidation on the kinetic parameters of CYP3A4 inactivation. Therefore, a simple multistaged time-dependent inactivation using UDP-glucuronosyltransferase-enabled and -absent reactions was built to understand the impact of the gut metabolism on inactivation potential. The results of these experiments demonstrated a 2.7-fold change in inactivation efficiency of CYP3A4. Incorporation of these results into a simulated midazolam drug-drug interaction study showed very little change in the pharmacokinetic parameters of the victim drug. In contrast, the absence of glucuronidation resulted in a 4.1-fold increase in the area under the curve (AUC) of midazolam, when in the presence of raloxifene, hence providing an understanding of the impact of intestinal glucuronidation on raloxifene's time-dependent inhibition of CYP3A4 and also providing a validation of a simple in vitro experiment to assess the influence of gut metabolism on time-dependent inhibitors at the discovery phase. PMID:22112384

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

    PubMed Central

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

    2014-01-01

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

  20. Functional ATP-binding cassette drug efflux transporters in isolated human and rat hepatocytes significantly affect assessment of drug disposition.

    PubMed

    Lundquist, Patrik; Englund, Gunilla; Skogastierna, Cristine; Lööf, Johan; Johansson, Jenny; Hoogstraate, Janet; Afzelius, Lovisa; Andersson, Tommy B

    2014-03-01

    Freshly isolated hepatocytes are considered the gold standard for in vitro studies of hepatic drug disposition. To ensure a reliable supply of cells, cryopreserved human hepatocytes are often used. ABC-superfamily drug efflux transporters are key elements in hepatic drug disposition. These transporters are often considered lost after isolation of hepatocytes. In the present study, the expression and activity of ABC transporters BCRP, BSEP, P-gp, MRP2, MRP3, and MRP4 in human and rat cryopreserved hepatocytes were investigated. In commercially available human cryopreserved hepatocytes, all drug efflux transporters except human BCRP (hBCRP) exhibited similar expression levels as in fresh liver biopsies. Expression levels of hBCRP were 60% lower in cryopreserved human hepatocytes than in liver tissue, which could lead to, at most, a 2.5-fold reduction in hBCRP-mediated efflux. Fresh rat hepatocytes showed significantly lower levels of rat BCRP compared with liver expression levels; expression levels of other ABC transporters were unchanged. ABC transporters in human cryopreserved cells were localized to the plasma membrane. Functional studies could demonstrate P-gp and BCRP activity in both human cryopreserved and fresh rat hepatocytes. Inhibiting P-gp-mediated efflux by elacridar in in vitro experiments significantly decreased fexofenadine efflux from hepatocytes, resulting in an increase in apparent fexofenadine uptake. The results from the present study clearly indicate that ABC transporter-mediated efflux in freshly isolated as well as cryopreserved rat and human hepatocytes should be taken into account in in vitro experiments used for modeling of drug metabolism and disposition. PMID:24396144

  1. Mining hidden knowledge for drug safety assessment: topic modeling of LiverTox as a case study

    PubMed Central

    2014-01-01

    Background Given the significant impact on public health and drug development, drug safety has been a focal point and research emphasis across multiple disciplines in addition to scientific investigation, including consumer advocates, drug developers and regulators. Such a concern and effort has led numerous databases with drug safety information available in the public domain and the majority of them contain substantial textual data. Text mining offers an opportunity to leverage the hidden knowledge within these textual data for the enhanced understanding of drug safety and thus improving public health. Methods In this proof-of-concept study, topic modeling, an unsupervised text mining approach, was performed on the LiverTox database developed by National Institutes of Health (NIH). The LiverTox structured one document per drug that contains multiple sections summarizing clinical information on drug-induced liver injury (DILI). We hypothesized that these documents might contain specific textual patterns that could be used to address key DILI issues. We placed the study on drug-induced acute liver failure (ALF) which was a severe form of DILI with limited treatment options. Results After topic modeling of the "Hepatotoxicity" sections of the LiverTox across 478 drug documents, we identified a hidden topic relevant to Hy's law that was a widely-accepted rule incriminating drugs with high risk of causing ALF in humans. Using this topic, a total of 127 drugs were further implicated, 77 of which had clear ALF relevant terms in the "Outcome and management" sections of the LiverTox. For the rest of 50 drugs, evidence supporting risk of ALF was found for 42 drugs from other public databases. Conclusion In this case study, the knowledge buried in the textual data was extracted for identification of drugs with potential of causing ALF by applying topic modeling to the LiverTox database. The knowledge further guided identification of drugs with the similar potential and most of them could be verified and confirmed. This study highlights the utility of topic modeling to leverage information within textual drug safety databases, which provides new opportunities in the big data era to assess drug safety. PMID:25559675

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

    PubMed Central

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

    2013-01-01

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

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

    PubMed

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

    2013-12-01

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

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

    PubMed Central

    Guo, Su

    2009-01-01

    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. PMID:19774094

  5. Nanoparticles Made From Xyloglucan-Block-Polycaprolactone Copolymers: Safety Assessment for Drug Delivery.

    PubMed

    Mazzarino, Letcia; Loch-Neckel, Gecioni; Dos Santos Bubniak, Lorena; Ourique, Fabiana; Otsuka, Issei; Halila, Sami; Curi Pedrosa, Rozangela; Santos-Silva, Maria Cludia; Lemos-Senna, Elenara; Curti Muniz, Edvani; Borsali, Redouane

    2015-09-01

    Xyloglucan-block-polycaprolactone (XGO-PCL) copolymer nanoparticles have been proposed as nanocarriers for drug delivery. However, the possible harmful effects of exposure to nanoparticles still remain a concern. Therefore, the aim of this study is to evaluate the potential toxicity of XGO-PCL nanoparticles using invitro and invivo assays. Cytotoxicity and genotoxicity studies were conducted on MRC-5 human fetal lung fibroblast cells upon exposure to XGO-PCL nanoparticles. No significant reduction in the cell viability and no DNA damage were observed at the different concentrations tested. Erythrocyte toxicity was assessed by the incubation of nanoparticles with human blood. XGO-PCL nanoparticles induced a hemolytic ratio of less than 1%, indicating good blood compatibility. Finally, the subacute toxicity of XGO-PCL nanoparticles (10?mg/kg/day) was evaluated in BALB/c mice when administered orally or intraperitoneally for 14 days. Results of the invivo toxicity study showed no clinical signs of toxicity, mortality, weight loss, or hematological and biochemical alterations after treatment with nanoparticles. Also, microscopic analysis of the major organs revealed no histopathological abnormalities, corroborating the previous results. Thus, it can be concluded that XGO-PCL nanoparticles induced no effect indicative of toxicity, indicating their potential use as drug delivery systems. PMID:26048652

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

    PubMed Central

    James, Martin W; Hawkey, Christopher J

    2003-01-01

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

  7. Project Towards No Drug Abuse (TND): Needs Assessment of a Social Service Referral Telephone Program for High Risk Youth

    PubMed Central

    SUSSMAN, STEVE; SKARA, SILVANA; PUMPUANG, PATCHAREEYA

    2011-01-01

    The purpose of this study was to conduct a needs assessment of a potential social service resource telephone program component among high risk youth who received the Project Towards No Drug Abuse (TND) classroom-based program (approximately 1 year earlier). Results supported youths’ overwhelming receptiveness of a social service referral program. The vast majority of respondents indicated a strong desire for resource and referral information on vocational, educational, recreational, transportation, and mental health and drug counseling. Further research is needed to investigate the effectiveness of the provision of social service resource information on drug use among emerging adults. PMID:18720266

  8. Comparison of indicators assessing the quality of drug prescribing for asthma.

    PubMed Central

    Veninga, C C; Denig, P; Pont, L G; Haaijer-Ruskamp, F M

    2001-01-01

    OBJECTIVE: To compare different indicators for assessing the quality of drug prescribing and establish their agreement in identifying doctors who may not adhere to treatment guidelines. DATA SOURCES/STUDY SETTING: Data from 181 general practitioners (GPs) from The Netherlands. The case of asthma is used as an example because, in this area, different quality indicators exist whose validity is questioned. The study is part of the European Drug Education Project. STUDY DESIGN: Spearman rank correlations were assessed among the GPs' scores on self-report instruments, aggregated prescribing indicators, and individualized prescribing indicators. Kappa values were calculated as agreement measures for identifying low adherence to the guidelines. DATA COLLECTION: Prescribing data from GPs were collected through pharmacies, public health insurance companies, or computerized GP databases. Two self-report instruments were mailed to the GPs. The GPs first received a questionnaire assessing their competence regarding the treatment of asthma patients. Three months later they received a series of 16 written asthma cases asking for their intended treatment for each case. PRINCIPAL FINDINGS: Correlations between scores based on self-report instruments and indicators based on actual prescribing data were mostly nonsignificant and varied between 0 and 0.21. GPs identified as not adhering to the guidelines by the prescribing indicators often had high scores on the self-report instruments. Correlations between 0.20 and 0.55 were observed among indicators based on aggregated prescribing data and those based on individualized data. The agreement for identifying low adherence was small, with kappa values ranging from 0.19 to 0.30. CONCLUSIONS: Indicators based on self-report instruments seem to overestimate guideline adherence. Indicators assessing prescribing quality at an aggregated level give clearly different results, as compared to indicators evaluating prescribing data on an individual patient level. Caution is needed when using such prescribing indicators to identify low adherence to guidelines. Further validation studies using a gold standard comparison are needed to define the best possible indicator. PMID:11324741

  9. Detecting patients with Alzheimer's disease suitable for drug treatment: comparison of three methods of assessment.

    PubMed Central

    Wilcock, G K; Ashworth, D L; Langfield, J A; Smith, P M

    1994-01-01

    BACKGROUND. Therapy to enhance cholinergic function in the brain is under evaluation for the treatment of Alzheimer's disease. Tetrahydroaminoacridine (tacrine) has recently received a product licence in the United States of America for the treatment of Alzheimer's disease, and the licence application in the United Kingdom will shortly be reviewed. It is therefore possible that this drug will become available for use in the UK in due course. There will then be a need for screening procedures for a large number of elderly patients to decide whether or not they have dementia and, if so, whether it is the result of Alzheimer's disease and is suitable for treatment with the new drug. METHOD. A total of 246 patients aged 75 years or over in two general practices in Bristol were assessed to investigate the potential workload such screening would engender. Three different assessment schedules for the diagnosis of dementia were compared--the mini-mental state examination, the Kew test, and the abbreviated mental test score. RESULTS. None of the assessment schedules was found to be particularly onerous, with median times for administration of five, three and two minutes, respectively. A score of 23 or less on the mini-mental state examination was taken as the main cut-off point for further evaluation. Sixty six patients obtained this score--in 25 the low score reflected factors other than dementia, and 11 others declined further assessment. Of the remaining 30 patients only four had probable Alzheimer's disease at an appropriate level of severity for treatment, and lived with a carer who could ensure compliance and monitor side effects. Two of these patients were receiving conflicting medical treatment and a third declined therapy, leaving only one person for whom treatment could be prescribed. CONCLUSION. It seems likely that of those medically suitable for treatment, it may not be possible to prescribe tacrine for an appreciable proportion. Nevertheless, all potential patients should be screened as the procedures involved are not onerous and at least some of those found suitable for treatment are likely to benefit from this new approach. PMID:8312036

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

    PubMed

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

    2014-09-01

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

  11. Detecting drug-induced prolongation of the QRS complex: New insights for cardiac safety assessment

    SciTech Connect

    Cros, C.; Skinner, M.; Moors, J.; Lainee, P.; Valentin, J.P.

    2012-12-01

    Background: Drugs slowing the conduction of the cardiac action potential and prolonging QRS complex duration by blocking the sodium current (I{sub Na}) may carry pro-arrhythmic risks. Due to the frequency-dependent block of I{sub Na}, this study assesses whether activity-related spontaneous increases in heart rate (HR) occurring during standard dog telemetry studies can be used to optimise the detection of class I antiarrhythmic-induced QRS prolongation. Methods: Telemetered dogs were orally dosed with quinidine (class Ia), mexiletine (class Ib) or flecainide (class Ic). QRS duration was determined standardly (5 beats averaged at rest) but also prior to and at the plateau of each acute increase in HR (3 beats averaged at steady state), and averaged over 1 h period from 1 h pre-dose to 5 h post-dose. Results: Compared to time-matched vehicle, at rest, only quinidine and flecainide induced increases in QRS duration (E{sub max} 13% and 20% respectively, P < 0.01–0.001) whereas mexiletine had no effect. Importantly, the increase in QRS duration was enhanced at peak HR with an additional effect of + 0.7 ± 0.5 ms (quinidine, NS), + 1.8 ± 0.8 ms (mexiletine, P < 0.05) and + 2.8 ± 0.8 ms (flecainide, P < 0.01) (calculated as QRS at basal HR-QRS at high HR). Conclusion: Electrocardiogram recordings during elevated HR, not considered during routine analysis optimised for detecting QT prolongation, can be used to sensitise the detection of QRS prolongation. This could prove useful when borderline QRS effects are detected. Analysing during acute increases in HR could also be useful for detecting drug-induced effects on other aspects of cardiac function. -- Highlights: ► We aimed to improve detection of drug-induced QRS prolongation in safety screening. ► We used telemetered dogs to test class I antiarrhythmics at low and high heart rate. ► At low heart rate only quinidine and flecainide induced an increase in QRS duration. ► At high heart rate the effects of two out of three antiarrhythmics were enhanced. ► Detection of a drug-induced prolongation of QRS was improved at high heart rate.

