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. A Quantitative Assessment of Nanoparticle Ligand Distributions: Implications for Targeted Drug and Imaging Delivery in Dendrimer Conjugates

    PubMed Central

    Mullen, Douglas G.; Fang, Ming; Desai, Ankur; Baker, James R.; Orr, Bradford G.; Banaszak Holl, Mark M.

    2010-01-01

    Functional nanoparticles often contain ligands including targeting molecules, fluorophores, and/or active moieties such as drugs. Characterizing the number of these ligands bound to each particle, and the distribution of nanoparticle-ligand species, is important for understanding the nanomaterials function. In this study, the amide coupling methods commonly used to conjugate ligands to poly(amidoamine) (PAMAM) dendrimers were examined. A skewed Poisson distribution was observed and quantified using HPLC for two sets of dendrimer-ligand samples prepared using the amine terminated form of the PAMAM dendrimer and a partially acetylated form of the PAMAM dendrimer that has been used for targeted in vivo drug delivery. The prepared samples had an average number of ligands per dendrimer ranging from 0.4 to 13. Distributions identified by HPLC are in excellent agreement with the mean ligand/dendrimer ratio, measured by 1H NMR, gel permeation chromatography (GPC), and potentiometric titration. These results provide insight into the heterogeneity of distributions that are obtained for many classes of nanomaterials to which ligands are conjugated and belie the use of simple cartoon models that present the average number of ligands bound as a physically meaningful representation for the material. PMID:20131876

  5. Safety assessment of drug residues

    SciTech Connect

    Jackson, B.A.

    1980-05-15

    The safety assessment of drug residues is part of the process for defining the conditions for the safe use of drugs in food-producing animals. The information needed to assess the safety of drug residues is provided by chemical and toxicity tests. Toxicity tests are conducted to identify the type of effect produced and to determine the exposure concentrations that would be expected not to produce the effect. These tests include acute, subacute, and chronic toxicity tests, as well as reproduction studies and other special tests. The results are used to find an acceptable daily intake for drug residues that can be used to set a tolerance.

  6. Distributed road assessment system

    SciTech Connect

    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.

  7. 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

  8. Autoradiography techniques and quantification of drug distribution.

    PubMed

    Solon, Eric G

    2015-04-01

    The use of radiolabeled drug compounds offers the most efficient way to quantify the amount of drug and/or drug-derived metabolites in biological samples. Autoradiography is a technique using X- ray film, phosphor imaging plates, beta imaging systems, or photo-nuclear emulsion to visualize molecules or fragments of molecules that have been radioactively labeled, and it has been used to quantify and localize drugs in tissues and cells for decades. Quantitative whole-body autoradiography or autoradioluminography (QWBA) using phosphor imaging technology has revolutionized the conduct of drug distribution studies by providing high resolution images of the spatial distribution and matching tissue concentrations of drug-related radioactivity throughout the body of laboratory animals. This provides tissue-specific pharmacokinetic (PK) compartmental analysis which has been useful in toxicology, pharmacology, and drug disposition/patterns, and to predict human exposure to drugs and metabolites, and also radioactivity, when a human radiolabeled drug study is necessary. Microautoradiography (MARG) is another autoradiographic technique that qualitatively resolves the localization of radiolabeled compounds to the cellular level in a histological preparation. There are several examples in the literature of investigators attempting to obtain drug concentration data from MARG samples; however, there are technical issues which make that problematic. These issues will be discussed. This review will present a synopsis of both techniques and examples of how they have been used for drug research in recent years. PMID:25604842

  9. Multistep, effective drug distribution within solid tumors.

    PubMed

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

    2015-11-24

    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

  10. 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

  11. 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

  12. 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

  13. Exploration of heterogeneity in distributed research network drug safety analyses.

    PubMed

    Hansen, Richard A; Zeng, Peng; Ryan, Patrick; Gao, Juan; Sonawane, Kalyani; Teeter, Benjamin; Westrich, Kimberly; Dubois, Robert W

    2014-12-01

    Distributed data networks representing large diverse populations are an expanding focus of drug safety research. However, interpreting results is difficult when treatment effect estimates vary across datasets (i.e., heterogeneity). In a previous study, risk estimates were generated for selected drugs and potential adverse outcomes. Analyses were replicated across eight distributed data sources using an identical analytic structure. To evaluate heterogeneity of risk estimates across data sources, the estimates were combined with summary-level data characterizing the population of each data source. Meta-analysis, meta-regression, and plots of the influence on overall results versus contribution to heterogeneity were examined and used to illustrate an approach to heterogeneity assessment. Heterogeneity, as measured by the I-squared statistic, was high with variability across outcomes. Plots of the relationship between influence on overall results and contribution to heterogeneity suggest that certain datasets and characteristics were influential but there was variability dependent on the drug and outcome being assessed. Exploratory meta-regression identified many possible influential factors, but may be subject to ecological bias and false positive conclusions. Distributed data network drug safety analyses can produce heterogeneous risk estimates that may not be easily explained. Approaches illustrated here can be useful for research that is subject to similar problems with heterogeneity. PMID:26052957

  14. Assessment of liposome disruption to quantify drug delivery in vitro.

    PubMed

    Nogueira, Eugnia; Cruz, Clia F; Loureiro, Ana; Nogueira, Patrcia; Freitas, Jaime; Moreira, Alexandra; Carmo, Alexandre M; Gomes, Andreia C; Preto, Ana; Cavaco-Paulo, Artur

    2016-02-01

    Efficient liposome disruption inside the cells is a key for success with any type of drug delivery system. The efficacy of drug delivery is currently evaluated by direct visualization of labeled liposomes internalized by cells, not addressing objectively the release and distribution of the drug. Here, we propose a novel method to easily assess liposome disruption and drug release into the cytoplasm. We propose the encapsulation of the cationic dye Hoechst 34580 to detect an increase in blue fluorescence due to its specific binding to negatively charged DNA. For that, the dye needs to be released inside the cell and translocated to the nucleus. The present approach correlates the intensity of detected fluorescent dye with liposome disruption and consequently assesses drug delivery within the cells. PMID:26589183

  15. 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

  16. 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

  17. 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

  18. 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)...

  19. 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)...

  20. 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)...

  1. 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)...

  2. 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...

  3. 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

  4. 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.

  5. 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

  6. 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

  7. 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

  8. 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

  9. 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

  10. 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 ADMINISTRATION, DEPARTMENT OF JUSTICE RECORDS AND REPORTS OF LISTED CHEMICALS AND CERTAIN MACHINES §...

  11. 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 ADMINISTRATION, DEPARTMENT OF JUSTICE RECORDS AND REPORTS OF LISTED CHEMICALS AND CERTAIN MACHINES §...

  12. 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 ADMINISTRATION, DEPARTMENT OF JUSTICE RECORDS AND REPORTS OF LISTED CHEMICALS AND CERTAIN MACHINES §...

  13. 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 ADMINISTRATION, DEPARTMENT OF JUSTICE RECORDS AND REPORTS OF LISTED CHEMICALS AND CERTAIN MACHINES §...

  14. 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 ADMINISTRATION, DEPARTMENT OF JUSTICE RECORDS AND REPORTS OF LISTED CHEMICALS AND CERTAIN MACHINES §...

  15. 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 ADMINISTRATION, DEPARTMENT OF JUSTICE RECORDS AND REPORTS OF LISTED CHEMICALS AND CERTAIN MACHINES §...

  16. Zebrafish model in drug safety assessment.

    PubMed

    Kanungo, Jyotshna; Cuevas, Elvis; Ali, Syed F; Paule, Merle G

    2014-01-01

    Over the past decade, zebrafish are being increasingly used in assessing the effects of chemical compounds. Especially, the embryos and larvae, due to their microscopically small size and optical transparency, are compatible with multi-well microtiter plates for high throughput screening. Being transparent, they allow for non-invasive visualization of internal organs during early development. The organization of the genome, the genetic pathways controlling signal transduction and the developmental pattern appear to be significantly conserved between zebrafish and humans. Major organ systems including the nervous, cardiovascular, digestive and visual systems of zebrafish are also similar to their mammalian counterparts at the anatomical, physiological and molecular levels. Therefore, zebrafish assays are ideal for evaluating multiple organ toxicities simultaneously that contrast in vitro assays performed on cultured cells or tissue explants and organ slices. Although research on zebrafish as a model system began a few decades ago, later studies on zebrafish developmental biology and developmental genetics resulted in the characterization of a large number of genes involved in vertebrate development and biological pathways thus establishing zebrafish as a relevant human disease model for research. Recently, zebrafish have become an attractive vertebrate model for pharmaceutical and toxicological studies. We have outlined in this review some of the toxicological screens and tools that used zebrafish early life stages, and the efforts made to validate zebrafish assays against mammalian drug screens. PMID:24502596

  17. Application of intracerebral microdialysis to study regional distribution kinetics of drugs in rat brain.

    PubMed

    de Lange, E C; Bouw, M R; Mandema, J W; Danhof, M; de Boer, A G; Breimer, D D

    1995-11-01

    1. The purpose of the present study was to determine whether intracerebral microdialysis can be used for the assessment of local differences in drug concentrations within the brain. 2. Two transversal microdialysis probes were implanted in parallel into the frontal cortex of male Wistar rats, and used as a local infusion and detection device respectively. Within one rat, three different concentrations of atenolol or acetaminophen were infused in randomized order. By means of the detection probe, concentration-time profiles of the drug in the brain were measured at interprobe distances between 1 and 2 mm. 3. Drug concentrations were found to be dependent on the drug as well as on the interprobe distance. It was found that the outflow concentration from the detection probe decreased with increasing lateral spacing between the probes and this decay was much steeper for acetaminophen than for atenolol. A model was developed which allows estimation of kbp/Deff (transfer coefficient from brain to blood/effective diffusion coefficient in brain extracellular fluid), which was considerably larger for the more lipohilic drug, acetaminophen. In addition, in vivo recovery values for both drugs were determined. 4. The results show that intracerebral microdialysis is able to detect local differences in drug concentrations following infusion into the brain. Furthermore, the potential use of intracerebral microdialysis to obtain pharmacokinetic parameters of drug distribution in brain by means of monitoring local concentrations of drugs in time is demonstrated. PMID:8581296

  18. 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

  19. 21 CFR 203.50 - Requirements for wholesale distribution of prescription drugs.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... HUMAN SERVICES (CONTINUED) DRUGS: GENERAL PRESCRIPTION DRUG MARKETING Wholesale Distribution 203.50 Requirements for wholesale distribution of prescription drugs. (a) Identifying statement for sales by... 21 Food and Drugs 4 2010-04-01 2010-04-01 false Requirements for wholesale distribution...