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

    SciTech Connect

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

    2013-12-01

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

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

    PubMed Central

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

    2012-01-01

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

  14. A first-principles model for prediction of product dose uniformity based on drug substance particle size distribution.

    PubMed

    Hilden, Jon; Schrad, Mark; Kuehne-Willmore, Jennifer; Sloan, Jessica

    2012-07-01

    The unit dose uniformity (UDU) of low-dose drug products can be affected by active pharmaceutical ingredient (API) particle size. UDU relative standard deviation increases as the fraction of large API particles increases and/or as the unit dose decreases. Control of API particle size has traditionally been based on the empirical relationship of d(90) and/or d(50) statistics to drug product uniformity. Several articles have been written that have identified a theoretical relationship between these particle size statistics, dose, and the probability of meeting US Pharmacopeial UDU testing criteria (Huang CY, Ku S. 2010. Int J Pharm 383:70-80; Rohrs B, Amidon G, Meury R, Secreast P, King H, Skoug C. 2006. J Pharm Sci 95(5):1049-1059; Huang CY, Ku S. 2010. J Pharm Sci 99:4351-4362; Yalkowsky SH, Bolton S. 1990. Pharm Res 7(9):962-966). However, these theoretical relationships assume a fixed shape for the API particle size distribution (PSD, i.e., lognormal) and do not account for changes in the distribution shape. A more rigorous method for predicting the effect of a given PSD on UDU is to evaluate the contribution of individual particle size bins on UDU variability. The latter approach is taken in this work, and the derivation reveals that the individual contribution of particles size bins can be expressed completely in terms of a single-particle-size statistic, D[6,3]. D[6,3] is therefore a valid predictor of UDU, regardless of the shape of the PSD (e.g., multimodal) and can form the basis of a particle size control strategy for low-dose drug products. PMID:22504845

  15. Regional drought assessment using a distributed hydrological model coupled with Standardized Runoff Index

    NASA Astrophysics Data System (ADS)

    Shen, H.; Yuan, F.; Ren, L.; Ma, M.; Kong, H.; Tong, R.

    2015-05-01

    Drought assessment is essential for coping with frequent droughts nowadays. Owing to the large spatio-temporal variations in hydrometeorology in most regions in China, it is very necessary to use a physically-based hydrological model to produce rational spatial and temporal distributions of hydro-meteorological variables for drought assessment. In this study, the large-scale distributed hydrological model Variable Infiltration Capacity (VIC) was coupled with a modified standardized runoff index (SRI) for drought assessment in the Weihe River basin, northwest China. The result indicates that the coupled model is capable of reasonably reproducing the spatial distribution of drought occurrence. It reflected the spatial heterogeneity of regional drought and improved the physical mechanism of SRI. This model also has potential for drought forecasting, early warning and mitigation, given that accurate meteorological forcing data are available.

  16. The assessment on impact of essential drugs policy on primary health care system in rural areas of Shandong Province policy and regulation division of the Health Department of Shandong Province.

    PubMed

    Li, Zhuge; Shu, Defeng; Xia, Mei; Gao, Dehai; Lu, Dan; Huang, Ning; Tian, Xiaoqing; An, Limei; Li, Shixue; Li, Sheng

    2015-01-01

    At present, China has achieved an initial establishment and gradual implementation of a framework for national essential drugs policy. With the further implementation of the national essential drugs policy, it is not clear how the policy works, whether it achieves the original intention of essential drugs policy, and what impact essential drugs policy exerts on the primary health care system. In view of it, we conducted a field research on sample areas of Shandong Province to understand the conditions of the implementation of the essential drugs policy in Shandong Province. From three perspectives of medical institutions, patients and medical staff, this thesis analyzes the impact of essential drugs policy on village-level and township-level health service system, summarizes the effectiveness of implementing essential drugs policy, discovers the problems of various aspects and conducts an in-depth analysis of the causes, and puts forward feasible suggestions to provide reference for improving the essential drugs policy. The assessment results show that the implementation of essential drugs policy in Shandong Province has played a positive role in promoting the sound development of the primary health care system, changed the situation of covering hospital expenses with medicine revenue in the past, contributed to the return of medical institutions to public welfare, and reduced the patient's economic burden of disease. But there emerge many problems as follows: impact on the doctor's diagnosis and treatment due to incompleteness of drug types, and distribution not in place, patient loss and operational difficulty of village clinic. Thus, this thesis makes recommendations of drugs catalog formulation, drug procurement, sales and use, and meanwhile points out that the supporting financial compensation policy and performance appraisal policy and other measures in place are a prerequisite for a positive role of essential drugs policy. PMID:26410322

  17. Database Extraction of Metabolite Information of Drug Candidates: Analysis of 27 AstraZeneca Compounds with Human Absorption, Distribution, Metabolism, and Excretion Data.

    PubMed

    Iegre, Jessica; Hayes, Martin A; Thompson, Richard A; Weidolf, Lars; Isin, Emre M

    2016-05-01

    As part of the drug discovery and development process, it is important to understand the human metabolism of a candidate drug prior to clinical studies. Preclinical in vitro and in vivo experiments across species are conducted to build knowledge concerning human circulating metabolites in preparation for clinical studies; therefore, the quality of these experiments is critical. Within AstraZeneca, all metabolite identification (Met-ID) information is stored in a global database using ACDLabs software. In this study, the Met-ID information derived from in vitro and in vivo studies for 27 AstraZeneca drug candidates that underwent human absorption, distribution, metabolism, and excretion studies was extracted from the database. The retrospective analysis showed that 81% of human circulating metabolites were previously observed in preclinical in vitro and/or in vivo experiments. A detailed analysis was carried out to understand which human circulating metabolites were not captured in the preclinical experiments. Metabolites observed in human hepatocytes and rat plasma but not seen in circulation in humans (extraneous metabolites) were also investigated. The majority of human specific circulating metabolites derive from multistep biotransformation reactions that may not be observed in in vitro studies within the limited time frame in which cryopreserved hepatocytes are active. Factors leading to the formation of extraneous metabolites in preclinical studies seemed to be related to species differences with respect to transporter activity, secondary metabolism, and enzyme kinetics. This retrospective analysis assesses the predictive value of Met-ID experiments and improves our ability to discriminate between metabolites expected to circulate in humans and irrelevant metabolites seen in preclinical studies. PMID:26868617

  18. Application of electroretinography (ERG) in early drug development for assessing retinal toxicity in rats.

    PubMed

    Huang, Wenhu; Collette, Walter; Twamley, Michelle; Aguirre, Shirley A; Sacaan, Aida

    2015-12-15

    Retinal ocular toxicity is among the leading causes of drug development attrition in the pharmaceutical industry. Electroretinography (ERG) is a non-invasive functional assay used to assess neuro-retinal physiological integrity by measuring the electrical responses. To directly assess the utility of ERG, a series of studies was conducted following intravitreal and/or iv administration of pan-cyclin-dependent kinase inhibitors: AG-012,986 and AG-024,322 in rats. Both compounds have previously shown to induce retinal toxicity. Retinal injury was evaluated by ERG, histopathology and TUNEL staining. Intravitreal injection of AG-012,986 at ≥ 10 μg/eye resulted in decreases (60%) in ERG b-wave and microscopic changes of mild to moderate retinal degeneration, and at 30 μg/eye led to additional ophthalmic findings. Intravenous administration of AG-012,986 daily at ≥ 5 mg/kg resulted in dose-related decreases (25 to 40%) in b-wave and sporadic to intense positive TUNEL staining. Intravitreal injection of AG-024,322 at 30 μg/eye also resulted in decreases (50 to 60%) in b-wave, mild to marked retinal degeneration and mild vitreous debris. These experiments demonstrate that ERG can be used as a sensitive and reliable functional tool to evaluate retinal toxicity induced by test compounds in rats complementing other classical ocular safety measurements. PMID:26482841

  19. Kinetic assessment of luminal degradation of orally effective prodrugs for rational drug development.

    PubMed

    Mizuma, Takashi

    2010-02-01

    Although prodrugging (prodrug derivatization) is a powerful technique for improving the pharmacokinetic characteristics of drugs, the intestinal pharmacokinetics of prodrugs has yet to be elucidated fully. A previous article reported the kinetic requirement of prodrugs to overcome membrane barriers. In the present article, the luminal degradation of prodrugs was kinetically assessed to understand crucial factors in the intestinal absorption of prodrugs and to show a rational development procedure. A kinetic model equation involving luminal degradation clearance (CL(deg)) was derived, and CL(deg) was estimated according to the equation with in vitro and in vivo reported data of two kinds of ampicillin prodrugs (lenampicillin and pivampicillin) and one acyclovir prodrug (valacyclovir). For lenampicillin ((2,2-dimethyl-1-oxopropoxy)methyl ester derivative), CL(deg) was approximately 1.7 times as large as absorption clearance (CL(abs)), whereas for pivampicillin ((5-methyl-2-oxo-1,3-dioxol-4-yl)methyl ester derivative), CL(deg) was approximately one tenth of CL(abs). For valacyclovir (acyclovir prodrug), CL(deg) was negligible. These results indicate that not only membrane permeability but also luminal stability should be assessed for the rational development of orally effective prodrugs, and that luminal stabilization can improve the intestinal absorption of prodrugs. A procedure was proposed to develop orally effective prodrugs considered for luminal degradation as well as membrane permeability. PMID:19623605

  20. Development and validation of an instrument to assess treatment adherence for each individual drug taken by a patient

    PubMed Central

    Sidorkiewicz, Stéphanie; Tran, Viet-Thi; Cousyn, Cécile; Perrodeau, Elodie; Ravaud, Philippe

    2016-01-01

    Objective To develop and validate an instrument to assess adherence to each individual drug taken by patients undergoing long-term treatment. Design Multicentre prospective observational validation study. Setting Six general practitioners' clinics and 6 university hospitals in Paris, France. Participants Patients 18 years and older receiving at least one long-term treatment. Methods The instrument was developed from a literature search and interviews with experts. Clarity and wording were assessed during pilot testing with 51 patients. The tool was validated in a sample of consecutive patients. We assessed agreement between adherence measured with our tool and drug diaries and compared measurements from our instrument with (1) the Lu instrument; (2) the Adherence Estimator (AE); (3) patient's adherence assessed by physicians; (4) the Morisky Medication Adherence Scale-4 items (MMAS-4); and (5) the Treatment Burden Questionnaire (TBQ). Reliability was assessed by a test–retest method. Results A total of 243 patients taking 961 drugs were recruited in 2014. We found good agreement between adherence measured by our tool and drug diaries (intraclass correlation coefficient (ICC) 0.69, 95% CI 0.34 to 0.91) and a linear relationship between measurement with our tool and (1) the Lu instrument (p<0.01); (2) 2 items of the AE (perceived need for medication (p<0.01) and concerns about medication (p<0.01)); (3) patients' adherence assessed by their physicians (p<0.01); (4) the MMAS-4 (p<0.01) and (5) the TBQ (p<0.01). Reliability of the retest was good (ICC 0.67, 95% CI 0.42 to 0.85). Conclusions We developed an instrument with acceptable validity and reliability to assess adherence for each drug taken by patients, usable in hospital and primary care settings. PMID:27165645

  1. Left ventricular pressure, contractility and dP/dt(max) in nonclinical drug safety assessment studies.

    PubMed

    Sarazan, R Dustan; Kroehle, John P; Main, Bradley W

    2012-09-01

    Increasing or decreasing cardiac contractility is an undesirable property of drugs being developed for noncardiovascular indications. The International Conference on Harmonization (ICH) Topic S7A and S7B guidelines only require the assessment of heart rate, blood pressure and the electrocardiogram in nonclinical in vivo safety pharmacology studies. Assessment of drug effects on contractility is only suggested as an optional follow-up study. However, these nonclinical safety assessment studies can detect these effects if properly designed and conducted using appropriate instrumentation. Left ventricular dP/dt is the first derivative of left ventricular pressure, which is computed by software algorithms by using calculus. Its peak value, dP/dt(max), is a common, robust and sensitive indicator of changes in cardiac contractility if experimental parameters such as preload, afterload and heart rate are well controlled. In order to ensure accuracy and avoid errors in the measurement of contractility in experimental animals, the frequency response of the pressure sensing system and the sample rate of the data acquisition system must be optimized for the signal. For dogs, nonhuman primates, and normotensive rats, all important information in a left ventricular pressure signal can be captured with a system with a frequency response of 100 Hz. Although systems with much higher frequency response can be used to measure left ventricular pressure, the output of these devices must be filtered to allow no frequencies to be acquired that are higher than one-half the sample rate of the acquisition system. Stated conversely, the sample rate of the acquisition system must be at least 2× the highest frequency contained in the signal. Failure to follow these principals can lead to incorrect results due to measurement artifacts from high frequency noise, which could be present but not detectable by the investigator. This manuscript has been written for biologists who do not have advanced knowledge of physics and/or engineering and is therefore less technical and more simplified than what would be found in the engineering literature. PMID:22659561

  2. Development of a Questionnaire to Assess Drug Abuse among High School Students of Isfahan Province, Iran: An Action Research

    PubMed Central

    Geramian, Nahid; Gharaat, Leila; Taheri, Shohreh Akhavan; Mohebpour, Fatemeh; Nahvizadeh, Mahmonir; Farajzadegan, Ziba; Heidari, Kamal

    2014-01-01

    Background: Considering the problem of drug abuse in Iran especially in adolescents and the youth, recent alterations in drug abuse rate and its trend, the necessity to have local information about this problem, applied research has a determining role in management of this problem and making proper decisions. Therefore, the current study was conducted to develop a questionnaire to assess the status of drug abuse among high school students of Isfahan Province, Iran. Methods: This cross-sectional study was conducted out in 2009 in 20 cities of Isfahan Province. A researcher-made questionnaire was developed to determine knowledge, attitude, and practice of high school students regarding addictive drugs and their associated causes. This was accomplished by recruiting 7137 students who were selected by multistage random cluster sampling. Results: The designed questionnaire identified the status quo of drug abuse according to age, gender, and different cities of Isfahan Province. We also accessed information about the type of abused drug, the most common causes of drug abuse for the first time, the most important causes of drug abuse, mean age of abusers and mean age at the first abuse, common time and locations of drug abuse, and the most common routes of drug abuse according to gender as well as urban and rural areas of Isfahan Province. Reliability of the questionnaire, based on the calculated Cronbach's alpha coefficient, was 77% considering a cut-off point of 0.07. Conclusions: According to the obtained results, the designed questionnaire is capable to assess the drug abuse status among high school students of Isfahan Province. Regarding the importance of teenage years in forming the future behaviors of adolescents and the opportunities provided at schools, it is prudent to pay more attention to interventions in this age group in order to increase their knowledge and correct their attitude toward illegal drugs and strengthening their confidence in this regard. These interventions can have an important role in decreasing the rate of drug abuse in this age group and consequently in the whole community. PMID:26157565

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

    PubMed

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

    2013-02-18

    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

  4. Assessment of Disease-Related Therapeutic Protein Drug-Drug Interaction for Etrolizumab in Patients With Moderately to Severely Active Ulcerative Colitis.