  20. 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

  1. 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…

  2. 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.

  3. Designer drugs 2015: assessment and management.

    PubMed

    Weaver, Michael F; Hopper, John A; Gunderson, Erik W

    2015-01-01

    Recent designer drugs, also known as "legal highs," include substituted cathinones (e.g., mephedrone, methylone, and methylenedioxypyrovalerone, often referred to as "bath salts"); synthetic cannabinoids (SCs; e.g., Spice); and synthetic hallucinogens (25I-NBOMe, or N-bomb). Compound availability has evolved rapidly to evade legal regulation and detection by routine drug testing. Young adults are the primary users, but trends are changing rapidly; use has become popular among members of the military. Acute toxicity is common and often manifests with a constellation of psychiatric and medical effects, which may be severe (e.g., anxiety, agitation, psychosis, and tachycardia), and multiple deaths have been reported with each of these types of designer drugs. Clinicians should keep designer drugs in mind when evaluating substance use in young adults or in anyone presenting with acute neuropsychiatric complaints. Treatment of acute intoxication involves supportive care targeting manifesting signs and symptoms. Long-term treatment of designer drug use disorder can be challenging and is complicated by a lack of evidence to guide treatment. PMID:25928069

  4. Layered double hydroxide nanocomposite for drug delivery systems; bio-distribution, toxicity and drug activity enhancement.

    PubMed

    Kura, Aminu Umar; Hussein, Mohd Zobir; Fakurazi, Sharida; Arulselvan, Palanisamy

    2014-01-01

    The production of layered double hydroxide(LDH) nanocomposite as an alternative drug delivery system against various ailments is on the increase. Their toxicity potential is usually dose and time dependent with particle sizes, shapes and surface charge playing some role both in the in vitro and in vivo studies. The reticular endothelial system of especially the liver and spleen were shown to sequestrate most of these nanocomposite, especially those with sizes greater than 50nm. The intracellular drug delivery by these particles is mainly via endocytotic pathways aided by the surface charges in most cases. However, structural modification of these nanocomposite via coating using different types of material may lower the toxicity where present. More importantly, the coating may serve as targeting ligand hence, directing drug distribution and leading to proper drug delivery to specific area of need; it equally decreases the unwanted nanocomposite accumulation in especially the liver and spleen. These nanocomposite have the advantage of wider bio-distribution irrespective of route of administration, excellent targeted delivery potential with ease of synthetic modification including coating. PMID:25177361

  5. 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

  6. Impact of drug conjugation on pharmacokinetics and tissue distribution of anti-STEAP1 antibody-drug conjugates in rats.

    PubMed

    Boswell, C Andrew; Mundo, Eduardo E; Zhang, Crystal; Bumbaca, Daniela; Valle, Nicole R; Kozak, Katherine R; Fourie, Aimee; Chuh, Josefa; Koppada, Neelima; Saad, Ola; Gill, Herman; Shen, Ben-Quan; Rubinfeld, Bonnee; Tibbitts, Jay; Kaur, Surinder; Theil, Frank-Peter; Fielder, Paul J; Khawli, Leslie A; Lin, Kedan

    2011-10-19

    Antibody-drug conjugates (ADCs) are designed to combine the exquisite specificity of antibodies to target tumor antigens with the cytotoxic potency of chemotherapeutic drugs. In addition to the general chemical stability of the linker, a thorough understanding of the relationship between ADC composition and biological disposition is necessary to ensure that the therapeutic window is not compromised by altered pharmacokinetics (PK), tissue distribution, and/or potential organ toxicity. The six-transmembrane epithelial antigen of prostate 1 (STEAP1) is being pursued as a tumor antigen target. To assess the role of ADC composition in PK, we evaluated plasma and tissue PK profiles in rats, following a single dose, of a humanized anti-STEAP1 IgG1 antibody, a thio-anti-STEAP1 (ThioMab) variant, and two corresponding thioether-linked monomethylauristatin E (MMAE) drug conjugates modified through interchain disulfide cysteine residues (ADC) and engineered cysteines (TDC), respectively. Plasma PK of total antibody measured by enzyme-linked immunosorbent assay (ELISA) revealed ?45% faster clearance for the ADC relative to the parent antibody, but no apparent difference in clearance between the TDC and unconjugated parent ThioMab. Total antibody clearances of the two unconjugated antibodies were similar, suggesting minimal effects on PK from cysteine mutation. An ELISA specific for MMAE-conjugated antibody indicated that the ADC cleared more rapidly than the TDC, but total antibody ELISA showed comparable clearance for the two drug conjugates. Furthermore, consistent with relative drug load, the ADC had a greater magnitude of drug deconjugation than the TDC in terms of free plasma MMAE levels. Antibody conjugation had a noticeable, albeit minor, impact on tissue distribution with a general trend toward increased hepatic uptake and reduced levels in other highly vascularized organs. Liver uptakes of ADC and TDC at 5 days postinjection were 2-fold and 1.3-fold higher, respectively, relative to the unmodified antibodies. Taken together, these results indicate that the degree of overall structural modification in anti-STEAP1-MMAE conjugates has a corresponding level of impact on both PK and tissue distribution. PMID:21913715

  7. 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.

  8. 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

  9. Subarachnoid hemorrhage and the distribution of drugs delivered into the cerebrospinal fluid

    PubMed Central

    Pluta, Ryszard M.; Butman, John A.; Schatlo, Bawarjan; Johnson, Dennis L.; Oldfield, Edward H.

    2016-01-01

    Object Investigators in experimental and clinical studies have used the intrathecal route to deliver drugs to prevent or treat vasospasm. However, a clot near an artery or arteries after subarachnoid hemorrhage (SAH) may hamper distribution and limit the effects of intrathecally delivered compounds. In a primate model of right middle cerebral artery (MCA) SAH, the authors examined the distribution of Isovue-M 300 and 3% Evans blue after infusion into the cisterna magna CSF. Methods Ten cynomolgus monkeys were assigned to SAH and sham SAH surgery groups (5 in each group). Monkeys received CSF injections as long as 28 days after SAH and were killed 3 hours after the contrast/Evans blue injection. The authors assessed the distribution of contrast material on serial CT within 2 hours after contrast injection and during autopsy within 3 hours after Evans blue staining. Results Computed tomography cisternographies showed no contrast in the vicinity of the right MCA (p < 0.05 compared with left); the distribution of contrast surrounding the entire right cerebral hemisphere was substantially reduced. Postmortem analysis demonstrated much less Evans blue staining of the right hemisphere surface compared with the left. Furthermore, the Evans blue dye did not penetrate into the right sylvian fissure, which occurred surrounding the left MCA. The authors observed the same pattern of changes and differences in contrast distribution between SAH and sham SAH animals and between the right and the left hemispheres on Days 1, 3, 7, 14, 21, and 28 after SAH. Conclusions Intrathecal drug distribution is substantially limited by SAH. Thus, when using intrathecal drug delivery after SAH, vasoactive drugs are unlikely to reach the arteries that are at the highest risk of delayed cerebral vasospasm. PMID:19374502

  10. 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

  11. microRNAs as pharmacogenomic biomarkers for drug efficacy and drug safety assessment.

    PubMed

    Koturbash, Igor; Tolleson, William H; Guo, Lei; Yu, Dianke; Chen, Si; Hong, Huixiao; Mattes, William; Ning, Baitang

    2015-11-01

    Much evidence has documented that microRNAs (miRNAs) play an important role in the modulation of interindividual variability in the production of drug metabolizing enzymes and transporters (DMETs) and nuclear receptors (NRs) through multidirectional interactions involving environmental stimuli/stressors, the expression of miRNA molecules and genetic polymorphisms. MiRNA expression has been reported to be affected by drugs and miRNAs themselves may affect drug metabolism and toxicity. In cancer research, miRNA biomarkers have been identified to mediate intrinsic and acquired resistance to cancer therapies. In drug safety assessment, miRNAs have been found associated with cardiotoxicity, hepatotoxicity and nephrotoxicity. This review article summarizes published studies to show that miRNAs can serve as early biomarkers for the evaluation of drug efficacy and drug safety. PMID:26501795

  12. 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...

  13. 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...

  14. 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...

  15. 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...

  16. 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...

  17. Modeling Intravascular Delivery from Drug-Eluting Stents with Biodurable Coating: Investigation of Anisotropic Vascular Drug Diffusivity and Arterial Drug Distribution

    PubMed Central

    Zhu, Xiaoxiang; Pack, Daniel W.; Braatz, Richard D.

    2012-01-01

    In-stent restenosis occurs in coronary arteries after implantation of drug-eluting stents with non-uniform restenosis thickness distribution in the artery cross-section. Knowledge of the spatiotemporal drug uptake in the arterial wall is useful for investigating restenosis growth but may often be very expensive/difficult to acquire experimentally. In this work, local delivery of a hydrophobic drug from a drug-eluting stent implanted in a coronary artery is mathematically modeled to investigate the drug release and spatiotemporal drug distribution in the arterial wall. The model integrates drug diffusion in the coating and drug diffusion with reversible binding in the arterial wall. The model is solved by the finite volume method for both high and low drug loadings relative to its solubility in the stent coating with varied isotropic/anisotropic vascular drug diffusivities. Drug release profiles in the coating are observed to depend not only on the coating drug diffusivity but also on the properties of the surrounding arterial wall. Time dependencies of the spatially-averaged free- and bound-drug levels in the arterial wall on the coating and vascular drug diffusivities are discussed. Anisotropic vascular drug diffusivities result in slightly different average drug levels in the arterial wall but very different spatial distributions. Higher circumferential vascular diffusivity results in more uniform drug loading in the upper layers and is potentially beneficial in reducing in-stent restenosis. An analytical expression is derived which can be used to determine regions in the arterial with higher free-drug concentration than bound-drug concentration. PMID:22512464

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

    PubMed

    Moreno, Asier; Angulo, Ignacio; Perallos, Asier; Landaluce, Hugo; Garca Zuazola, Ignacio Julio; Azpilicueta, Leire; Astrain, Jos Javier; Falcone, Francisco; Villadangos, Jess

    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

  19. 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

  20. 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...

  1. 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...

  2. 45 CFR 156.295 - Prescription drug distribution and cost reporting.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 45 Public Welfare 1 2012-10-01 2012-10-01 false Prescription drug distribution and cost reporting... drug distribution and cost reporting. (a) General requirement. In a form, manner, and at such times... the percentage of prescriptions for which a generic drug was available and dispensed compared to...

  3. 45 CFR 156.295 - Prescription drug distribution and cost reporting.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 45 Public Welfare 1 2013-10-01 2013-10-01 false Prescription drug distribution and cost reporting... drug distribution and cost reporting. (a) General requirement. In a form, manner, and at such times... the percentage of prescriptions for which a generic drug was available and dispensed compared to...

  4. 45 CFR 156.295 - Prescription drug distribution and cost reporting.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 45 Public Welfare 1 2014-10-01 2014-10-01 false Prescription drug distribution and cost reporting... drug distribution and cost reporting. (a) General requirement. In a form, manner, and at such times... the percentage of prescriptions for which a generic drug was available and dispensed compared to...

  5. 77 FR 20025 - Draft Guidance for Industry on Compliance Policy for Reporting Drug Sample Distribution...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-04-03

    ... HUMAN SERVICES Food and Drug Administration Draft Guidance for Industry on Compliance Policy for Reporting Drug Sample Distribution Information; Availability AGENCY: Food and Drug Administration, HHS. ACTION: Notice. SUMMARY: The Food and Drug Administration (FDA) is announcing the availability of a...

  6. 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

  7. A hybrid Markov chain-von Mises density model for the drug-dosing interval and drug holiday distributions.

    PubMed

    Fellows, Kelly; Rodriguez-Cruz, Vivian; Covelli, Jenna; Droopad, Alyssa; Alexander, Sheril; Ramanathan, Murali

    2015-03-01

    Lack of adherence is a frequent cause of hospitalizations, but its effects on dosing patterns have not been extensively investigated. The purpose of this work was to critically evaluate a novel pharmacometric model for deriving the relationships of adherence to dosing patterns and the dosing interval distribution. The hybrid, stochastic model combines a Markov chain process with the von Mises distribution. The model was challenged with electronic medication monitoring data from 207 hypertension patients and against 5-year persistence data. The model estimates distributions of dosing runs, drug holidays, and dosing intervals. Drug holidays, which can vary between individuals with the same adherence, were characterized by the patient cooperativity index parameter. The drug holiday and dosing run distributions deviate markedly from normality. The dosing interval distribution exhibits complex patterns of multimodality and can be long-tailed. Dosing patterns are an important but under recognized covariate for explaining within-individual variance in drug concentrations. PMID:25609224

  8. 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

  9. [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

  10. Successful integration of insecticide-treated bed net distribution with mass drug administration in Central Nigeria.

    PubMed

    Blackburn, Brian G; Eigege, Abel; Gotau, Habila; Gerlong, George; Miri, Emmanuel; Hawley, William A; Mathieu, Els; Richards, Frank

    2006-10-01

    In Africa anopheline mosquitoes transmit malaria and lymphatic filariasis (LF); insecticide-treated bed nets significantly reduce transmission of both. Insecticide-treated bed net provision to children under 5 (U5) and pregnant women (PW) is a major goal of malaria control initiatives, but use in Africa remains low because of cost and logistics. We therefore integrated insecticide-treated bed net distribution with the 2004 LF/onchocerciasis mass drug administration (MDA) program in Central Nigeria. Community volunteers distributed 38,600 insecticide-treated bed nets, while simultaneously treating 150,800 persons with ivermectin/albendazole (compared with 135,600 in 2003). This was subsequently assessed with a 30-cluster survey. Among surveyed households containing U5/PW, 80% (95% CI, 72-87%) owned > or = 1 insecticide-treated bed net, a 9-fold increase from 2003. This first linkage of insecticide-treated bed net distribution with mass drug administration resulted in substantial improvement in insecticide-treated bed net ownership and usage, without adversely affecting mass drug administration coverage. Such integration allowed two programs to share resources while realizing mutual benefit, and is one model for rapidly improving insecticide-treated bed net coverage objectives. PMID:17038688

  11. 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

  12. [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

  13. 7 CFR 1230.72 - Distribution of assessments.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 7 Agriculture 10 2010-01-01 2010-01-01 false Distribution of assessments. 1230.72 Section 1230.72 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING SERVICE (MARKETING... 1230.72 Distribution of assessments. Assessments remitted to the Board shall be distributed as...

  14. 7 CFR 1230.72 - Distribution of assessments.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 7 Agriculture 10 2014-01-01 2014-01-01 false Distribution of assessments. 1230.72 Section 1230.72 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING SERVICE (MARKETING... 1230.72 Distribution of assessments. Assessments remitted to the Board shall be distributed as...

  15. 7 CFR 1230.72 - Distribution of assessments.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... 7 Agriculture 10 2012-01-01 2012-01-01 false Distribution of assessments. 1230.72 Section 1230.72 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING SERVICE (MARKETING... 1230.72 Distribution of assessments. Assessments remitted to the Board shall be distributed as...

  16. 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

  17. The impact of the concentration of drug binding plasma proteins on drug distribution according to ie-Tozer's model.

    PubMed

    Svennebring, Andreas Mats

    2016-04-01

    1.?New equations have been developed from an updated version of ie-Tozer's model expressing how the free concentration and volume of distribution change in relation to changes in the concentration of drug binding plasma proteins. This updated model accommodates more than one drug binding plasma protein to contribute to the plasma protein binding. 2.?Demonstrations of the model show that variability in the concentration of one plasma protein has considerably less impact on the free drug concentration and volume of distribution if other plasma proteins contribute to binding, than if they don't. PMID:26259025

  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. 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 90curvature 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

  20. 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

  1. Critical Assessment of Implantable Drug Delivery Devices in Glaucoma Management

    PubMed Central

    Manickavasagam, Dharani; Oyewumi, Moses O.

    2013-01-01

    Glaucoma is a group of heterogeneous disorders involving progressive optic neuropathy that can culminate into visual impairment and irreversible blindness. Effective therapeutic interventions must address underlying vulnerability of retinal ganglion cells (RGCs) to degeneration in conjunction with correcting other associated risk factors (such as elevated intraocular pressure). However, realization of therapeutic outcomes is heavily dependent on suitable delivery system that can overcome myriads of anatomical and physiological barriers to intraocular drug delivery. Development of clinically viable sustained release systems in glaucoma is a widely recognized unmet need. In this regard, implantable delivery systems may relieve the burden of chronic drug administration while potentially ensuring high intraocular drug bioavailability. Presently there are no FDA-approved implantable drug delivery devices for glaucoma even though there are several ongoing clinical studies. The paper critically assessed the prospects of polymeric implantable delivery systems in glaucoma while identifying factors that can dictate (a) patient tolerability and acceptance, (b) drug stability and drug release profiles, (c) therapeutic efficacy, and (d) toxicity and biocompatibility. The information gathered could be useful in future research and development efforts on implantable delivery systems in glaucoma. PMID:24066234

  2. Risk assessment of drug-induced QT prolongation

    PubMed Central

    Isbister, Geoffrey K

    2015-01-01

    SUMMARY Drugs can cause prolongation of the QT interval, alone or in combination, potentially leading to fatal arrhythmias such as torsades de pointes. When prescribing drugs that prolong the QT interval, the balance of benefit versus harm should always be considered. Readouts from automated ECG machines are unreliable. The QT interval should be measured manually. Changes in heart rate influence the absolute QT interval. Heart rate correction formulae are inaccurate, particularly for fast and slow heart rates. The QT nomogram, a plot of QT interval versus heart rate, can be used as a risk assessment tool to detect an abnormal QT interval. PMID:26648606

  3. 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.

  4. 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

  5. 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…

  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. 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

  8. 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

  9. 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.

  10. Estimation of Drug Binding to Brain Tissue: Methodology and in Vivo Application of a Distribution Assay in Brain Polar Lipids.