    PubMed

    Wei, Xiaohui; Kenny, Jane R; Dickmann, Leslie; Maciuca, Romeo; Looney, Caroline; Tang, Meina T

    2016-06-01

    The efficacy and safety of etrolizumab, a humanized IgG1 mAb, were evaluated in patients with ulcerative colitis (UC) in a phase 2 study (EUCALYPTUS). The current study assessed the risk of therapeutic protein drug-drug interaction (TP-DDI) of etrolizumab on CYP3A activity in patients with UC. Literature review was performed to compare serum proinflammatory cytokine levels and pharmacokinetic (PK) parameters of CYP3A substrate drugs between patients with inflammatory bowel disease (IBD) and healthy subjects. Treatment effect of etrolizumab on CYP3A activity was evaluated by measuring colonic CYP3A4 mRNA expression and serum C-reactive protein (CRP) in EUCALYPTUS patients. Literature data suggested similar levels between IBD patients and healthy subjects for serum proinflammatory cytokines and PK parameters of CYP3A substrate drugs. Additionally, treatment with etrolizumab did not change colonic CYP3A4 mRNA expression or serum CRP levels in UC patients. In conclusion, our results indicate a low TP-DDI risk for etrolizumab in UC patients, particularly on medications metabolized by CYP3A. PMID:26412221

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

    PubMed

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

    2014-11-01

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

  6. In vivo assessment of antiemetic drugs and mechanism of lycorine-induced nausea and emesis.

    PubMed

    Kretzing, Sascha; Abraham, Getu; Seiwert, Bettina; Ungemach, Fritz Rupert; Krügel, Ute; Teichert, Jens; Regenthal, Ralf

    2011-12-01

    Lycorine is the main alkaloid of many Amaryllidaceae and known to cause poisoning with still unknown mechanisms. Longer lasting toxicological core symptoms of nausea and emesis may become a burden for human and animal patients and may result in substantial loss of water and electrolytes. To optimise the only empirical symptomatic antiemetic drug treatment at present, it is important to elucidate the causative involved targets of lycorine-induced emesis. Therefore, in the current study, we have tested the actions of a various antiemetic drugs with selective receptor affinities on lycorine-induced nausea and emesis in vivo in dogs. Beagle dogs were pre-treated in a saline vehicle-controlled crossover and random design with diphenhydramine, maropitant, metoclopramide, ondansetron or scopolamine prior lycorine administration (2 mg/kg subcutaneously). In vivo effects were assessed by a scoring system for nausea and emesis as well as by the number and lag time of emetic events for at least 3 h. Moreover, plasma pharmacokinetic analysis was carried out for ondansetron before and after lycorine injection. The data show that histaminergic (H₁), muscarinic and dopaminergic (D₂) receptors are presumably not involved in lycorine-induced emetic effects. While ondansetron significantly reduced the number of emetic events, lycorine-induced emesis was completely blocked by maropitant. Only ondansetron also significantly decreased the level of nausea and was able to prolong the lag time until onset of emesis suggesting a preferential participation of 5-HT₃ receptors in lycorine-induced nausea. Thus, it is the first in vivo report evidencing that predominantly neurokinin-1 (NK₁) and to a lesser extent 5-hydroxytryptamine 3 (5-HT₃) receptors are involved in lycorine-induced emesis facilitating a target-oriented therapy. PMID:21626407

  7. The role of health technology assessment bodies in shaping drug development

    PubMed Central

    Ciani, Oriana; Jommi, Claudio

    2014-01-01

    The use of health technology assessment (HTA) to inform policy-making is established in most developed countries. Compared to licensing agencies, HTA agencies have different interests and, therefore, different evidence requirements. Criteria for coverage or reimbursement decisions on pharmaceutical compounds vary; however, it is common to include, as part of the HTA, a comparative effectiveness evaluation. This type of clinical data might go beyond that required for market authorization, thus creating an additional evidence gap between the regulatory and the reimbursement submission. The relevance of submissions to HTA agencies is consistently increasing in a pharmaceutical company’s perspective, as market prospects are strongly influenced by third-party payers’ coverage. In this study, we aim to describe current HTA activities with a potential impact throughout the drug development process of pharmaceuticals, with a comparative emphasis on the systems in place in Italy and in the UK. Based on an extensive literature and website review, we identified three major classes of HTA activities, beyond mainstream HTA, with the potential to influence the drug development program: 1) horizon scanning and early HTA; 2) bipartite and tripartite early dialogue between manufacturers, regulators, and HTA assessors; and 3) managed market entry agreements. From early stages of clinical research up to postauthorization studies, there is a trend toward increased collaboration between parties, anticipation of market access evidence collection, and postmarketing risk-sharing. Heterogeneity of HTA practices increases the complexity of the market access environment. Overall, there are signals that market access departments are gaining importance in the pharmaceutical companies, but there is still a lack of evidence and reporting on how the increasing relevance of HTA has reshaped the way clinical development is designed and managed. PMID:25419117

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

    PubMed Central

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

    2014-01-01

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

  9. The role of health technology assessment bodies in shaping drug development.

    PubMed

    Ciani, Oriana; Jommi, Claudio

    2014-01-01

    The use of health technology assessment (HTA) to inform policy-making is established in most developed countries. Compared to licensing agencies, HTA agencies have different interests and, therefore, different evidence requirements. Criteria for coverage or reimbursement decisions on pharmaceutical compounds vary; however, it is common to include, as part of the HTA, a comparative effectiveness evaluation. This type of clinical data might go beyond that required for market authorization, thus creating an additional evidence gap between the regulatory and the reimbursement submission. The relevance of submissions to HTA agencies is consistently increasing in a pharmaceutical company's perspective, as market prospects are strongly influenced by third-party payers' coverage. In this study, we aim to describe current HTA activities with a potential impact throughout the drug development process of pharmaceuticals, with a comparative emphasis on the systems in place in Italy and in the UK. Based on an extensive literature and website review, we identified three major classes of HTA activities, beyond mainstream HTA, with the potential to influence the drug development program: 1) horizon scanning and early HTA; 2) bipartite and tripartite early dialogue between manufacturers, regulators, and HTA assessors; and 3) managed market entry agreements. From early stages of clinical research up to postauthorization studies, there is a trend toward increased collaboration between parties, anticipation of market access evidence collection, and postmarketing risk-sharing. Heterogeneity of HTA practices increases the complexity of the market access environment. Overall, there are signals that market access departments are gaining importance in the pharmaceutical companies, but there is still a lack of evidence and reporting on how the increasing relevance of HTA has reshaped the way clinical development is designed and managed. PMID:25419117

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

    PubMed Central

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

    2013-01-01

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

  11. 75 FR 4400 - Draft Guidance for Industry on Assessment of Abuse Potential of Drugs; Availability

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-01-27

    ... central nervous system, drugs that are chemically or pharmacologically similar to other drugs with known... Abuse (NIDA), as described in a Memorandum of Understanding (MOU) of March 8, 1985 (50 FR 9518). When...

  12. Assessing the Effects of Non-steroidal Anti-inflammatory Drugs on Antihypertensive Drug Therapy Using Post-Marketing Surveillance Database

    PubMed Central

    Ishiguro, Chieko; Fujita, Toshiharu; Omori, Takashi; Fujii, Yosuke; Mayama, Takeshi; Sato, Tosiya

    2008-01-01

    Background Antihypertensive and non-steroidal anti-inflammatory drugs (NSAIDs) are used to treat many common diseases. However, it has been suspected that interactions between these drugs exist. Here, we assessed the interactions between non-selective NSAIDs and several classes of antihypertensive drugs. Methods The study design was a cohort study using “The Antihypertensive Drug Database,” which is a collection of data accumulated from Drug Use Investigations. Subjects newly starting antihypertensive drug therapy were identified in the database. We compared the “User” group, who were co-administered NSAIDs, with the “Non-user” group, who were not. The outcome measure was the change in systolic blood pressure from the baseline after 2 months of treatment. We estimated the non-adjusted and adjusted differences in the change in systolic blood pressure between the “User” and “Non-user” groups. Results Data were collected for a total of 1,204 subjects, of whom 364 were prescribed beta blockers, 60 were prescribed diuretics, 628 were prescribed angiotensin-converting enzyme inhibitors, and 152 were prescribed calcium channel blockers. The adjusted difference in the change in systolic blood pressure between the User (n = 301) and Non-user (n = 903) groups was 2.88 mmHg (95% confidence interval: 0.89, 4.87); thus, systolic blood pressure in the Non-User group decreased further from the baseline than that in the User group. In subjects administered beta blockers, diuretics, angiotensin-converting enzyme inhibitors, and calcium channel blockers, the corresponding differences were 0.37 mmHg (-3.24, 3.98), 6.11 mmHg (-3.16, 15.37), 3.85 mmHg (1.16, 6.66), and 3.50 mmHg (-2.03, 9.02). Conclusion The effectiveness of antihypertensive drugs was attenuated by the co-administration of NSAIDs. The differences in the effects of NSAIDs varied with different classes of antihypertensive drugs. PMID:18469490

  13. Assessing tephra total grain-size distribution: Insights from field data analysis

    NASA Astrophysics Data System (ADS)

    Costa, A.; Pioli, L.; Bonadonna, C.

    2016-06-01

    The Total Grain-Size Distribution (TGSD) of tephra deposits is crucial for hazard assessment and provides fundamental insights into eruption dynamics. It controls both the mass distribution within the eruptive plume and the sedimentation processes and can provide essential information on the fragmentation mechanisms. TGSD is typically calculated by integrating deposit grain-size at different locations. The result of such integration is affected not only by the number, but also by the spatial distribution and distance from the vent of the sampling sites. In order to evaluate the reliability of TGSDs, we assessed representative sampling distances for pyroclasts of different sizes through dedicated numerical simulations of tephra dispersal. Results reveal that, depending on wind conditions, a representative grain-size distribution of tephra deposits down to ∼100 μm can be obtained by integrating samples collected at distances from less than one tenth up to a few tens of the column height. The statistical properties of TGSDs representative of a range of eruption styles were calculated by fitting the data with a few general distributions given by the sum of two log-normal distributions (bi-Gaussian in Φ-units), the sum of two Weibull distributions, and a generalized log-logistic distribution for the cumulative number distributions. The main parameters of the bi-lognormal fitting correlate with height of the eruptive columns and magma viscosity, allowing general relationships to be used for estimating TGSD generated in a variety of eruptive styles and for different magma compositions. Fitting results of the cumulative number distribution show two different power law trends for coarse and fine fractions of tephra particles, respectively. Our results shed light on the complex processes that control the size of particles being injected into the atmosphere during volcanic explosive eruptions and represent the first attempt to assess TGSD on the basis of pivotal physical quantities, such as magma viscosity and plume height. Our empirical method can be used to assess the main features of TGSD necessary for numerical simulations aimed to real-time forecasting and long-term hazard assessment when more accurate field-derived TGSDs are not available.