    PubMed

    Belli, Sara; Assmus, Frauke; Wagner, Bjoern; Honer, Michael; Fischer, Holger; Schuler, Franz; Alvarez-Snchez, Rubn

    2015-12-01

    The unbound drug concentration-effect relationship in brain is a key aspect in CNS drug discovery and development. In this work, we describe an in vitro high-throughput distribution assay between an aqueous buffer and a microemulsion of porcine brain polar lipids (BPL). The derived distribution coefficient LogDBPL was applied to the prediction of unbound drug concentrations in brain (Cu,b) and nonspecific binding to brain tissue. The in vivo relevance of the new assay was assessed for a large set of proprietary drug candidates and CNS drugs by (1) comparing observed compound concentrations in rat CSF with Cu,b calculated using the LogDBPL assay in combination with total drug brain concentrations, (2) comparing Cu,b derived from LogDBPL and total drug brain concentrations to Cu,b estimated using in vitro P-glycoprotein efflux ratio data and unbound drug plasma levels, and (3) comparing tissue nonspecific binding data from human brain autoradiography studies for 17 PET tracer candidates to distribution in BPL. In summary, the LogDBPL assay provides a predicted drug fraction unbound in brain tissue that is nearly identical to brain homogenate equilibrium dialysis with an estimation of in vivo Cu,b that is superior to LogD in octanol. LogDBPL complements the approach for predicting Cu,b based on in vitro P-glycoprotein efflux ratio and in vivo unbound plasma concentration and stands as a fast and cost-effective tool for nonspecific brain binding optimization of PET ligand candidates. PMID:26560069

  11. 77 FR 44177 - Antimicrobial Animal Drug Sales and Distribution Reporting

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-07-27

    ... requirements applicable to antimicrobial new animal drug sponsors to determine whether additional information... http://www.regulations.gov , including any personal information provided. For additional information on submitting comments, see the ``Comments'' heading of the SUPPLEMENTARY INFORMATION section of this...

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

    PubMed

    ?otysz, S?awomir

    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

  13. 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

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

    PubMed

    Korhonen, Eveliina; Rnkk, Seppo; Hillebrand, Satu; Riikonen, Joakim; Xu, Wujun; Jrvinen, 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 200?g/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

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

    PubMed

    Singh, Sonal; Loke, Yoon K

    2012-01-01

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

  17. Bioluminescence for assessing drug potency against nonreplicating Mycobacterium tuberculosis.

    PubMed

    Vocat, Anthony; Hartkoorn, Ruben C; Lechartier, Benoit; Zhang, Ming; Dhar, Neeraj; Cole, Stewart T; Sala, Claudia

    2015-07-01

    Targeting dormant Mycobacterium tuberculosis represents a challenge to antituberculosis drug discovery programs. We previously reported and validated the use of the streptomycin (STR)-dependent M. tuberculosis 18b strain as a tool for assessing drug potency against nonreplicating bacteria both in vitro and in vivo. In this study, we generated a luminescent 18b strain, named 18b-Lux, by transforming the bacteria with a vector expressing the luxCDABE operon from Photorhabdus luminescens. Luciferase expression was demonstrated under replicating conditions, and, more importantly, luminescence levels significantly above background were detected following STR removal. The sensitivity of STR-starved 18b-Lux to approved and candidate antituberculosis therapeutic agents was evaluated by means of a luciferase assay in a 96-well format. Results mirrored the data obtained with the standard resazurin reduction microplate assay, and the luminescence readout allowed time course assessments of drug efficacy in vitro. Specifically, we proved that bedaquiline, the rifamycins, and sutezolid displayed time-dependent activity against dormant bacteria, while pyrazinamide and SQ109 showed bactericidal effects at the highest concentrations tested. Overall, we established the optimal conditions for an inexpensive, simple, and very sensitive assay with great potential for future applications. PMID:25896710

  18. 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

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

    PubMed Central

    Lozano-Blzquez, Ana; Calvo-Pita, Cecilia; Carbajales-lvarez, Mnica; Surez-Gil, Patricio; Martnez-Martnez, Fernando; Calleja-Hernndez, Miguel ngel

    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 committees 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

  20. 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,…

  1. Assessment of drug-drug interactions in hypertensive patients at a superspeciality hospital

    PubMed Central

    Sivva, Divya; Mateti, Uday Venkat; Neerati, Venu Madhav; Thiruthopu, Nimbagiri Swamy; Martha, Srinivas

    2015-01-01

    Objective: The objective of the study was to assess the incidence and pattern of drug-drug interactions (DDIs) in hypertensive patients by using Micromedex and Medscape databases. Materials and Methods: A prospective observational study was carried out in a superspeciality hospital setting in South India for period of 9 months. Hypertensive patients who admitted into the hospital with the age more than 18 years, received more than 3 drugs per prescription and length of hospital stay for more than 24 hours were included in the study. An appropriate data was collected and assessed for DDIs with the help of Micromedex and Medscape databases. Results: A total of 227 patients were enrolled during the study period. Among the 227 patients, 48 of them developed 53 clinically significant DDIs. Out of 48 patients, most of them were in the age-group of 5060 years [18 (37.49%)]. The percentage of DDIs were higher in males [30 (62.5%)] compared to females [18 (37.5%)]. The most common drugs responsible for DDIs in the present study were Insulin [18 (33.96%)] followed by Metoprolol [10 (18.86%)], Torsemide [8 (15.09%)], and Hydrochlorothiazide [8 (15.09%)]. The most commonly interacting pairs were Ciprofloxacin-Insulin [6 (11.32%)], followed by Metoprolol-Insulin [4 (7.54%)] and Atenolol-Insulin [4 (7.54%)]. The most common consequences of interacting pairs were reduced serum potassium levels and hyperglycemia. Conclusion: The overall incidence rate of DDIs was found to be 21.14% and the increasing number of co-morbidities (P ? 0.003) and polypharmacy (P ? 0.002) were the risk factor for the development of significant number of DDIs. PMID:25878964

  2. 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

  3. 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

  4. 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)...

  5. 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)...

  6. 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)...

  7. 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)...

  8. 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)...

  9. 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...

  10. 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...

  11. 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...

  12. 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...

  13. 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...

  14. 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...

  15. 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...

  16. 28 CFR 83.210 - To whom must I distribute my drug-free workplace statement?

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... workplace statement? 83.210 Section 83.210 Judicial Administration DEPARTMENT OF JUSTICE (CONTINUED) GOVERNMENT-WIDE REQUIREMENTS FOR DRUG-FREE WORKPLACE (GRANTS) Requirements for Recipients Other Than Individuals 83.210 To whom must I distribute my drug-free workplace statement? You must require that a...

  17. 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...

  18. Drug use and distribution in a pain rehabilitation center.

    PubMed

    Beckner, T F; Idsvoog, P

    1975-03-01

    A 23-bed hospital unit specializing in rehabilitating patients suffering from chronic pain by (1) reducing their consumption of and dependence on medication, (2) increasing their level of daily activity and (3) discouraging pain-oriented behavior is described. In addition to aspirin or acetaminophen, four drugs--amitriptyline, diphenylhydantoin, cobra venom extract and methadone--are used to reduce pain while other therapeutic measures are used to rehabilitate the patients. Methods for reducing the amount of analgesics taken by chronic pain patients are discussed. Unit dose packaging is used because the oral solid dosage forms (including placebos) are made to look alike. PMID:1136977

  19. 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

  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. 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

  2. 7 CFR 1230.73 - Uses of distributed assessments.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ....73 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING SERVICE (MARKETING AGREEMENTS AND ORDERS; MISCELLANEOUS COMMODITIES), DEPARTMENT OF AGRICULTURE PORK... its distribution of assessments pursuant to 1230.72, as well as any proceeds from the investment...

  3. 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

  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. 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)

  6. The value of assessing cognitive function in drug development

    PubMed Central

    Wesnes, Keith A.

    2000-01-01

    This paper reviews the value and utility of measuring cognitive function in the development of new medicines by reference to the most widely used automated system in clinical research. Evidence is presented from phase 1 to 3 of the nature and quality of the information that can be obtained by applying the Cognitive Drug Research computerized assessment system to ongoing clinical trials. Valuable evidence can be obtained even in the first trial in which a novel compound is administered to man. One application of such testing is to ensure that novel compounds are relatively free from cognition-impairing properties, particularly in relation to competitor products. Another is to ensure that unwanted interactions with alcohol and other medications do not occur, or, if they do, to put them in context. In many patient populations, cognitive dysfunction occurs as a result of the disease process, and newer medicines which can treat the symptoms of the disease without further impairing function can often reveal benefits as the disease-induced cognitive dysfunction is reduced. Another major application is to identify benefits for compounds designed to enhance cognitive function. Such effects can be sought in typical phase 1 trials, or a scopolamine model of the core deficits of Alzheimer's disease can be used to screen potential antidernentia drugs. Ultimately, of course, such effects can be demonstrated using properly validated and highly sensitive automated procedures in the target populations. The data presented demonstrate that the concept of independently assessing a variety of cognitive functions is crucial in helping differentiate drugs, types of dementia, and different illnesses. Such information offers a unique insight into how the alterations to various cognitive functions will manifest themselves in everyday behavior. This reveals a major limitation of scales that yield a single score, because such limited information does not permit anything but a quantitative interpretation; and the concept of more cognitive function or less is manifestly inappropriate for something as complex and diverse as the interplay between cognitive function and human behavior. Finally, the next generations of cognitive testing are described. Testing via the telephone has just been introduced and will have dramatic effects on the logistics of conducting cognitive testing in large patient trials. Testing via the Internet is not far off either, and will come fully into play as the proportion of homes connected to the Internet increases in Europe and North America. There are no sound reasons for not wishing to include cognitive function testing in the development protocol of any novel medicine. PMID:22033754

  7. 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.

  8. Assessing Interactions for Fixed-Dose Drug Combinations in Subcutaneous Tumor Xenograft Studies

    PubMed Central

    Wu, Jianrong

    2016-01-01

    Drug combinations in preclinical tumor xenograft studies are often assessed using fixed doses. Assessing the joint action of drug combinations with fixed doses has not been well developed in the literature. Here, an interaction index is proposed for fixed-dose drug combinations in a subcutaneous tumor xenograft model. Furthermore, a boot-strap percentile interval of the interaction index is also developed. The joint action of two drugs can be assessed based on confidence limits of the interaction index. Tumor xenograft data from actual two-drug combination studies are analyzed to illustrate the proposed method. PMID:23471653

  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... Regional Offices-General Services Administration 74-GOVERNMENTWIDE REQUIREMENTS FOR DRUG-FREE WORKPLACE... distribute my drug-free workplace statement? You must require that a copy of the statement described in §...

  10. 21 CFR 809.40 - Restrictions on the sale, distribution, and use of OTC test sample collection systems for drugs...

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... OTC test sample collection systems for drugs of abuse testing. 809.40 Section 809.40 Food and Drugs... Restrictions on the sale, distribution, and use of OTC test sample collection systems for drugs of abuse testing. (a) Over-the-counter (OTC) test sample collection systems for drugs of abuse testing (...

  11. 21 CFR 809.40 - Restrictions on the sale, distribution, and use of OTC test sample collection systems for drugs...

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... OTC test sample collection systems for drugs of abuse testing. 809.40 Section 809.40 Food and Drugs... Restrictions on the sale, distribution, and use of OTC test sample collection systems for drugs of abuse testing. (a) Over-the-counter (OTC) test sample collection systems for drugs of abuse testing (...

  12. 21 CFR 809.40 - Restrictions on the sale, distribution, and use of OTC test sample collection systems for drugs...

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... OTC test sample collection systems for drugs of abuse testing. 809.40 Section 809.40 Food and Drugs... Restrictions on the sale, distribution, and use of OTC test sample collection systems for drugs of abuse testing. (a) Over-the-counter (OTC) test sample collection systems for drugs of abuse testing (...

  13. 21 CFR 809.40 - Restrictions on the sale, distribution, and use of OTC test sample collection systems for drugs...

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... OTC test sample collection systems for drugs of abuse testing. 809.40 Section 809.40 Food and Drugs... Restrictions on the sale, distribution, and use of OTC test sample collection systems for drugs of abuse testing. (a) Over-the-counter (OTC) test sample collection systems for drugs of abuse testing (...

  14. 21 CFR 809.40 - Restrictions on the sale, distribution, and use of OTC test sample collection systems for drugs...

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... OTC test sample collection systems for drugs of abuse testing. 809.40 Section 809.40 Food and Drugs... Restrictions on the sale, distribution, and use of OTC test sample collection systems for drugs of abuse testing. (a) Over-the-counter (OTC) test sample collection systems for drugs of abuse testing (...

  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. 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.

  17. A study of the distribution of schistosomicidal drug H-3-7505 in mice

    SciTech Connect

    Hao, T.

    1985-05-01

    The authors have studied the distribution of H-3 labelled schistosomicidal drug in mice by autoradiography. The H-3-labelled substances were found in liver and kidney and in successfully decreasing amounts in brain, lung, heart, fat, testis, pancreas and spleen. In various cells the silver granules were present mainly in the cytoplasms but a few in the nucleus. After administration of this labelled schistosomicidal drug, the mice were killed and studied in groups successively at 4, 8, 24 hrs. No difference in the distribution of silver granules were observed. This fact indicated that, this drug was rapidly absorbed and highly concentrated with a long duration of reservation in liver. All of these favours the schistosomicidal effect of the drug. As this drug was highly concentrated in the cytoplasm of liver cells, that might provide a pathophysiologic basis for the explanation of jaundice in the clinical practice. Moreover, the appearance of toxic reaction in nervous system may be related to the relatively high concentration of the drug distributed in the brain.

  18. [Assessment of actual benefits of new drugs by the Transparency Committee].

    PubMed

    Le Jeunne, C

    2008-01-01

    When a drug has been granted a marketing authorization, if the pharmaceutical company wants it to be covered by the National Health Insurance, the company has to submit a file with all the studies concerning the drug, especially drug-drug comparative studies, to be assessed by the Transparency Committee. Drugs are assessed on two criteria: actual or expected benefit (AB) and improvement in actual benefit (IAB). Actual benefit mainly takes into account the severity of the disease concerned, the level of efficacy relative to known side effects (risk-benefit ratio), and the place the drug is intended to take in the therapeutic strategy. At the end of the assessment, AB is considered as important, moderate, poor or insufficient (to justify inclusion of the drug on the list of products to be reimbursed). After actual benefit is determined, improvement of actual benefit is assessed, comparing the estimated benefit of this drug with one of drugs with the same indication that is already reimbursed, to assess whether this drug will improve the patient's disease. This can be assessed by direct comparison (two drugs compared in the same clinical trial) or by indirect comparison (separate studies with the same design). There are four levels of added value, from I (major improvement) to IV (minor improvement). Level V represents no improvement. This second assessment is always relative to another drug. It never provides an absolute score. However, IAB is very important for pharmaceutical companies, because it is a fundamental criterion to determine the price of the drug, which is discussed with the Economic Committee of Health Products in a final phase. Actual benefit and improvement in actual benefit are allocated for each indication of a drug. PMID:18401307

  19. Drug compliance in adolescents: assessing and managing modifiable risk factors.

    PubMed

    Staples, Betty; Bravender, Terrill

    2002-01-01

    Many studies have found that adolescence represents a problem in compliance with prescribed drug regimens. Multiple factors contribute to this problem, including the developmental evolution taking place in the adolescent physique and psyche. Health belief and patient demographic factors, inherent disease and regimen factors, as well as the dynamics between patient and provider may also contribute to problems with compliance to treatment. Simple interventions such as working with the teen to construct a tolerable treatment regimen, assessing anticipated compliance, discussing potential adverse effects, and establishing cues from the adolescent's daily routine can positively impact treatment compliance. Healthcare providers should recognize the fact that psychosocial changes in an adolescent's life can impact upon compliance with medications and enlist the help of their patients in constructing treatment regimens taking into account the individual's lifestyle that may impact upon compliance. In particular, the healthcare provider should ask the adolescents what they anticipate their success with compliance to treatment might be, adverse effects they are concerned about and what cues could best aid the treatment plan. The healthcare provider should then synthesize this information to create the best treatment plan for that patient. PMID:12126454

  20. 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. ?he concentrations of some compounds varied significantly with depth suggesting that currents play an important role in the dilution of the target compounds. PMID:26473711

  1. 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

  2. Assessment of pharmacokinetic drug-drug interaction between pradigastat and atazanavir or probenecid.

    PubMed

    Mendonza, Anisha; Hanna, Imad; Meyers, Dan; Koo, Phillip; Neelakantham, Srikanth; Zhu, Bing; Majumdar, Tapan; Rebello, Sam; Sunkara, Gangadhar; Chen, Jin

    2016-03-01

    Pradigastat, a novel diacylglycerol acyltransferase-1 inhibitor, has activity in common metabolic diseases associated with abnormal accumulation of triglycerides. In vitro studies suggest that glucuronidation is the predominant metabolism pathway for elimination of pradigastat in humans and confirmed the role of uridine 5'-diphosphoglucuronosyltransferase (UGT) enzymes, UGT1A1, -1A3, and -2B7. The in vitro studies using atazanavir as a selective inhibitor of UGT1A1 and -1A3 indicated that these enzymes contribute ?55% toward the overall glucuronidation pathway. Therefore, a clinical study was conducted to assess the potential for drug interaction between pradigastat and probenecid (purported general UGT inhibitor) or atazanavir (selective UGT1A1, -1A3 inhibitor). The study included 2 parallel cohorts, each with 3 sequential treatment periods and 22 healthy subjects per cohort. The 90%CI of the geometric mean ratios for Cmax,ss and AUC?,ss of pradigastat were within 0.80-1.25 when administered in combination with probenecid. However, the Cmax,ss and AUC?,ss of pradigastat decreased by 31% (90%CI: 0.62-0.78) and 26% (0.67-0.82), respectively, when administered in combination with atazanavir. This magnitude of decrease in pradigastat steady-state exposure is not considered clinically relevant. Pradigastat was well tolerated by all subjects, either alone or in combination with atazanavir or probenecid. PMID:26189431

  3. 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...

  4. 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...

  5. 10 CFR 32.72 - Manufacture, preparation, or transfer for commercial distribution of radioactive drugs containing...

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... 10 Energy 1 2012-01-01 2012-01-01 false Manufacture, preparation, or transfer for commercial distribution of radioactive drugs containing byproduct material for medical use under part 35. 32.72 Section 32.72 Energy NUCLEAR REGULATORY COMMISSION SPECIFIC DOMESTIC LICENSES TO MANUFACTURE OR TRANSFER CERTAIN ITEMS CONTAINING BYPRODUCT...

  6. 10 CFR 32.72 - Manufacture, preparation, or transfer for commercial distribution of radioactive drugs containing...

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 10 Energy 1 2010-01-01 2010-01-01 false Manufacture, preparation, or transfer for commercial distribution of radioactive drugs containing byproduct material for medical use under part 35. 32.72 Section 32.72 Energy NUCLEAR REGULATORY COMMISSION SPECIFIC DOMESTIC LICENSES TO MANUFACTURE OR TRANSFER CERTAIN ITEMS CONTAINING BYPRODUCT...

  7. 10 CFR 32.21 - Radioactive drug: Manufacture, preparation, or transfer for commercial distribution of capsules...