  14. Distribution of hepatitis C virus genotypes among injecting drug users in Lebanon

    PubMed Central

    2010-01-01

    Background The aim of this study is to determine the prevalence of anti-HCV among injecting drug users (IDUs) in Lebanon, to establish the current prevalence of HCV genotypes in this population and to determine whether demographic characteristics and behavioral variables differ between participants who were HCV-RNA positive and those who were HCV-RNA negative or between the different genotypes. Participants were recruited using respondent-driven sampling method. The blood samples were collected as dried blood spots and then eluted to be tested for HCV, HBV and HIV by ELISA. Anti-HCV positive samples were subjected to RNA extraction followed by qualitative detection and genotyping. Results Among 106 IDUs, 56 (52.8%) were anti-HCV-positive. The two groups did not differ in terms of age, marital status, and nationality. As for the behavioral variable, there was a trend of increased risky behaviors among the HCV-RNA positive group as compared to the HCV-RNA negative group but none of the variables reached statistical significance. Half (50%) of the 56 anti-HCV-positive were HCV-RNA positive. Genotype 3 was the predominant one (57.1%) followed by genotype 1 (21%) and genotype 4 (18%). Conclusions The predominance of genotype 3 seems to be the predominant genotype among IDUs in Lebanon, a situation similar to that among IDUs in Western Europe. This study provides a base-line against possible future radical epidemiological variant that might occur in IDUs. PMID:20465784

  15. The Differences across Distributed Leadership Practices by School Position According to the Comprehensive Assessment of Leadership for Learning (CALL)

    ERIC Educational Resources Information Center

    Blitz, Mark H.; Modeste, Marsha

    2015-01-01

    The Comprehensive Assessment of Leadership for Learning (CALL) is a multi-source assessment of distributed instructional leadership. As part of the validation of CALL, researchers examined differences between teacher and leader ratings in assessing distributed leadership practices. The authors utilized a t-test for equality of means for the…

  16. The Differences across Distributed Leadership Practices by School Position According to the Comprehensive Assessment of Leadership for Learning (CALL)

    ERIC Educational Resources Information Center

    Blitz, Mark H.; Modeste, Marsha

    2015-01-01

    The Comprehensive Assessment of Leadership for Learning (CALL) is a multi-source assessment of distributed instructional leadership. As part of the validation of CALL, researchers examined differences between teacher and leader ratings in assessing distributed leadership practices. The authors utilized a t-test for equality of means for the

  17. Distribution of the most Common Genetic Variants Associated with a Variable Drug Response in the Population of the Republic of Macedonia.

    PubMed

    Kapedanovska Nestorovska, A; Jakovski, K; Naumovska, Z; Hiljadnikova Bajro, M; Sterjev, Z; Eftimov, A; Matevska Geskovska, N; Suturkova, L; Dimitrovski, K; Labacevski, N; Dimovski, A J

    2014-12-01

    Genetic variation in the regulation, expression and activity of genes coding for Phase I, Phase II drug metabolizing enzymes (DMEs) and drug targets, can be defining factors for the variability in both the effectiveness and occurrence of drug therapy side effects. Information regarding the geographic structure and multi-ethnic distribution of clinically relevant genetic variations is becoming increasingly useful for improving drug therapy and explaining inter-individual and inter-ethnic differences in drug response. This study summarizes our current knowledge about the frequency distribution of the most common allelic variants in three broad gene categories: the Phase I oxidation-cytochrome P450 (CYP450) family (CYP2C9, CYP2C19, CYP3A5, CYP2D6); the Phase II conjugation (GSTT1, SULT1A1; UGT1A1) and drug target (TYMS-TSER, MTHFR and VKORC1) in the population of the Republic of Macedonia and compares the information obtained with data published for other indigenous European populations. Our findings define the population of the Republic of Macedonia as an ethnic group with a highly polymorphic genetic profile. These results add to the evidence regarding the distribution of clinically important variant alleles in DME and drug target genes in populations of European ancestry. PMID:25937793

  18. Distribution of the most Common Genetic Variants Associated with a Variable Drug Response in the Population of the Republic of Macedonia

    PubMed Central

    Kapedanovska Nestorovska, A; Jakovski, K; Naumovska, Z; Hiljadnikova Bajro, M; Sterjev, Z; Eftimov, A; Matevska Geskovska, N; Suturkova, L; Dimitrovski, K; Labacevski, N; Dimovski, AJ

    2014-01-01

    Genetic variation in the regulation, expression and activity of genes coding for Phase I, Phase II drug metabolizing enzymes (DMEs) and drug targets, can be defining factors for the variability in both the effectiveness and occurrence of drug therapy side effects. Information regarding the geographic structure and multi-ethnic distribution of clinically relevant genetic variations is becoming increasingly useful for improving drug therapy and explaining inter-individual and inter-ethnic differences in drug response. This study summarizes our current knowledge about the frequency distribution of the most common allelic variants in three broad gene categories: the Phase I oxidation-cytochrome P450 (CYP450) family (CYP2C9, CYP2C19, CYP3A5, CYP2D6); the Phase II conjugation (GSTT1, SULT1A1; UGT1A1) and drug target (TYMS-TSER, MTHFR and VKORC1) in the population of the Republic of Macedonia and compares the information obtained with data published for other indigenous European populations. Our findings define the population of the Republic of Macedonia as an ethnic group with a highly polymorphic genetic profile. These results add to the evidence regarding the distribution of clinically important variant alleles in DME and drug target genes in populations of European ancestry. PMID:25937793

  19. Assessing the drug release from nanoparticles: Overcoming the shortcomings of dialysis by using novel optical techniques and a mathematical model.

    PubMed

    Xie, Li; Beyer, Susanne; Vogel, Vitali; Wacker, Matthias G; Mäntele, Werner

    2015-07-01

    The aim of the present investigation was to develop a reliable method which can be applied to the measurement of in vitro drug release from nanocarriers. Since the limited membrane transport is one major obstacle to the assessment of drug release with dialysis techniques, the determination of this parameter was our objective. Therefore, a novel drug release automatic monitoring system (DREAMS) was designed to conduct continuous measurements during the dialysis process. Moreover, a mathematical model was used for evaluation of the experimental data. This combination of mathematical and analytical tools enabled the quantification of the total amount of free drug in the system. Eudragit(®) RS 100 nanoparticles loaded with the model compound 5,10,15,20-tetrakis(m-hydroxypheny)chlorin (mTHPC) were investigated and the drug release was continuously monitored by using a fluorescence spectrometer that is part of the setup. Free drug and drug-loaded nanoparticles were tested to discriminate between the two formulations. In addition, two types of membranes composed of different materials were evaluated and the kinetics of membrane transport was determined. The data obtained from the apparatus were further treated by a mathematical model, which yielded distinguishable release profiles between samples of different compositions. The method offers a promising option for release testing of nanoparticles. PMID:25847513

  20. Quantitative whole-body autoradiography, LC-MS/MS and MALDI for drug-distribution studies in biological samples: the ultimate matrix trilogy.

    PubMed

    McEwen, Andrew B; Henson, Claire M; Wood, Stuart G

    2014-02-01

    The drug-development process requires an understanding of the ADME properties of the novel therapeutic agent. Determination of drug concentrations and identity in excreta (urine and feces) examines the products of these processes. Similar measurements made on plasma, while accurately determining exposure, show only what is being transported around the body. Both activities fail to confirm the nature of components at the pharmacologically relevant matrix - the tissue. Attention is therefore being directed towards methods that can be employed to address this lack in our current methodologies, to provide better quality data on which risk assessments can be made, so that pharmacological models can be refined, and drug safety improved. In this article, we will look at the current methods used to obtain tissue drug and drug metabolite concentrations, and their potential use in drug discovery. PMID:24471957

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

    EPA Science Inventory

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

  2. Governance and assessment in a widely distributed medical education program in Australia.

    PubMed

    Solarsh, Geoff; Lindley, Jennifer; Whyte, Gordon; Fahey, Michael; Walker, Amanda

    2012-06-01

    The learning objectives, curriculum content, and assessment standards for distributed medical education programs must be aligned across the health care systems and community contexts in which their students train. In this article, the authors describe their experiences at Monash University implementing a distributed medical education program at metropolitan, regional, and rural Australian sites and an offshore Malaysian site, using four different implementation models. Standardizing learning objectives, curriculum content, and assessment standards across all sites while allowing for site-specific implementation models created challenges for educational alignment. At the same time, this diversity created opportunities to customize the curriculum to fit a variety of settings and for innovations that have enriched the educational system as a whole.Developing these distributed medical education programs required a detailed review of Monash's learning objectives and curriculum content and their relevance to the four different sites. It also required a review of assessment methods to ensure an identical and equitable system of assessment for students at all sites. It additionally demanded changes to the systems of governance and the management of the educational program away from a centrally constructed and mandated curriculum to more collaborative approaches to curriculum design and implementation involving discipline leaders at multiple sites.Distributed medical education programs, like that at Monash, in which cohorts of students undertake the same curriculum in different contexts, provide potentially powerful research platforms to compare different pedagogical approaches to medical education and the impact of context on learning outcomes. PMID:22643380

  3. On the Assessment of Income Distribution: A Comment on the Secretariat Papers.

    ERIC Educational Resources Information Center

    Kravis, Irving B.

    An assessment of three other conference papers summarizing knowledge of the inequalities in the distribution of personal income, education, and educational opportunities leads to fundamental questions about the appropriate framework and goals of public policy in the field of education, inequality, and life chances. Without a clear perception of…

  4. Development of Risk Assessment Methodology for Land Application and Distribution and Marketing of Municipal Sludge

    EPA Science Inventory

    This is one of a series of reports that present methodologies for assessing the potential risks to humans or other organisms from the disposal or reuse of municipal sludge. The sludge management practices addressed by this series include land application practices, distribution a...

  5. Impact of drying on solid state modifications and drug distribution in ibuprofen-loaded calcium stearate pellets.

    PubMed

    Schrank, S; Kann, B; Saurugger, E; Ehmann, H; Werzer, O; Windbergs, M; Glasser, B J; Zimmer, A; Khinast, J; Roblegg, E

    2014-02-01

    Drying is a common pharmaceutical process, whose potential to alter the final drug properties-even at relatively low temperatures-is often neglected. The present study addresses the impact of drying at 20 and 50 °C on wet-extruded calcium stearate (CaSt) pellets. Drying at 20 °C caused the majority of ibuprofen to accumulate at the pellet surface due to a strong convective flow from the pellet's center to the surface. In contrast, pellets dried at 50 °C still contained ibuprofen in the pellet's interior due to the higher drying rate and the associated film breakage during drying. Moreover, the higher drying temperature caused CaSt to form a second lamellar phase and ibuprofen to convert (partly) into its amorphous state. Overall, the drying process affected the solid state and the spatial ibuprofen distribution within the pellet. Knowledge of these effects can aid in tailoring advanced multipellet formulations. PMID:24400735

  6. In vitro assessment of metabolic drug-drug interaction potential of apixaban through cytochrome P450 phenotyping, inhibition, and induction studies.

    PubMed

    Wang, Lifei; Zhang, Donglu; Raghavan, Nirmala; Yao, Ming; Ma, Li; Frost, Charles E; Frost, Charles A; Maxwell, Brad D; Chen, Shiang-yuan; He, Kan; Goosen, Theunis C; Humphreys, W Griffith; Grossman, Scott J

    2010-03-01

    Apixaban is an oral, direct, and highly selective factor Xa inhibitor in late-stage clinical development for the prevention and treatment of thromboembolic diseases. The metabolic drug-drug interaction potential of apixaban was evaluated in vitro. The compound did not show cytochrome P450 inhibition (IC(50) values >20 microM) in incubations of human liver microsomes with the probe substrates of CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6, or 3A4/5. Apixaban did not show any effect at concentrations up to 20 muM on enzyme activities or mRNA levels of selected P450 enzymes (CYP1A2, 2B6, and 3A4/5) that are sensitive to induction in incubations with primary human hepatocytes. Apixaban showed a slow metabolic turnover in incubations of human liver microsomes with formation of O-demethylation (M2) and hydroxylation products (M4 and M7) as prominent in vitro metabolites. Experiments with human cDNA-expressed P450 enzymes and P450 chemical inhibitors and correlation with P450 activities in individual human liver microsomes demonstrated that the oxidative metabolism of apixaban for formation of all metabolites was predominantly catalyzed by CYP3A4/5 with a minor contribution of CYP1A2 and CYP2J2 for formation of M2. The contribution of CYP2C8, 2C9, and 2C19 to metabolism of apixaban was less significant. In addition, a human absorption, distribution, metabolism, and excretion study showed that more than half of the dose was excreted as unchanged parent (f(m CYP) <0.5), thus significantly reducing the overall metabolic drug-drug interaction potential of apixaban. Together with a low clinical efficacious concentration and multiple clearance pathways, these results demonstrate that the metabolic drug-drug interaction potential between apixaban and coadministered drugs is low. PMID:19940026

  7. Comparison of Estimators of Gumbel Distribution for Assessment of Seasonal and Annual Rainfall

    NASA Astrophysics Data System (ADS)

    Vivekanandan, N.

    2015-09-01

    Estimation of seasonal and annual rainfall for a river basin is of importance in planning and management of water resources projects. This study illustrates the use of six different parameter estimation methods for Gumbel distribution for assessment of seasonal and annual rainfall for Krishna and Godavari river basins. Goodness-of-Fit tests involving Anderson-Darling and Kolmogorov-Smirnov are used for checking the adequacy of fitting of Gumbel distribution to the recorded rainfall data. Model performance indicators such as correlation coefficient, model efficiency and root mean square error are used for the selection of suitable method for estimation of rainfall. The study shows that the probability weighted moments are better suited for determination of parameters of Gumbel distribution for assessment of seasonal and annual rainfall for Krishna and Godavari basins.

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

    SciTech Connect

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

    1986-03-05

    (-)-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.

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

    SciTech Connect

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

    2014-09-15

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

  10. Preclinical assessment of CNS drug action using eye movements in mice

    PubMed Central

    Cahill, Hugh; Rattner, Amir; Nathans, Jeremy

    2011-01-01

    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. PMID:21821912

  11. Drug and herb induced liver injury: Council for International Organizations of Medical Sciences scale for causality assessment

    PubMed Central

    Teschke, Rolf; Wolff, Albrecht; Frenzel, Christian; Schwarzenboeck, Alexander; Schulze, Johannes; Eickhoff, Axel

    2014-01-01

    Causality assessment of suspected drug induced liver injury (DILI) and herb induced liver injury (HILI) is hampered by the lack of a standardized approach to be used by attending physicians and at various subsequent evaluating levels. The aim of this review was to analyze the suitability of the liver specific Council for International Organizations of Medical Sciences (CIOMS) scale as a standard tool for causality assessment in DILI and HILI cases. PubMed database was searched for the following terms: drug induced liver injury; herb induced liver injury; DILI causality assessment; and HILI causality assessment. The strength of the CIOMS lies in its potential as a standardized scale for DILI and HILI causality assessment. Other advantages include its liver specificity and its validation for hepatotoxicity with excellent sensitivity, specificity and predictive validity, based on cases with a positive reexposure test. This scale allows prospective collection of all relevant data required for a valid causality assessment. It does not require expert knowledge in hepatotoxicity and its results may subsequently be refined. Weaknesses of the CIOMS scale include the limited exclusion of alternative causes and qualitatively graded risk factors. In conclusion, CIOMS appears to be suitable as a standard scale for attending physicians, regulatory agencies, expert panels and other scientists to provide a standardized, reproducible causality assessment in suspected DILI and HILI cases, applicable primarily at all assessing levels involved. PMID:24653791

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

    NASA Astrophysics Data System (ADS)

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

    1997-05-01

    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.

  13. 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

    2011-01-01

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

  14. Occurrence of several acidic drugs in sewage treatment plants in Switzerland and risk assessment.

    PubMed

    Tauxe-Wuersch, A; De Alencastro, L F; Grandjean, D; Tarradellas, J

    2005-05-01

    The occurrence and fate of five acidic drugs (Mefenamic acid, Ibuprofen, Ketoprofen, Diclofenac and Clofibric acid) were analysed in three sewage treatment plants (STP) over 4-7 consecutive days. The results point out that the five substances were persistent in wastewater effluents after municipal wastewater treatment. At the most, half of Mefenamic acid was eliminated. Ibuprofen was well removed (80%) by one sewage treatment plant. The removal of Ibuprofen is dependent on the residence time of wastewater in the STPs. A long raining period induce an important decrease of removal of Ibuprofen and Ketoprofen. Removal rates showed a great variability according to sewage treatment plants and types of treatments (e.g. biological, physico-chemical). The concentrations of Ibuprofen, Mefenamic acid and Diclofenac were relatively high in the effluents (150-2000 ng/l), showing a potential contamination of surface water. An environmental risk assessment is presented. Mefenamic acid seems to present a risk for the aquatic environment, with a ratio PEC/PNEC higher than one. PMID:15899274

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

    PubMed Central

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

    2006-01-01

    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. PMID:17019567

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

    PubMed

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

    2008-02-15

    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

  17. Pharmacology of antithrombotic drugs: an assessment of oral antiplatelet and anticoagulant treatments.

    PubMed

    Mega, Jessica L; Simon, Tabassome

    2015-07-18

    Antithrombotic drugs, which include antiplatelet and anticoagulant therapies, prevent and treat many cardiovascular disorders and, as such, are some of the most commonly prescribed drugs worldwide. The first drugs designed to inhibit platelets or coagulation factors, such as the antiplatelet clopidogrel and the anticoagulant warfarin, significantly reduced the risk of thrombotic events at the cost of increased bleeding in patients. However, both clopidogrel and warfarin have some pharmacological limitations including interpatient variability in antithrombotic effects in part due to the metabolism, interactions (eg, drug, environment, and genetic), or targets of the drugs. Increased knowledge of the pharmacology of antithrombotic drugs and the mechanisms underlying thrombosis has led to the development of newer drugs with faster onset of action, fewer interactions, and less interpatient variability in their antithrombotic effects than previous antithrombotic drugs. Treatment options now include the next-generation antiplatelet drugs prasugrel and ticagrelor, and, in terms of anticoagulants, inhibitors that directly target factor IIa (dabigatran) or Xa (rivaroxaban, apixaban, edoxaban) are available. In this Series paper we review the pharmacological properties of these most commonly used oral antithrombotic drugs, and explore the development of antiplatelet and anticoagulant therapies. PMID:25777662

  18. Cetyl gellan copolymer micelles and hydrogels: in vitro and pharmacodynamic assessment for drug delivery.

    PubMed

    Kundu, Payel; Maiti, Sabyasachi

    2015-01-01

    In this study, gellan polymer was conferred amphiphilic character by conjugating alkyl carbon chain (C16) to its backbone via etherification reaction. The amphiphilic copolymer self-assembled into water and formed spherical micellar structures with a mean diameter of 832 nm. Copolymer micellization caused a considerable rise in solubility of simvastatin in water. Later on, the micelle-incorporated drug and pure drug were loaded into aluminium gellan hydrogel beads and characterized. Scanning electron microscopy revealed spherical shape of the beads. The drug entrapment efficiency of the beads (917-927 μm) was found to be 90-94%. Higher dissolution efficiency and consequently, higher rate of drug dissolution was evident in phosphate buffer solution (pH 6.8) than in HCl solution (pH 1.2). The changes in drug release rate as a function of pH correlated with the swelling behaviour of beads. The release of drug was controlled by anomalous diffusion mechanism. Fourier transform infrared spectroscopy and X-ray diffraction analyses suggested compatibility of drug in the beads. The gellan beads, loaded with micellar drug, reduced 83.45% LDL-cholesterol level in rabbit model following 18 h of oral administration. Thus, the gellan beads containing micellar drug showed their potential in controlling drug release rate and improving pharmacodynamic activity. PMID:25316420

  19. Measuring topology of low-intensity DNA methylation sites for high-throughput assessment of epigenetic drug-induced effects in cancer cells

    SciTech Connect

    Gertych, Arkadiusz; Bioinformatics, Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, CA ; Farkas, Daniel L.; Tajbakhsh, Jian

    2010-11-15

    Epigenetic anti-cancer drugs with demethylating effects have shown to alter genome organization in mammalian cell nuclei. The interest in the development of novel epigenetic drugs has increased the demand for cell-based assays to evaluate drug performance in pre-clinical studies. An imaging-based cytometrical approach that can measure demethylation effects as changes in the spatial nuclear distributions of methylated cytosine and global DNA in cancer cells is introduced in this paper. The cells were studied by immunofluorescence with a specific antibody against 5-methylcytosine (MeC), and 4,6-diamidino-2-phenylindole (DAPI) for delineation of methylated sites and global DNA in nuclei. In the preprocessing step the segmentation of nuclei in three-dimensional images (3-D) is followed by an automated assessment of nuclear DAPI/MeC patterns to exclude dissimilar entities. Next, low-intensity MeC (LIM) and low-intensity DNA (LID) sites of similar nuclei are localized and processed to obtain specific nuclear density profiles. These profiles sampled at half of the total nuclear volume yielded two parameters: LIM{sub 0.5} and LID{sub 0.5}. The analysis shows that zebularine and 5-azacytidine-the two tested epigenetic drugs introduce changes in the spatial distribution of low-intensity DNA and MeC signals. LIM{sub 0.5} and LID{sub 0.5} were significantly different (p < 0.001) in 5-azacytidine treated (n = 660) and zebularine treated (n = 496) vs. untreated (n = 649) DU145 human prostate cancer cells. In the latter case the LIM sites were predominantly found at the nuclear border, whereas treated populations showed different degrees of increase in LIMs towards the interior nuclear space, in which a large portion of heterochromatin is located. The cell-by-cell evaluation of changes in the spatial reorganization of MeC/DAPI signals revealed that zebularine is a more gentle demethylating agent than 5-azacytidine. Measuring changes in the topology of low-intensity sites can potentially be a valuable component in the high-throughput assessment of demethylation and risk of chromatin reorganization in epigenetic-drug screening tasks.

  20. Assessment of thiopurine methyltransferase activity in patients prescribed azathioprine or other thiopurine-based drugs.

    PubMed Central

    Booth, Ronald A; Ansari, Mohammed T; Tricco, Andrea C; Loit, Evelin; Weeks, Laura; Doucette, Steve; Skidmore, Becky; Hoch, Jeffrey S; Tsouros, Sophia; Sears, Margaret; Sy, Richmond; Karsh, Jacob; Mani, Suja; Galipeau, James; Yurkiewich, Alexander; Daniel, Raymond; Tsertsvadze, Alexander; Yazdi, Fatemeh

    2010-01-01

    OBJECTIVES To examine whether pretreatment determination of thiopurine methyltransferase (TPMT) enzymatic activity (phenotyping) or TPMT genotype, to guide thiopurine therapy in chronic autoimmune disease patients, reduces treatment harms. Other objectives included assessing: preanalytic, analytic, and postanalytic requirements for TPMT testing; diagnostic accuracy of TPMT genotyping versus phenotyping; association of thiopurine toxicity with TPMT genotypic or phenotypic status; and costs of testing, care, and treating drug-associated complications. DATA SOURCES MEDLINE®, EMBASE®, and Healthstar were searched from inception to May 2010; the Cochrane Library® to October 2009; and BIOSIS®, Genetics Abstracts, and EconLit™ to May 2009, for English language records. REVIEW METHODS A reviewer screened records, and a second reviewer verified exclusions and subsequent selection of relevant studies. Studies in patients with leukemia and organ transplant were excluded. Additionally, laboratories that provide TPMT analytical services were surveyed to assess means of TPMT testing in practice. Where possible, risk of bias was assessed using standard criteria. Meta-analyses estimated diagnostic sensitivity, and specificity; and odds ratios of associations. RESULTS 1790 titles or abstracts, and 538 full text records were screened. 114 observational studies and one RCT were included. Majority of studies were rated fair quality, except for diagnostic studies with 37 percent of studies rated poor. In general, there were few patients who were homozygous (or compound heterozygous) for TPMT variant alleles in the included studies limiting applicability. There is insufficient evidence examining effectiveness of pretesting in terms of reduction in clinical adverse events. Sufficient preanalytical data were available regarding preferred specimen collection, stability and storage conditions for TPMT testing. There was no clinically significant effect of age, gender, various coadministered drugs, or most morbidities (with the exception of renal failure and dialysis). TPMT phenotyping methods had coefficients of variation generally below 10 percent. TPMT genotyping reproducibility is generally between 95-100 percent. The sensitivity of genotyping to identify patients with low or intermediate TPMT enzymatic activity is imprecise, ranging from 70.70 to 82.10 percent (95 percent CI, lower bound range 37.90 to 54.00 percent; upper bound range 84.60 to 96.90 percent). Sensitivity of homozygous TPMT genotype to correctly identify patients with low to absent enzymatic activity was 87.10 percent (95 percent CI 44.30 to 98.30 percent). Genotyping specificity approached 100 percent. Leukopenia was significantly associated with low and intermediate enzymatic activity (low activity OR 80.00, 95 percent CI 11.5 to 559; and intermediate activity OR 2.96, 95 percent CI 1.18 to 7.42), and homozygous and heterozygous TPMT variant allele genotype (OR 18.60, 95 percent CI 4.12 to 83.60; and 4.62, 95 percent CI 2.34 to 9.16, respectively). In general, TPMT phenotyping costs less than genotyping, although estimates across studies are quite heterogeneous. CONCLUSIONS There is insufficient direct evidence regarding the effectiveness of pretesting of TPMT status in patients with chronic autoimmune diseases. Indirect evidence confirms strong association of leukopenia with lower levels of TPMT activity and carrier genotype already established in the literature. PMID:23126559

  1. A formalism to generate probability distributions for performance-assessment modeling

    SciTech Connect

    Kaplan, P.G.

    1990-12-31

    A formalism is presented for generating probability distributions of parameters used in performance-assessment modeling. The formalism is used when data are either sparse or nonexistent. The appropriate distribution is a function of the known or estimated constraints and is chosen to maximize a quantity known as Shannon`s informational entropy. The formalism is applied to a parameter used in performance-assessment modeling. The functional form of the model that defines the parameter, data from the actual field site, and natural analog data are analyzed to estimate the constraints. A beta probability distribution of the example parameter is generated after finding four constraints. As an example of how the formalism is applied to the site characterization studies of Yucca Mountain, the distribution is generated for an input parameter in a performance-assessment model currently used to estimate compliance with disposal of high-level radioactive waste in geologic repositories, 10 CFR 60.113(a)(2), commonly known as the ground water travel time criterion. 8 refs., 2 figs.

  2. Illicit Drug Use Among South Korean Offenders: Assessing the Generality of Social Learning Theory.

    PubMed

    Yun, Minwoo; Kim, Eunyoung

    2015-10-01

    Since the mid-1990s, illicit drug use has become a problem in Korean society. This trend is likely due to the rapid globalization and expansion that occurred with the Internet revolution, which led to greater numbers of people socially learning about drug culture. The current study attempts to uncover criminogenic causality of such social learning about drug use by studying adult felony drug offenders in South Korea. The data used for the study were obtained from self-reported surveys, originally collected by the Korean Institution of Criminology (KIC). The final sample comprised 1,452 felony offenders convicted of illicit drug use, and their responses were analyzed with a set of multiple logistic regression tests. The current study found supportive evidence for the generalizability of social learning theory from the sample of the South Korean adult drug offenders. We argue that the current study provides additional empirical evidence that supports the generalizability of social learning theory. PMID:24752638

  3. 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)

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

    2011-04-01

    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.

  4. Spatial point pattern analysis of aerial survey data to assess clustering in wildlife distributions

    NASA Astrophysics Data System (ADS)

    Khaemba, Wilson Mwale

    Assessing clustering in wildlife populations is crucial for understanding their dynamics. This assessment is made difficult for data obtained through aerial surveys because the shape and size of sampling units (strip transects) result in poor data supports, which generally hampers spatial analysis of these data. The problem may be solved by having more detailed data where exact locations of observed animal groups are recorded. These data, obtainable through GPS technology, are amenable to spatial analysis, thereby allowing spatial point pattern analysis to be used to assess observed spatial patterns relative to environmental factors like vegetation. Distance measures like the G-statistic and K-function classify such patterns into clustered, regular or completely random patterns, while independence between species is assessed through a multivariate extension of the K-function. Quantification of clustering is carried out using spatial regression. The techniques are illustrated with field data on three ungulates observed in an ecosystem in Kenya. Results indicate a relation between species spatial distribution and their dietary requirements, thereby concluding the usefulness of spatial point pattern analysis in investigating species spatial distribution. It also provides a technique for explaining and differentiating the distribution of wildlife species.