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 10 Energy 1 2010-01-01 2010-01-01 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...

  8. 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...

  9. 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... NUCLEAR REGULATORY COMMISSION SPECIFIC DOMESTIC LICENSES TO MANUFACTURE OR TRANSFER CERTAIN ITEMS..., preparation, or transfer for commercial distribution of capsules containing carbon-14 urea each for “in...

  10. 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 for commercial distribution of capsules containing carbon-14 urea each for in vivo diagnostic use for humans to persons exempt from licensing; Requirements for a license. 32.21 Section 32.21 Energy NUCLEAR REGULATORY COMMISSION SPECIFIC...

  11. 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

  12. 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

    ... Abuse (NIDA), as described in a Memorandum of Understanding (MOU) of March 8, 1985 (50 FR 9518). When a... HUMAN SERVICES Food and Drug Administration Draft Guidance for Industry on Assessment of Abuse Potential... ``Assessment of Abuse Potential of Drugs.'' This draft guidance is intended to assist sponsors who...

  13. In silico assessment of adverse drug reactions and associated mechanisms.

    PubMed

    Ivanov, Sergey M; Lagunin, Alexey A; Poroikov, Vladimir V

    2016-01-01

    During recent years, various in silico approaches have been developed to estimate chemical and biological drug features, for example chemical fragments, protein targets, pathways, among others, that correlate with adverse drug reactions (ADRs) and explain the associated mechanisms. These features have also been used for the creation of predictive models that enable estimation of ADRs during the early stages of drug development. In this review, we discuss various in silico approaches to predict these features for a certain drug, estimate correlations with ADRs, establish causal relationships between selected features and ADR mechanisms and create corresponding predictive models. PMID:26272036

  14. Interrogating the relationship between rat invivo 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 invivo outcomes have been compared to in silico and invitro drug property data to determine the most influential properties governing drug distribution. Consistent with current knowledge, invivo 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

  15. Reactive oxygen species assay-based risk assessment of drug-induced phototoxicity: classification criteria and application to drug candidates.

    PubMed

    Onoue, Satomi; Kawamura, Kiyoshi; Igarashi, Naoko; Zhou, Yu; Fujikawa, Masaaki; Yamada, Hiroshi; Tsuda, Yoshiko; Seto, Yoshiki; Yamada, Shizuo

    2008-08-01

    We have previously demonstrated that the phototoxic potential of chemicals could be partly predicted by the determination of reactive oxygen species (ROS) from photo-irradiated compounds. In this study, ROS assay strategy was applied to 39 marketed drugs and 210 drug candidates in order to establish provisional classification criteria for risk assessment of drug-induced phototoxicity. The photosensitizing properties of 39 model compounds consisting of phototoxic and non-phototoxic chemicals, as well as ca. 210 drug candidates including 11 chemical series were evaluated using ROS assay and the 3T3 neutral red uptake phototoxicity test (NRU PT). With respect to marketed drugs, most phototoxic drugs tended to cause type I and/or II photochemical reactions, resulting in generation of singlet oxygen and superoxide. There seemed to be a clear difference between phototoxic drugs and non-phototoxic compounds in their abilities to induce photochemical reactions. A plot analysis of ROS data on the marked drugs provided classification criteria to discriminate the photosensitizers from non-phototoxic substances. Of all drug candidates tested, 35.2% compounds were identified as phototoxic or likely phototoxic on the basis of the 3T3 NRU PT, and all ROS data for these phototoxic compounds were found to be over the threshold value. Furthermore, 46.3% of non-phototoxic drug candidates were found to be in the subthreshold region. These results verify the usefulness of the ROS assay for understanding the phototoxicity risk of pharmaceutical substances, and the ROS assay can be used for screening purposes in the drug discovery stage. PMID:18455898

  16. 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

  17. 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.

  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. 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.

  20. Gelatin-carrageenan hydrogels: role of pore size distribution on drug delivery process.

    PubMed

    Varghese, Jina Susan; Chellappa, Nisha; Fathima, Nishter Nishad

    2014-01-01

    Naturally occurring biomaterials, such as gelatin and carrageenan are known to act as good drug delivering agents. The physical properties of these hydrogels are derived from their pore network. The effect of pore size distribution of hydrogel on the drug delivery process has been studied in this work. Gelatin-carrageenan hydrogel has been characterized using DSC, TGA and SEM. Thermoporometry technique has been used since it offers the measurement to be carried out in native state without drying the sample. Release of quercetin (Q,3,5,7,3',4'-pentahydroxyflavone), a member of the flavonoids family, which exerts many beneficial health effects has been studied using gelatin-carrageenan hydrogel. The addition of gelatin to carrageenan is found to improve the thermal stability of the gelatin-carrageenan fibers in the composite hydrogels. The in vitro drug release studies have shown that an increase in porosity results in the improved drug release. The tuning of pore size distribution for drug delivery applications using thermoporometry is feasible. PMID:24126319

  1. 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

  2. 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...

  3. 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...

  4. 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...

  5. Multivariate analysis applied to the study of spatial distributions found in drug-eluting stent coatings by confocal Raman microscopy.

    PubMed

    Balss, Karin M; Long, Frederick H; Veselov, Vladimir; Orana, Argjenta; Akerman-Revis, Eugena; Papandreou, George; Maryanoff, Cynthia A

    2008-07-01

    Multivariate data analysis was applied to confocal Raman measurements on stents coated with the polymers and drug used in the CYPHER Sirolimus-eluting Coronary Stents. Partial least-squares (PLS) regression was used to establish three independent calibration curves for the coating constituents: sirolimus, poly(n-butyl methacrylate) [PBMA], and poly(ethylene-co-vinyl acetate) [PEVA]. The PLS calibrations were based on average spectra generated from each spatial location profiled. The PLS models were tested on six unknown stent samples to assess accuracy and precision. The wt % difference between PLS predictions and laboratory assay values for sirolimus was less than 1 wt % for the composite of the six unknowns, while the polymer models were estimated to be less than 0.5 wt % difference for the combined samples. The linearity and specificity of the three PLS models were also demonstrated with the three PLS models. In contrast to earlier univariate models, the PLS models achieved mass balance with better accuracy. This analysis was extended to evaluate the spatial distribution of the three constituents. Quantitative bitmap images of drug-eluting stent coatings are presented for the first time to assess the local distribution of components. PMID:18510342

  6. 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

  7. 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

  8. 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

  9. 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

  10. Assessment of drug-drug interactions between daclatasvir and methadone or buprenorphine-naloxone.

    PubMed

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

    2015-09-01

    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 (AUC?) or maximum concentration in plasma (C max) 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 AUC? 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 AUC? 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 C max 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. 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

  13. Comparison of self-reported drug use with quantitative and qualitative urinalysis for assessment of drug use in treatment studies.

    PubMed

    Preston, K L; Silverman, K; Schuster, C R; Cone, E J

    1997-01-01

    The effectiveness of substance abuse treatment programs can be monitored by self-reported drug use and objectively measured by qualitative and quantitative urinalysis. The advantages and disadvantages of each of these three methods of assessing drug use are reviewed. Data collected in a clinical trial of a behavioral treatment for cocaine abuse are used to evaluate the relationships among qualitative and quantitative urinalysis for cocaine metabolite and self-reported cocaine use. Qualitative and quantitative urine testing showed greater rates of drug use than that shown by self-report, though there were significant correlations between self-reported use and urine toxicology results. Benzoylecgonine concentrations in urine specimens supported the suggestions that rates of drug use as determined by qualitative urinalysis are artificially high due to carryover and were informative about subjects' patterns of use. PMID:9243560

  14. Limitations of in vitro assessments of the drug interaction potential of botanical supplements.

    PubMed

    Markowitz, John S; Zhu, Hao-Jie

    2012-09-01

    Although there are inherent and recognized limitations of in vitro screening methodologies to assess conventional drug-drug interactions (DDIs) per industry guidelines and those adopted by independent laboratories, further limitations are being appreciated which are unique to the evaluation of botanical products and potential DDIs in which they may participate. Among the larger issues faced are the uncertainty in assigning hepatic concentrations of multiple constituents and their potential metabolites, accounting for oral bioavailability, distribution, first-pass metabolism and active metabolites. Furthermore, the wide variability in the chemical composition of commercially available botanical supplement formulations continues to be a major concern, and manufacturing standards or enforcement thereof is essentially nonexistent in most countries. Differing formulations, unspecified product excipients, administration and absorption of the therapeutic ingredient(s) of a standardized dosage form, the very presence and/or concentration of one or more phytoconstituents within a supplement are typically unknown and nontarget entities. A further issue is the absence of authentic analytical standards, and the inability to accurately screen the entities as mixtures to even approximate typical scenarios, which may occur following the ingestion of dietary supplements, adds additional layers of complexity to experimental design and difficulty in interpreting experimental results. Multiple challenges exist in experimental methodologies employed in performing in vitro research with conventional pharmaceuticals and those unique to botanical extracts. These obstacles prevent the investigators from effectively utilizing high-throughput models to accomplish more than essentially "flag" suspected sources of drug interactions which must be further evaluated in vivo, at present, in order to confirm clinical significance. This review is intended to discuss the problems and challenges in evaluating botanical-drug interactions using in vitro methodologies. PMID:22814819

  15. 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.

  16. 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...

  17. 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...

  18. 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...

  19. 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...

  20. 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...