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

    PubMed

    Nessi, Simone; Rigamonti, Lucia; Grosso, Mario

    2014-11-15

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

  6. Tentative Method for the Qualitative Detection and Quantitative Assessment of Air Contamination by Drugs

    PubMed Central

    Buogo, A.; Eboli, V.

    1972-01-01

    A method for detecting and measuring air contamination by drugs is described which uses an electrostatic bacterial air sampler, sprayers for micronizing drugs, and Mueller-Hinton medium seeded with a highly susceptible strain of Sarcina lutea. Three antibiotics (penicillin, tetracycline, aminosidine) and a sulfonamide (sulfapyrazine) were identified by pretreating portions of medium, showing no bacterial growth, with penicillinase or p-aminobenzoic acid solution and subsequently determining how both drug- susceptible and drug-resistant strains of Staphylococcus aureus were affected by this pretreatment. Quantitative determinations were also attempted by measuring the size of the inhibition zones. Images PMID:4483536

  7. Pathogen distribution and drug resistance in a burn ward: a three-year retrospective analysis of a single center in China

    PubMed Central

    Cen, Hanghui; Wu, Zhenbo; Wang, Fan; Han, Chunmao

    2015-01-01

    To investigate the spread of multiple-resistant strain in a burn ward to inform clinical administration of antibiotic drugs, burn wound treatment and decision-making for infection control. A 3-year retrospective analysis was conducted. Specimens from wounds, blood, catheter, sputum, urine and stool collected from inpatients of the Second Affiliated Hospital of Zhejiang University of Medicine between January 1, 2011 and December 31, 2013 were cultured and strains were identified by automatic bacteria analysis. Sensitivity to 30 commonly used antibiotics was assessed by K-B disk diffusion. A total of 2212 strains of pathogenic bacteria or fungi were isolated (33.9% Gram-positive and 52.7% Gram-negative bacteria and 13.4% fungi), including 1466 from wound extracts, 128 from blood culture, 335 from urine culture, 5 from stool culture, 153 from sputum culture and 125 from catheters. The most frequently detected pathogens in wound secretions were Staphylococcus aureus, Pseudomonas aeruginosa and Acinetobacter baumannii. The Gram-positive bacteria Staphylococcus epidermidis, Enterococcus faecalis and Enterococcus faecium, and the Gram-negative bacteria Escherichia coli, Klebsiella pneumoniae, Enterobacter cloacae, Stenotrophomonas maltophilia, Proteus mirabilis were also frequently detected. The most frequently detected strains of fungi were Candida albicans; tropicalis, glabrata and parapsilosis, and all were highly sensitive to itraconazole, fluconazole and voriconazole but resistant to ketoconazole. Attention should be paid to MRSA, multi-resistant A. baumanni, ESBL-producing enterobacteriaceae and Carbapenem-resistant P. aeruginosa. Understanding the distribution of bacterial infections in Chinese hospitals will be crucial to reduce hospital-acquired infection and drug resistance. PMID:26770555

  8. Pathogen distribution and drug resistance in a burn ward: a three-year retrospective analysis of a single center in China.

    PubMed

    Cen, Hanghui; Wu, Zhenbo; Wang, Fan; Han, Chunmao

    2015-01-01

    To investigate the spread of multiple-resistant strain in a burn ward to inform clinical administration of antibiotic drugs, burn wound treatment and decision-making for infection control. A 3-year retrospective analysis was conducted. Specimens from wounds, blood, catheter, sputum, urine and stool collected from inpatients of the Second Affiliated Hospital of Zhejiang University of Medicine between January 1, 2011 and December 31, 2013 were cultured and strains were identified by automatic bacteria analysis. Sensitivity to 30 commonly used antibiotics was assessed by K-B disk diffusion. A total of 2212 strains of pathogenic bacteria or fungi were isolated (33.9% Gram-positive and 52.7% Gram-negative bacteria and 13.4% fungi), including 1466 from wound extracts, 128 from blood culture, 335 from urine culture, 5 from stool culture, 153 from sputum culture and 125 from catheters. The most frequently detected pathogens in wound secretions were Staphylococcus aureus, Pseudomonas aeruginosa and Acinetobacter baumannii. The Gram-positive bacteria Staphylococcus epidermidis, Enterococcus faecalis and Enterococcus faecium, and the Gram-negative bacteria Escherichia coli, Klebsiella pneumoniae, Enterobacter cloacae, Stenotrophomonas maltophilia, Proteus mirabilis were also frequently detected. The most frequently detected strains of fungi were Candida albicans; tropicalis, glabrata and parapsilosis, and all were highly sensitive to itraconazole, fluconazole and voriconazole but resistant to ketoconazole. Attention should be paid to MRSA, multi-resistant A. baumanni, ESBL-producing enterobacteriaceae and Carbapenem-resistant P. aeruginosa. Understanding the distribution of bacterial infections in Chinese hospitals will be crucial to reduce hospital-acquired infection and drug resistance. PMID:26770555

  9. Simulation tool for assessing the release and environmental distribution of nanomaterials

    PubMed Central

    Bilal, Muhammad; Lazareva, Anastasiya; Keller, Arturo

    2015-01-01

    Summary An integrated simulation tool was developed for assessing the potential release and environmental distribution of nanomaterials (RedNano) based on a life cycle assessment approach and multimedia compartmental modeling coupled with mechanistic intermedia transport processes. The RedNano simulation tool and its web-based software implementation enables rapid “what-if?” scenario analysis, in order to assess the response of an environmental system to various release scenarios of engineered nanomaterials (ENMs). It also allows for the investigation of the impact of geographical and meteorological parameters on ENM distribution in the environment, comparison of the impact of ENM production and potential releases on different regions, and estimation of source release rates based on monitored ENM concentrations. Moreover, the RedNano simulation tool is suitable for research, academic, and regulatory purposes. Specifically, it has been used in environmental multimedia impact assessment courses at both the undergraduate and graduate levels. The RedNano simulation tool can also serve as a decision support tool to rapidly and critically assess the potential environmental implications of ENMs and thus ensure that nanotechnology is developed in a productive and environmentally responsible manner. PMID:25977865

  10. Methodological approach to determine minor, considerable, and major treatment effects in the early benefit assessment of new drugs.

    PubMed

    Skipka, Guido; Wieseler, Beate; Kaiser, Thomas; Thomas, Stefanie; Bender, Ralf; Windeler, Jürgen; Lange, Stefan

    2016-01-01

    At the beginning of 2011, the early benefit assessment of new drugs was introduced in Germany with the Act on the Reform of the Market for Medicinal Products (AMNOG). The Federal Joint Committee (G-BA) generally commissions the Institute for Quality and Efficiency in Health Care (IQWiG) with this type of assessment, which examines whether a new drug shows an added benefit (a positive patient-relevant treatment effect) over the current standard therapy. IQWiG is required to assess the extent of added benefit on the basis of a dossier submitted by the pharmaceutical company responsible. In this context, IQWiG was faced with the task of developing a transparent and plausible approach for operationalizing how to determine the extent of added benefit. In the case of an added benefit, the law specifies three main extent categories (minor, considerable, major). To restrict value judgements to a minimum in the first stage of the assessment process, an explicit and abstract operationalization was needed. The present paper is limited to the situation of binary data (analysis of 2 × 2 tables), using the relative risk as an effect measure. For the treatment effect to be classified as a minor, considerable, or major added benefit, the methodological approach stipulates that the (two-sided) 95% confidence interval of the effect must exceed a specified distance to the zero effect. In summary, we assume that our approach provides a robust, transparent, and thus predictable foundation to determine minor, considerable, and major treatment effects on binary outcomes in the early benefit assessment of new drugs in Germany. After a decision on the added benefit of a new drug by G-BA, the classification of added benefit is used to inform pricing negotiations between the umbrella organization of statutory health insurance and the pharmaceutical companies. PMID:26134089

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

    SciTech Connect

    Myllynen, Paeivi . E-mail: paivi.k.myllynen@oulu.fi; Pienimaeki, Paeivi; Vaehaekangas, Kirsi

    2005-09-01

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

  12. School-Based Drug Prevention Program: Quantitative Assessment of Life Skills Training Elementary School Program

    ERIC Educational Resources Information Center

    Kindle, Silverlene J.

    2013-01-01

    Since the 1960s long-term studies have documented nation-wide patterns of adolescent smoking, drinking and illicit drug use. The federal government responded by passing the Safe and Drug Free Schools and Communities Act, which funded school-based prevention programs. The problem for school counselors in a Georgia Public School District was…

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

    ERIC Educational Resources Information Center

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

    2003-01-01

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

  14. Combining ESI, ASL and PET for quantitative assessment of drug-resistant focal epilepsy.

    PubMed

    Storti, Silvia Francesca; Boscolo Galazzo, Ilaria; Del Felice, Alessandra; Pizzini, Francesca Benedetta; Arcaro, Chiara; Formaggio, Emanuela; Mai, Roberto; Manganotti, Paolo

    2014-11-15

    When localization of the epileptic focus is uncertain, the epileptic activity generator may be more accurately identified with non-invasive imaging techniques which could also serve to guide stereo-electroencephalography (sEEG) electrode implantation. The aim of this study was to assess the diagnostic value of perfusion magnetic resonance imaging with arterial spin labeling (ASL) in the identification of the epileptogenic zone, as compared to the more invasive positron-emission tomography (PET) and other established investigation methods for source imaging of electroencephalography (EEG) data. In 6 patients with drug-resistant focal epilepsy, standard video-EEG was performed to identify clinical seizure semeiology, and high-density EEG, ASL and FDG-PET to non-invasively localize the epileptic focus. A standardized source imaging procedure, low-resolution brain electromagnetic tomography constrained to the individual matter, was applied to the averaged spikes of high-density EEG. Quantification of current density, cerebral blood flow, and standardized uptake value were compared over the same anatomical areas. In most of the patients, source in the interictal phase was associated with an area of hypoperfusion and hypometabolism. Conversely, in the patients presenting with early post-ictal discharges, the brain area identified by electrical source imaging (ESI) as the generating zone appeared to be hyperperfused. In 2 patients in whom the focus remained uncertain, the postoperative follow-up showed the disappearance of epileptic activity. As an innovative and more comprehensive approach to the study of epilepsy, the combined use of ESI, perfusion MRI, and PET may play an increasingly important role in the non-invasive evaluation of patients with refractory focal epilepsy. PMID:23792219

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

    NASA Astrophysics Data System (ADS)

    Aksoy, Ece; Panagos, Panos; Montanarella, Luca

    2013-04-01

    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.

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

    SciTech Connect

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

    1994-06-01

    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.

  17. Assessment of size-dependent mercury distribution in King Mackerel, Scomberomorus cavalla

    SciTech Connect

    Voit, E.O.; Balthis, W.L. |

    1994-12-31

    The assessment of health risks from fish contamination and the issuance of advisories require accurate characterizations of the actual contaminant concentrations in fish of every relevant size. Such characterizations should not only contain statistical measures of location and variation, but provide a complete parameterization of the contaminant distribution for each given size class. This paper proposes two methods for determining such distributions from scatter diagrams of contaminant concentration versus fish length and illustrates them with an analysis of mercury contaminant in king mackerel, Scomberomorus cavalla. The first method consists of fitting contamination data with a family of S-distributions. This family shows trends in its defining parameter values, and these trends provide a comprehensive characterization of the measured contaminant concentrations. Each S-distribution has a rather simple mathematical structure from which one readily obtains secondary characteristics like quantiles, which are necessary for advanced simulation purposes. The second method takes into account that contaminant accumulation is the outcome of a metabolic process. When this process is modeled as a system of differential equations, it can be reformulated in such a way that it describes how the contaminant distribution changes over a given period of time. The resulting distributions have a more complicated structure than those obtained with the first method, but they allow them to bridge the gap between individual metabolic accumulation processes and trends in populations.

  18. Non-contact assessment of melanin distribution via multispectral temporal illumination coding

    NASA Astrophysics Data System (ADS)

    Amelard, Robert; Scharfenberger, Christian; Wong, Alexander; Clausi, David A.

    2015-03-01

    Melanin is a pigment that is highly absorptive in the UV and visible electromagnetic spectra. It is responsible for perceived skin tone, and protects against harmful UV effects. Abnormal melanin distribution is often an indicator for melanoma. We propose a novel approach for non-contact melanin distribution via multispectral temporal illumination coding to estimate the two-dimensional melanin distribution based on its absorptive characteristics. In the proposed system, a novel multispectral, cross-polarized, temporally-coded illumination sequence is synchronized with a camera to measure reflectance under both multispectral and ambient illumination. This allows us to eliminate the ambient illumination contribution from the acquired reflectance measurements, and also to determine the melanin distribution in an observed region based on the spectral properties of melanin using the Beer-Lambert law. Using this information, melanin distribution maps can be generated for objective, quantitative assessment of skin type of individuals. We show that the melanin distribution map correctly identifies areas with high melanin densities (e.g., nevi).

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

    PubMed Central

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

    2007-01-01

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

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

    PubMed Central

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

    2014-01-01

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

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

    PubMed

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

    2009-02-01

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

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

    PubMed Central

    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

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

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

    NASA Technical Reports Server (NTRS)

    Schmeckpeper, K. R.

    1987-01-01

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

  4. Optimal Capacity and Location Assessment of Natural Gas Fired Distributed Generation in Residential Areas

    NASA Astrophysics Data System (ADS)

    Khalil, Sarah My

    With ever increasing use of natural gas to generate electricity, installed natural gas fired microturbines are found in residential areas to generate electricity locally. This research work discusses a generalized methodology for assessing optimal capacity and locations for installing natural gas fired microturbines in a distribution residential network. The overall objective is to place microturbines to minimize the system power loss occurring in the electrical distribution network; in such a way that the electric feeder does not need any up-gradation. The IEEE 123 Node Test Feeder is selected as the test bed for validating the developed methodology. Three-phase unbalanced electric power flow is run in OpenDSS through COM server, and the gas distribution network is analyzed using GASWorkS. The continual sensitivity analysis methodology is developed to select multiple DG locations and annual simulation is run to minimize annual average losses. The proposed placement of microturbines must be feasible in the gas distribution network and should not result into gas pipeline reinforcement. The corresponding gas distribution network is developed in GASWorkS software, and nodal pressures of the gas system are checked for various cases to investigate if the existing gas distribution network can accommodate the penetration of selected microturbines. The results indicate the optimal locations suitable to place microturbines and capacity that can be accommodated by the system, based on the consideration of overall minimum annual average losses as well as the guarantee of nodal pressure provided by the gas distribution network. The proposed method is generalized and can be used for any IEEE test feeder or an actual residential distribution network.

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

    NASA Astrophysics Data System (ADS)

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

    2015-02-01

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

  6. Ex Vivo Assessment of Drug Activity in Patient Tumor Cells as a Basis for Tailored Cancer Therapy.

    PubMed

    Blom, Kristin; Nygren, Peter; Alvarsson, Jonathan; Larsson, Rolf; Andersson, Claes R

    2016-02-01

    Although medical cancer treatment has improved during the past decades, it is difficult to choose between several first-line treatments supposed to be equally active in the diagnostic group. It is even more difficult to select a treatment after the standard protocols have failed. Any guidance for selection of the most effective treatment is valuable at these critical stages. We describe the principles and procedures for ex vivo assessment of drug activity in tumor cells from patients as a basis for tailored cancer treatment. Patient tumor cells are assayed for cytotoxicity with a panel of drugs. Acoustic drug dispensing provides great flexibility in the selection of drugs for testing; currently, up to 80 compounds and/or combinations thereof may be tested for each patient. Drug response predictions are obtained by classification using an empirical model based on historical responses for the diagnosis. The laboratory workflow is supported by an integrated system that enables rapid analysis and automatic generation of the clinical referral response. PMID:26246423

  7. Assessment of dye distribution in sensitized solar cells by microprobe techniques

    NASA Astrophysics Data System (ADS)

    Barreiros, M. A.; Corregidor, V.; Alves, L. C.; Guimarães, F.; Mascarenhas, J.; Torres, E.; Brites, M. J.

    2015-04-01

    Dye sensitized solar cells (DSCs) have received considerable attention once this technology offers economic and environmental advantages over conventional photovoltaic (PV) devices. The PV performance of a DSC relies on the characteristics of its photoanode, which typically consists of a nanocrystalline porous TiO2 film, enabled with a large adsorptive surface area. Dye molecules that capture photons from light during device operation are attached to the film nanoparticles. The effective loading of the dye in the TiO2 electrode is of paramount relevance for controlling and optimizing solar cell parameters. Relatively few methods are known today for quantitative evaluation of the total dye adsorbed on the film. In this context, microprobe techniques come out as suitable tools to evaluate the dye surface distribution and depth profile in sensitized films. Electron Probe Microanalysis (EPMA) and Ion Beam Analytical (IBA) techniques using a micro-ion beam were used to quantify and to study the distribution of the Ru organometallic dye in TiO2 films, making use of the different penetration depth and beam sizes of each technique. Different 1D nanostructured TiO2 films were prepared, morphologically characterized by SEM, sensitized and analyzed by the referred techniques. Dye load evaluation in different TiO2 films by three different techniques (PIXE, RBS and EPMA/WDS) provided similar results of Ru/Ti mass fraction ratio. Moreover, it was possible to assess dye surface distribution and its depth profile, by means of Ru signal, and to visualize the dye distribution in sample cross-section through X-ray mapping by EPMA/EDS. PIXE maps of Ru and Ti indicated an homogeneous surface distribution. The assessment of Ru depth profile by RBS showed that some films have homogeneous Ru depth distribution while others present different Ru concentration in the top layer (2 μm thickness). These results are consistent with the EPMA/EDS maps obtained.

  8. Rapid assessment of drug resistance of cancer cells to gefitinib and carboplatin using optical imaging.

    PubMed

    Luo, Zhen; Samadzadeh, Kiana Michelle; Nitin, Nitin

    2016-07-01

    The overall goal of this study was to evaluate optical molecular imaging approaches to determine the drug response of chemotherapy and molecular targeted agents in drug sensitive and drug resistant cell lines. The optical molecular imaging approaches selected in this study were based on changes in intracellular uptake and retention of choline and glucose molecules. The breast cancer cell lines were treated with a molecular targeted anti-EGFR therapy. The bladder cancer cell lines were treated with a conventional chemotherapy approach. Sensitivity of optical molecular imaging approach was also compared with conventional cell viability and cell growth inhibition assays. Results demonstrate that optical molecular imaging of changes in intracellular uptake of metabolites was effective in detecting drug susceptibility for both molecular targeted therapy in breast cancer cells and chemotherapy in bladder cancer cells. Between the selected metabolites for optical molecular imaging, changes in glucose metabolic activity showed higher sensitivity in discrimination between the drug sensitive and drug resistant cell lines. The results demonstrated that optical molecular imaging approaches more significantly sensitive as compared to the conventional cell viability and growth assays. Overall, the results demonstrate potential of optical molecular imaging of metabolic activity to improve sensitivity of in-vitro drug response assays. PMID:27059751

  9. Therapeutic drug monitoring for triazoles: A needs assessment review and recommendations from a Canadian perspective

    PubMed Central

    Laverdiere, Michel; Bow, Eric J; Rotstein, Coleman; Autmizguine, Julie; Broady, Raewyn; Garber, Gary; Haider, Shariq; Hussaini, Trana; Husain, Shahid; Ovetchkine, Philippe; Seki, Jack T; Théorêt, Yves

    2014-01-01

    Invasive fungal infections cause significant morbidity and mortality in patients with concomitant underlying immunosuppressive diseases. The recent addition of new triazoles to the antifungal armamentarium has allowed for extended-spectrum activity and flexibility of administration. Over the years, clinical use has raised concerns about the degree of drug exposure following standard approved drug dosing, questioning the need for therapeutic drug monitoring (TDM). Accordingly, the present guidelines focus on TDM of triazole antifungal agents. A review of the rationale for triazole TDM, the targeted patient populations and available laboratory methods, as well as practical recommendations based on current evidence from an extended literature review are provided in the present document. PMID:25587296

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

    PubMed Central

    Adams, David J.

    2012-01-01

    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. PMID:22410081

  11. Assessment of the Characteristics of Orientation Distribution Functions in HARDI Using Morphological Metrics

    PubMed Central

    Sun, Chang-yu; Zhu, Yue-min; Chu, Chun-yu; Yang, Feng; Liu, Wan-yu; Korenberg, Julie R.; Hsu, Edward W.

    2016-01-01

    Orientation distribution functions (ODFs) are widely used to resolve fiber crossing problems in high angular resolution diffusion imaging (HARDI). The characteristics of the ODFs are often assessed using a visual criterion, although the use of objective criteria is also reported, which are directly borrowed from classic signal and image processing theory because they are intuitive and simple to compute. However, they are not always pertinent for the characterization of ODFs. We propose a more general paradigm for assessing the characteristics of ODFs. The idea consists in regarding an ODF as a three-dimensional (3D) point cloud, projecting the 3D point cloud onto an angle-distance map, constructing an angle-distance matrix, and calculating metrics such as length ratio, separability, and uncertainty. The results from both simulated and real data show that the proposed metrics allow for the assessment of the characteristics of ODFs in a quantitative and relatively complete manner. PMID:26919477

  12. Assessment of the Characteristics of Orientation Distribution Functions in HARDI Using Morphological Metrics.

    PubMed

    Sun, Chang-Yu; Zhu, Yue-Min; Chu, Chun-Yu; Yang, Feng; Liu, Wan-Yu; Korenberg, Julie R; Hsu, Edward W

    2016-01-01

    Orientation distribution functions (ODFs) are widely used to resolve fiber crossing problems in high angular resolution diffusion imaging (HARDI). The characteristics of the ODFs are often assessed using a visual criterion, although the use of objective criteria is also reported, which are directly borrowed from classic signal and image processing theory because they are intuitive and simple to compute. However, they are not always pertinent for the characterization of ODFs. We propose a more general paradigm for assessing the characteristics of ODFs. The idea consists in regarding an ODF as a three-dimensional (3D) point cloud, projecting the 3D point cloud onto an angle-distance map, constructing an angle-distance matrix, and calculating metrics such as length ratio, separability, and uncertainty. The results from both simulated and real data show that the proposed metrics allow for the assessment of the characteristics of ODFs in a quantitative and relatively complete manner. PMID:26919477

  13. Correction: NanoSIMS analysis of an isotopically labelled organometallic ruthenium(II) drug to probe its distribution and state in vitro.

    PubMed

    Lee, Ronald F S; Escrig, Stphane; Croisier, Marie; Clerc-Rosset, Stphanie; Knott, Graham W; Meibom, Anders; Davey, Curt A; Johnsson, Kai; Dyson, Paul J

    2015-11-28

    Correction for 'NanoSIMS analysis of an isotopically labelled organometallic ruthenium(II) drug to probe its distribution and state in vitro' by Ronald F. S. Lee et al., Chem. Commun., 2015, DOI: 10.1039/c5cc06983a. PMID:26507472

  14. In vitro and in vivo efficacy, toxicity, bio-distribution and resistance selection of a novel antibacterial drug candidate

    PubMed Central

    Brunetti, Jlenia; Falciani, Chiara; Roscia, Giulia; Pollini, Simona; Bindi, Stefano; Scali, Silvia; Arrieta, Unai Cossio; Gómez-Vallejo, Vanessa; Quercini, Leila; Ibba, Elisa; Prato, Marco; Rossolini, Gian Maria; Llop, Jordi; Bracci, Luisa; Pini, Alessandro

    2016-01-01

    A synthetic antimicrobial peptide was identified as a possible candidate for the development of a new antibacterial drug. The peptide, SET-M33L, showed a MIC90 below 1.5 μM and 3 μM for Pseudomonas aeruginosa and Klebsiella pneumoniae, respectively. In in vivo models of P. aeruginosa infections, the peptide and its pegylated form (SET-M33L-PEG) enabled a survival percentage of 60–80% in sepsis and lung infections when injected twice i.v. at 5 mg/Kg, and completely healed skin infections when administered topically. Plasma clearance showed different kinetics for SET-M33L and SET-M33L-PEG, the latter having greater persistence two hours after injection. Bio-distribution in organs did not show significant differences in uptake of the two peptides. Unlike colistin, SET-M33L did not select resistant mutants in bacterial cultures and also proved non genotoxic and to have much lower in vivo toxicity than antimicrobial peptides already used in clinical practice. The characterizations reported here are part of a preclinical development plan that should bring the molecule to clinical trial in the next few years. PMID:27169671

  15. In vitro and in vivo efficacy, toxicity, bio-distribution and resistance selection of a novel antibacterial drug candidate.

    PubMed

    Brunetti, Jlenia; Falciani, Chiara; Roscia, Giulia; Pollini, Simona; Bindi, Stefano; Scali, Silvia; Arrieta, Unai Cossio; Gómez-Vallejo, Vanessa; Quercini, Leila; Ibba, Elisa; Prato, Marco; Rossolini, Gian Maria; Llop, Jordi; Bracci, Luisa; Pini, Alessandro

    2016-01-01

    A synthetic antimicrobial peptide was identified as a possible candidate for the development of a new antibacterial drug. The peptide, SET-M33L, showed a MIC90 below 1.5 μM and 3 μM for Pseudomonas aeruginosa and Klebsiella pneumoniae, respectively. In in vivo models of P. aeruginosa infections, the peptide and its pegylated form (SET-M33L-PEG) enabled a survival percentage of 60-80% in sepsis and lung infections when injected twice i.v. at 5 mg/Kg, and completely healed skin infections when administered topically. Plasma clearance showed different kinetics for SET-M33L and SET-M33L-PEG, the latter having greater persistence two hours after injection. Bio-distribution in organs did not show significant differences in uptake of the two peptides. Unlike colistin, SET-M33L did not select resistant mutants in bacterial cultures and also proved non genotoxic and to have much lower in vivo toxicity than antimicrobial peptides already used in clinical practice. The characterizations reported here are part of a preclinical development plan that should bring the molecule to clinical trial in the next few years. PMID:27169671

  16. Temporal Distinctiveness in Task Switching: Assessing the Mixture-Distribution Assumption

    PubMed Central

    Grange, James A.