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

    PubMed

    Hsiao, Hao-Ming; Chiu, Yi-Hsiang

    2013-01-01

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

  2. Scientometric assessment of drugs for chronic pain, 19792013: rapid growth of publications, paucity of successful drugs

    PubMed Central

    Kissin, Igor

    2014-01-01

    The aim of this study was to find signs of progress in the pharmacotherapy of chronic pain over the past 35 years using scientometric analysis. The following scientometric indices were used: 1) popularity index, representing the share of articles on a specific drug(s) relative to all articles in the field of chronic pain; 2) index of change, representing the degree of growth in publications on a topic from one period to the next; 3) index of expectations, representing the ratio of the number of articles on a topic in the top 20 journals relative to the number of articles in all (>5,000) biomedical journals covered by PubMed; and 4) index of ultimate success, representing a publication outcome when a new drug takes the place of a common drug previously used for the same purpose. Publications on 55 drugs used in the treatment of chronic pain were assessed during seven 5-year periods, from 1979 to 2013. The rate of rise in the number of publications on chronic pain was exponential, with an increase of nearly ninefold from 2,346 articles over the 5-year period 19791983 to 21,095 articles in 20092013. However, despite this huge increase in publications, our scientometric analysis did not reveal signs of really successful drugs in this field. For the 20092013 period, the popularity index had a meaningful magnitude (from 0.52.8) for only 13 of 55 drugs. Five of them were opioids, including morphine, which had the highest index value of all drugs (2.8). None of the drugs had a high index of expectations in 20092013. The index of ultimate success was positive only with triptans in the relatively limited area of acute treatment of migraine. As a result, despite rapid growth in the number of publications, our scientometric analysis did not reveal signs of substantial progress in the field of pharmacotherapy for chronic pain. PMID:25187736

  3. 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

  4. Parents Subjective Assessment of Effects of Antiepileptic Drug Discontinuation

    PubMed Central

    Kim, Gun-Ha; Byeon, Jung Hye; Eun, So-Hee; Eun, Baik-Lin

    2015-01-01

    Background and Purpose: Many parents express worries about potential negative side effects of antiepileptic drugs (AED) on cognition, behavior, mood, and academic achievement. We aimed to evaluate parents subjective feelings about cognitive or behavioral changes in their children and their quality of life after antiepileptic drug (AED) discontinuation. Methods: A modified questionnaire based on the Korean-Quality of Life in Childhood Epilepsy and the Korean-Child Behavior Checklist was answered by parents whose children were seizure-free over the course of 1 month after AED discontinuation. All children were seizure-free for at least 2 years before AED withdrawal. Results: Fifty-eight eligible patients (mean age, 14.1 4.5 years) were examined. Except valproate in cognition (p = 0.03), parents did not feel significant change after discontinuation of different drugs. They felt improvement of behavior in generalized epilepsy (p = 0.04) and better quality of life in children less than 6 year of age at diagnosis of epilepsy (p = 0.02). Conclusions: We propose that factors such as earlier age at diagnosis of epilepsy or type of epilepsy might influence parents subjective feelings about their childrens well-being after drug discontinuation, rather than the drug itself. PMID:26157667

  5. 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

  6. Opinion: Assessing the Barriers to Image Guided Drug Delivery

    PubMed Central

    Lanza, Gregory M.; Moonen, Chrit; Baker, James R.; Chang, Esther; Cheng, Zheng; Grodzinski, Piotr; Ferrara, Katherine; Hynynen, Kullervo; Kelloff, Gary; Koo Lee, Yong-Eun; Patri, Anil K; Sept, David; Schnitzer, Jan E.; Wood, Bradford J.; Zhang, Miqin; Zheng, Gang; Farahani, Keyvan

    2014-01-01

    Imaging has become a cornerstone for medical diagnosis and the guidance of patient management. A new field called Image Guided Drug Delivery (IGDD) now combines the vast potential of the radiological sciences with the delivery of treatment and promises to fulfill the vision of personalized medicine. Whether imaging is used to deliver focused energy to drug-laden particles for enhanced, local drug release around tumors, or it is invoked in the context of nanoparticle-based agents to quantify distinctive biomarkers that could risk-stratify patients for improved targeted drug delivery efficiency, the overarching goal of IGDD is to use imaging to maximize effective therapy in diseased tissues and to minimize systemic drug exposure in order to reduce toxicities. Over the last several years innumerable reports and reviews covering the gamut of IGDD technologies have been published, but inadequate attention has been directed towards identifying and addressing the barriers limiting clinical translation. In this consensus opinion, the opportunities and challenges impacting the clinical realization of IGDD-based personalized medicine were discussed as a panel and recommendations were proffered to accelerate the field forward. PMID:24339356

  7. 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.

  8. 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

  9. 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.

  10. Quantitative spatial distribution of sirolimus and polymers in drug-eluting stents using confocal Raman microscopy.

    PubMed

    Balss, K M; Llanos, G; Papandreou, G; Maryanoff, C A

    2008-04-01

    Raman spectroscopy was used to differentiate each component found in the CYPHER Sirolimus-eluting Coronary Stent. The unique spectral features identified for each component were then used to develop three separate calibration curves to describe the solid phase distribution found on drug-polymer coated stents. The calibration curves were obtained by analyzing confocal Raman spectral depth profiles from a set of 16 unique formulations of drug-polymer coatings sprayed onto stents and planar substrates. The sirolimus model was linear from 0 to 100 wt % of drug. The individual polymer calibration curves for poly(ethylene-co-vinyl acetate) [PEVA] and poly(n-butyl methacrylate) [PBMA] were also linear from 0 to 100 wt %. The calibration curves were tested on three independent drug-polymer coated stents. The sirolimus calibration predicted the drug content within 1 wt % of the laboratory assay value. The polymer calibrations predicted the content within 7 wt % of the formulation solution content. Attenuated total reflectance Fourier transform infrared (ATR-FTIR) spectra from five formulations confirmed a linear response to changes in sirolimus and polymer content. PMID:17876804

  11. 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

  12. 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

  13. 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

  14. 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

  15. 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

  16. 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...

  17. 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…

  18. 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

  19. 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…

  20. 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,

  1. 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)

  2. 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...

  3. Assessing the benefit:risk ratio of a drug - randomized and naturalistic evidence

    PubMed Central

    Curtin, Franois; Schulz, Pierre

    2011-01-01

    Randomized evidence from clinical trials and naturalistic evidence collected from pharmacoepidemiology and pharmacovigilance activities both contribute to the initial and continuous assessment of the benefits and risks of a drug, ie, the balance between therapeutic efficacy and safety risks. Benefit-risk assessment (BRA) mainly relies on a qualitative assessment of quantitative data. Current attempts to quantify BRA are reviewed and discussed, along with the expectations of regulatory authorities such as the Food and Drug Administration and the European Medicines Agency. No method provides a fully satisfactory solution regarding BRA, because it is difficult to reduce its multidimensional aspect to simple metrics, in a context where other therapeutic alternatives play a role. Consistency and transparency are key in this assessment, which is performed throughout the whole drug life cycle. BRA is mainly based on randomized clinical studies during clinical development, and it is continued and consolidated by naturalistic data once the drug is on the market. PMID:21842615

  4. CDER risk assessment exercise to evaluate potential risks from the use of nanomaterials in drug products.

    PubMed

    Cruz, Celia N; Tyner, Katherine M; Velazquez, Lydia; Hyams, Kenneth C; Jacobs, Abigail; Shaw, Arthur B; Jiang, Wenlei; Lionberger, Robert; Hinderling, Peter; Kong, Yoon; Brown, Paul C; Ghosh, Tapash; Strasinger, Caroline; Suarez-Sharp, Sandra; Henry, Don; Van Uitert, Maat; Sadrieh, Nakissa; Morefield, Elaine

    2013-07-01

    The Nanotechnology Risk Assessment Working Group in the Center for Drug Evaluation and Research (CDER) within the United States Food and Drug Administration was established to assess the possible impact of nanotechnology on drug products. The group is in the process of performing risk assessment and management exercises. The task of the working group is to identify areas where CDER may need to optimize its review practices and to develop standards to ensure review consistency for drug applications that may involve the application of nanotechnology. The working group already performed risk management exercises evaluating the potential risks from administering nanomaterial active pharmaceutical ingredients (API) or nanomaterial excipients by various routes of administration. This publication outlines the risk assessment and management process used by the working group, using nanomaterial API by the oral route of administration as an example. PMID:23512727

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

    PubMed Central

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

    2009-01-01

    A high-throughput method has been developed to measure drug-cyclodextrin binding constants. It measures the distribution ratio of a drug between a polymer film [polyvinyl chloride (PVC) with 67% (w/w) dioctyl sebacate (DOS)] and a cyclodextrin-containing buffer in a 96-well format. Measurements of distribution ratios at several cyclodextrin concentrations lead to binding constants. Binding constants for econazole with six CDs have been determined in one 96-well microplate with four replications of each condition in 10 h. The K1:1/103 M?1 values are 3.980.13, 3.900.22, 29.32.2, 0.660.04 1.780.30, 4.080.50, with (2-hydroxyethyl)-?-cyclodextrin, (2-hydroxypropyl)-?-cyclodextrin, 2,6-di-O-methyl-?-cyclodextrin, hepta-kis(2,3,6-tri-O-methyl)-?-cyclodextrin, ?-cyclodextrin, ?-cyclodextrin, respectively. It is likely that 1:2 complexes are also formed in some cases. This method has also been applied to study the binding behavior as a function of the drug concentration and pH. Binding weakens at higher drug concentration which may be due to the self-association of the drug. An acidic environment decreases the binding constant of CD with the basic econazole. The formation of the 1:2 complexes is completely suppressed in acid as well. This protocol is faster than the phase-solubility method. Moreover, the material requirement is up to four orders of magnitude lower. PMID:18428984

  6. 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

  7. 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

  8. 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

  9. 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.

  10. 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.