    2016-01-01

    In task switching, increasing the response–cue interval has been shown to reduce the switch cost. This has been attributed to a time-based decay process influencing the activation of memory representations of tasks (task-sets). Recently, an alternative account based on interference rather than decay has been successfully applied to this data (Horoufchin et al., 2011a). In this account, variation of the RCI is thought to influence the temporal distinctiveness (TD) of episodic traces in memory, thus affecting their retrieval probability. This can affect performance as retrieval probability influences response time: If retrieval succeeds, responding is fast due to positive priming; if retrieval fails, responding is slow, due to having to perform the task via a slow algorithmic process. This account—and a recent formal model (Grange and Cross, 2015)—makes the strong prediction that all RTs are a mixture of one of two processes: a fast process when retrieval succeeds, and a slow process when retrieval fails. The present paper assesses the evidence for this mixture-distribution assumption in TD data. In a first section, statistical evidence for mixture-distributions is found using the fixed-point property test. In a second section, a mathematical process model with mixture-distributions at its core is fitted to the response time distribution data. Both approaches provide good evidence in support of the mixture-distribution assumption, and thus support temporal distinctiveness accounts of the data. PMID:26941697

  17. Temporal Distinctiveness in Task Switching: Assessing the Mixture-Distribution Assumption.

    PubMed

    Grange, James A

    2016-01-01

    In task switching, increasing the response-cue interval has been shown to reduce the switch cost. This has been attributed to a time-based decay process influencing the activation of memory representations of tasks (task-sets). Recently, an alternative account based on interference rather than decay has been successfully applied to this data (Horoufchin et al., 2011a). In this account, variation of the RCI is thought to influence the temporal distinctiveness (TD) of episodic traces in memory, thus affecting their retrieval probability. This can affect performance as retrieval probability influences response time: If retrieval succeeds, responding is fast due to positive priming; if retrieval fails, responding is slow, due to having to perform the task via a slow algorithmic process. This account-and a recent formal model (Grange and Cross, 2015)-makes the strong prediction that all RTs are a mixture of one of two processes: a fast process when retrieval succeeds, and a slow process when retrieval fails. The present paper assesses the evidence for this mixture-distribution assumption in TD data. In a first section, statistical evidence for mixture-distributions is found using the fixed-point property test. In a second section, a mathematical process model with mixture-distributions at its core is fitted to the response time distribution data. Both approaches provide good evidence in support of the mixture-distribution assumption, and thus support temporal distinctiveness accounts of the data. PMID:26941697

  18. Modeling 3D soil and sediment distributions for assessing catchment structure and hydrological feedbacks

    NASA Astrophysics Data System (ADS)

    Maurer, Thomas; Brück, Yasemine; Hinz, Christoph; Gerke, Horst H.

    2015-04-01

    Structural heterogeneity, namely the spatial distribution of soils and sediments (represented by mineral particles), characterizes catchment hydrological behavior. In natural catchments, local geology and the specific geomorphic processes determine the characteristics and spatial distribution of structures. In constructed catchments, structural features are determined primarily by the construction processes and the geological origin of the parent material. Objectives are scenarios of 3D catchment structures in form of complete 3D description of soil hydraulic properties generated from the knowledge of the formation processes. The constructed hydrological catchment 'Hühnerwasser' (Lower Lusatia, Brandenburg, Germany) was used for the calibration and validation of model results due to its well-known conditions. For the modelling of structural features, a structure generator was used to model i) quasi-deterministic sediment distributions using input data from a geological model of the parent material excavation site; ii) sediment distributions that are conditioned to measurement data from soil sampling; and iii) stochastic component sediment distributions. All three approaches allow a randomization within definable limits. Furthermore, the spoil cone / spoil ridge orientation, internal layering, surface compaction and internal spoil cone compaction were modified. These generated structural models were incorporated in a gridded 3D volume model constructed with the GOCAD software. For selected scenarios, the impact of structure variation was assessed by hydrological modelling with HYDRUS 2D/3D software. For that purpose, 3D distributions of soil hydraulic properties were estimated based on generated sediment properties using adapted pedotransfer functions. Results from the hydrological model were compared them to measured discharges from the catchment. The impact of structural feature variation on flow behaviour was analysed by comparing different simulation scenarios. The established initial sediment distributions provide a basis for the consecutive modelling of feedbacks between surface and subsurface water flow and changes in soil properties, e.g. by using a landscape evolution model. The results should allow conclusions about the effect of different initial structural setups on the further dynamic landscape development at catchment scale.

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

    PubMed Central

    2013-01-01

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

  20. Identification of phototransformation products of the antiepileptic drug gabapentin: Biodegradability and initial assessment of toxicity.

    PubMed

    Herrmann, Manuel; Menz, Jakob; Olsson, Oliver; Kümmerer, Klaus

    2015-11-15

    The anticonvulsant drug Gabapentin (GAB) is used for the treatment of various diseases (e.g. epilepsy, bipolar disorder, neuropathic pain) and is being consumed in high amounts. As GAB is not metabolized and shows a weak elimination in sewage treatment plants (STPs), it has been detected in surface water and even in raw potable water. Moreover, the confirmed teratogenic effects of GAB indicate the need for further investigations regarding options for the elimination of GAB in the water cycle. Little is known about the behavior of GAB during treatment with UV light, which is normally used for the disinfection of potable water and discussed for advanced wastewater treatment. In this study, GAB was exposed to polychromatic UV irradiation at different initial concentrations in aqueous solution. Afterwards the structures of the resulting phototransformation products (PTPs) were identified and elucidated by means of high-resolution mass spectrometry. GAB and photolytic mixtures were submitted to the Closed Bottle Test (CBT; OECD 301 D) to assess biodegradability. Furthermore, the toxicity of GAB and its photolytic mixtures was initially addressed on screening level using a modified luminescent bacteria test (LBT) and the umu-test (ISO/FDIS 13829). Environmentally realistic concentrations of GAB were disclosed by predicting STP influent concentrations (24.3 and 23.2 μg L(-1)). GAB with initial concentration of 100 mg L(-1) was eliminated by 80% after 128 min of direct UV irradiation, but just 9% of non-purgeable organic carbon (NPOC) was removed indicating the formation of dead-end transformation products (TPs). Structures of different PTPs were elucidated and several identical PTPs could also be identified at lower initial treatment concentrations (20 mg L(-1), 5 mg L(-1), 1 mg L(-1) and 0.1 mg L(-1)). GAB was classified as not readily biodegradable. Moreover, photo treatment did not result in better biodegradable PTPs. With increasing UV treatment duration, photolytic mixtures of GAB showed an increased inhibition of both, the bacterial luminescence emission as well as the growth in the modified LBT. In the umu-test no significant induction of the umuC gene as an indicator of genotoxicity was observed. Our results show that UV irradiation of GAB containing water would lead to the formation of recalcitrant PTPs. Considering that GAB was found in raw drinking water, the formation of toxic PTPs during drinking water treatment with UV light might be possible. Therefore, further studies should be conducted regarding the fate and effects on human health and the environment of GAB and the PTPs identified within this study. PMID:26281960

  1. Assessing protein conformational sampling methods based on bivariate lag-distributions of backbone angles

    PubMed Central

    Maadooliat, Mehdi; Huang, Jianhua Z.

    2013-01-01

    Despite considerable progress in the past decades, protein structure prediction remains one of the major unsolved problems in computational biology. Angular-sampling-based methods have been extensively studied recently due to their ability to capture the continuous conformational space of protein structures. The literature has focused on using a variety of parametric models of the sequential dependencies between angle pairs along the protein chains. In this article, we present a thorough review of angular-sampling-based methods by assessing three main questions: What is the best distribution type to model the protein angles? What is a reasonable number of components in a mixture model that should be considered to accurately parameterize the joint distribution of the angles? and What is the order of the local sequence–structure dependency that should be considered by a prediction method? We assess the model fits for different methods using bivariate lag-distributions of the dihedral/planar angles. Moreover, the main information across the lags can be extracted using a technique called Lag singular value decomposition (LagSVD), which considers the joint distribution of the dihedral/planar angles over different lags using a nonparametric approach and monitors the behavior of the lag-distribution of the angles using singular value decomposition. As a result, we developed graphical tools and numerical measurements to compare and evaluate the performance of different model fits. Furthermore, we developed a web-tool (http://www.stat.tamu.edu/∼madoliat/LagSVD) that can be used to produce informative animations. PMID:22926831

  2. Review of the predictive value of the Langendorff heart model (Screenit system) in assessing the proarrhythmic potential of drugs.

    PubMed

    Valentin, Jean-Pierre; Hoffmann, Peter; De Clerck, Fred; Hammond, Tim G; Hondeghem, Luc

    2004-01-01

    Prolongation of the QTc interval of the electrocardiogram (ECG) is used as a surrogate marker for a rare, but life threatening, ventricular arrhythmia known as torsades de pointes (TdP). However, the clear link between QTc prolongation and the arrhythmogenic risk has not been demonstrated unequivocally. In the present review article, we examine (a) the current understanding of electrophysiological and pharmacological mechanisms linking changes in action potential (AP) properties with proarrhythmia and (b) the value of the isolated, paced Langendorff-perfused female rabbit heart model (Screenit system) in predicting the torsadogenic potential of drugs in man. The Screenit system records monophasic action potentials (MAPs) from which the following parameters are evaluated: action potential duration (APD), conduction, instability (indicative of beat to beat APD variability), triangulation (indicative of changes of Phase 3 repolarization), and reverse-use dependency (indicating that the APD is more prolonged at slow heart rates). So far, over 16,000 experiments have been conducted, including approximately 300 dedicated tests to evaluate, in a blinded manner, approximately 70 clinically used drugs. The drugs tested covered a wide range of compounds from various pharmacological and chemical classes with clinical torsadogenic propensity, as well as drugs without the latter effect in clinical settings. Overall, the Screenit system and its associated analysis classified the drugs based on their effects on AP morphology and conduction and additionally identified, in a qualitative manner, drugs clinically associated with TdP. Such an identification is based on the triangulation, reverse-use dependency, and instability of the AP, as well as on the direct indexes of proarrhythmia such as early afterdepolarization (EADs), ventricular tachycardia (VT), and ventricular fibrillation (VF). Overall, drugs that readily induce arrhythmia and/or EADs and/or causes triangulation, reverse-use dependency, and/or instability and/or a chaotic Poincaré plot in a range of concentrations likely to be achieved in man is likely to cause TdP in man, eventually. Only if none of these elements is present, at concentrations well exceeding the free therapeutic plasma concentration, can one expect that the drug will probably be devoid of torsadonenicity. Therefore, this in vitro model provides detailed information on the overall profile of drug-induced electrophysiological effects. In combination with other in vitro and in vivo repolarization assays and with pharmacokinetic data in man, it is a valuable tool to establish an integrated cardiovascular risk assessment of pharmaceutical compounds. PMID:15172013

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

    PubMed

    Dansereau, Raymond N

    2014-11-01

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

  4. Multi-risk assessment of L'Aquila gas distribution network

    NASA Astrophysics Data System (ADS)

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

    2012-04-01

    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.

  5. Hp-β-CD-Voriconazole In Situ Gelling System for Ocular Drug Delivery: In Vitro, Stability, and Antifungal Activities Assessment

    PubMed Central

    Pawar, Pravin; Kashyap, Heena; Malhotra, Sakshi; Sindhu, Rakesh

    2013-01-01

    The objective of the present study was to design ophthalmic delivery systems based on polymeric carriers that undergo sol-to-gel transition upon change in temperature or in the presence of cations so as to prolong the effect of HP-β-CD Voriconazole (VCZ) in situ gelling formulations. The in situ gelling formulations of Voriconazole were prepared by using pluronic F-127 (PF-127) or with combination of pluronic F-68 (PF-68) and sodium alginate by cold method technique. The prepared formulations were evaluated for their physical appearance, drug content, gelation temperature (Tgel), in vitro permeation studies, rheological properties, mucoadhesion studies, antifungal studies, and stability studies. All batches of in situ formulations had satisfactory pH ranging from 6.8 to 7.4, drug content between 95% and 100%, showing uniform distribution of drug. As the concentration of each polymeric component was increased, that is, PF-68 and sodium alginate, there was a decrease in Tgel with increase in viscosity and mucoadhesive strength. The in vitro drug release decreased with increase in polymeric concentrations. The stability data concluded that all formulations showed the low degradation and maximum shelf life of 2 years. The antifungal efficiency of the selected formulation against Candida albicans and Asperigillus fumigatus confirmed that designed formulation has prolonged effect and retained its properties against fungal infection. PMID:23762839

  6. Paclitaxel Drug-Eluting Stents in Peripheral Arterial Disease: A Health Technology Assessment

    PubMed Central

    2015-01-01

    Background Peripheral arterial disease is a condition in which atherosclerotic plaques partially or completely block blood flow to the legs. Although percutaneous transluminal angioplasty and metallic stenting have high immediate success rates in treating peripheral arterial disease, long-term patency and restenosis rates in long and complex lesions remain unsatisfactory. Objective The objective of this analysis was to evaluate the clinical effectiveness, safety, cost-effectiveness and budget impact of Zilver paclitaxel self-expanding drug-eluting stents for the treatment of de novo or restenotic lesions in above-the-knee peripheral arterial disease. Data Sources Literature searches were performed using Ovid MEDLINE, Ovid MEDLINE In-Process and Other Non-Indexed Citations, Ovid Embase, EBSCO Cumulative Index to Nursing & Allied Health Literature (CINAHL), and EBM Reviews. For the economic review, a search filter was applied to limit search results to economics-related literature. Data sources for the budget impact analysis included expert opinion, published literature, and Ontario administrative data. Review Methods Systematic reviews, meta-analyses, randomized controlled trials, and observational studies were included in the clinical effectiveness review, and full economic evaluations were included in the economic litera