  11. 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

  12. 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

  13. Exemplifying the Screening Power of Mass Spectrometry Imaging over Label-Based Technologies for Simultaneous Monitoring of Drug and Metabolite Distributions in Tissue Sections.

    PubMed

    Goodwin, Richard J A; Nilsson, Anna; Mackay, C Logan; Swales, John G; Johansson, Maria K; Billger, Martin; Andrn, Per E; Iverson, Suzanne L

    2016-02-01

    Mass spectrometry imaging (MSI) provides pharmaceutical researchers with a suite of technologies to screen and assess compound distributions and relative abundances directly from tissue sections and offer insight into drug discovery-applicable queries such as blood-brain barrier access, tumor penetration/retention, and compound toxicity related to drug retention in specific organs/cell types. Label-free MSI offers advantages over label-based assays, such as quantitative whole-body autoradiography (QWBA), in the ability to simultaneously differentiate and monitor both drug and drug metabolites. Such discrimination is not possible by label-based assays if a drug metabolite still contains the radiolabel. Here, we present data exemplifying the advantages of MSI analysis. Data of the distribution of AZD2820, a therapeutic cyclic peptide, are related to corresponding QWBA data. Distribution of AZD2820 and two metabolites is achieved by MSI, which [(14)C]AZD2820 QWBA fails to differentiate. Furthermore, the high mass-resolving power of Fourier transform ion cyclotron resonance MS is used to separate closely associated ions. PMID:26701101

  14. 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.

  15. 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.

  16. The effects of microRNA on the absorption, distribution, metabolism and excretion of drugs.

    PubMed

    He, Y; Chevillet, J R; Liu, G; Kim, T K; Wang, K

    2015-06-01

    The importance of genetic factors (e.g. sequence variation) in the absorption, distribution, metabolism, excretion (ADME) and overall efficacy of therapeutic agents is well established. Our ability to identify, interpret and utilize these factors is the subject of much clinical investigation and therapeutic development. However, drug ADME and efficacy are also heavily influenced by epigenetic factors such as DNA/histone methylation and non-coding RNAs [especially microRNAs (miRNAs)]. Results from studies using tools, such as in silico?miRNA target prediction, in vitro functional assays, nucleic acid profiling/sequencing and high-throughput proteomics, are rapidly expanding our knowledge of these factors and their effects on drug metabolism. Although these studies reveal a complex regulation of drug ADME, an increased understanding of the molecular interplay between the genome, epigenome and transcriptome has the potential to provide practically useful strategies to facilitate drug development, optimize therapeutic efficacy, circumvent adverse effects, yield novel diagnostics and ultimately become an integral component of personalized medicine. PMID:25296724

  17. The future of population-based postmarket drug risk assessment: a regulator's perspective.

    PubMed

    Hammad, T A; Neyarapally, G A; Iyasu, S; Staffa, J A; Dal Pan, G

    2013-09-01

    The US Food and Drug Administration emphasizes the role of regulatory science in the fulfillment of its mission to promote and protect public health and foster innovation. With respect to the evaluation of drug effects in the real world, regulatory science plays an important role in drug risk assessment and management. This article discusses opportunities and challenges with population-based drug risk assessment as well as related regulatory science knowledge gaps in the following areas: (i) population-based data sources and methods to evaluate drug safety issues; (ii) evidence-based thresholds to account for uncertainty in postmarket data; (iii) approaches to optimize the integration and interpretation of evidence from different sources; and (iv) approaches to evaluate the real-world impact of regulatory decisions. Regulators should continue the ongoing dialogue with multiple stakeholders to strengthen regulatory safety science and address these and other critical knowledge gaps. PMID:23739537

  18. 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

  19. Preclinical assessment of proconvulsant drug activity and its relevance for predicting adverse events in humans.

    PubMed

    Lscher, Wolfgang

    2009-05-21

    Safety pharmacology studies, which are performed before first studies with investigational drugs in humans, often include experiments on proconvulsant drug activity, because such drugs are thought to promote seizures by decreasing seizure threshold. A commonly used model for the assessment of proconvulsant activity of investigational or marketed drugs is the timed intravenous pentylenetetrazole (PTZ) infusion seizure test, in which the latency to myoclonic or clonic seizures is determined by PTZ infusion in mice or rats. This test provides an extremely sensitive parametric method for assessing seizure threshold and allows detecting both anticonvulsant and proconvulsant drug effects. The aim of this review is to critically review the concept of "proconvulsant" drug activity and discuss data obtained by the PTZ and other seizure threshold tests as well as the various factors that may affect seizure threshold determinations. Furthermore, preclinical and clinical data on proconvulsant drug activity are compared. It is concluded that a battery of different tests is needed to provide the most reliable conclusions about the proconvulsant profile, if any, of drugs. Furthermore, misconceptions regarding proconvulsant drug effects, which can result in the undertreatment of brain diseases, are discussed. PMID:19292981

  20. 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

  1. Early benefit assessment of new drugs in Germany - results from 2011 to 2012.

    PubMed

    Hrn, Helmut; Nink, Katrin; McGauran, Natalie; Wieseler, Beate

    2014-06-01

    Rising drug costs in Germany led to the Act on the Reform of the Market for Medicinal Products (AMNOG) in January 2011. For new drugs, pharmaceutical companies have to submit dossiers containing all available evidence to demonstrate an added benefit versus an appropriate comparator therapy. The Federal Joint Committee (G-BA), the main decision-making body of the statutory healthcare system, is responsible for the overall procedure of "early benefit assessment". The Institute for Quality and Efficiency in Health Care (IQWiG) largely conducts the dossier assessments, which inform decisions by the G-BA on added benefit and support price negotiations. Of the 25 dossiers (excluding orphan drugs) assessed until 31 December 2012, 14 contained sufficient data from randomized active-controlled trials investigating patient-relevant outcomes or at least acceptable surrogates; 11 contained insufficient data. The most common indications were oncology (6) and viral infections (4). For the 14 drugs assessed, the extent of added benefit was rated as minor, considerable, and non-quantifiable in 3, 8, and 2 cases; the remaining drug showed no added benefit. Despite some shortcomings, for the first time it has been possible in Germany to implement a systematic procedure for assessing new drugs at market entry, thus providing support for price negotiations and informed decision-making for patients, clinicians and policy makers. PMID:24472328

  2. Drug Distribution in Microspheres Enhances Their Anti-Inflammatory Properties in the Gottingen Minipig.

    PubMed

    Kastellorizios, Michail; Tipnis, Namita; Papadimitrakopoulos, Fotios; Burgess, Diane J

    2015-09-01

    The foreign body reaction (FBR), one of the body's defense mechanisms against foreign materials, results in loss of implant biocompatibility. A popular strategy to prevent FBR is the constant release of dexamethasone in the tissue surrounding the implant. However, FBR prevention has not been sufficiently studied in large animal models, which offer a better representation of the human subcutaneous tissue physiology. Accordingly, a long-term strategy to prevent FBR to subcutaneous implants in a large animal model is necessary to translate the existing research for clinical applications. Here, a poly(lactic-co-glycolic) (PLGA) microsphere/poly(vinyl alcohol) (PVA) hydrogel composite coating for one-month prevention of FBR in Gottingen minipigs was developed. A modified PLGA microsphere formulation process is presented, that utilizes coprecipitation of dexamethasone and PLGA. Traditional methods result in heterogeneous distribution of large drug crystals in the microsphere matrix, which in turn results in low drug loading since the drug crystal size is close to that of the microspheres. The modified microsphere preparation method showed homogeneous distribution of dexamethasone, which in turn gave rise to increased drug loading, low burst release, and minimal lag phase. Elimination of the lag phase was dictated from previous work that compared FBR between rats and minipigs. The ability of the coatings to improve implant biocompatibility was successfully tested in vivo via histological examination of explanted tissue from the area surrounding the implants. The biocompatible coatings presented here are suitable for miniaturized implantable devices, such as biosensors, that require constant communication with the local microenvironment. PMID:26237140

  3. Assessment of drugs in schizophrenia. Diagnosis and patient selection.

    PubMed Central

    Forrest, A D

    1976-01-01

    It would seem that some set of operational definitions are required for the spectrum of psychotic patients often embraced by the rubric schizophrenia. The problems of acute (first-admission) and chronic patients have been described. At the present time 'relapse re-admissions' would seem to constitute the best population for drug evaluations. The importance of factors such as age, sex, ethnics, geography and length of history has been emphasized. Finally the importance of carefully excluding patients who would be at risk from pre-existing disease or hypersensitivity has been emphasized. PMID:791323

  4. [Brazilian policy for the distribution and production of antiretroviral drugs: a privilege or a right?].

    PubMed

    Galvao, Jane

    2002-01-01

    This article focuses on the Brazilian National AIDS Program and its policy of distributing and producing antiretroviral drugs, emphasizing links between local decisions and global HIV/AIDS policies. Emphasizing recent developments in the Brazilian and international scenario with regard to access to treatment for people with HIV/AIDS, the article highlights the participation by the pharmaceutical industry, governments, civil society, and UN agencies in establishing responses to the pandemic. The author concludes by identifying transnational activism as a key response to both the power of pharmaceutical corporations and the law of the market (including patent laws), thus fostering global solidarity for people with HIV/AIDS. PMID:11910440

  5. 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…

  6. 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

  7. 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

  8. 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

  9. 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

  10. 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

  11. New investigation of distribution imaging and content uniformity of very low dose drugs using hot-melt extrusion method.

    PubMed

    Park, Jun-Bom; Kang, Chin-Yang; Kang, Wie-Soo; Choi, Han-Gon; Han, Hyo-Kyung; Lee, Beom-Jin

    2013-12-31

    The content uniformity of low dose drugs in dosage forms is very important for quality assurance. The aim of this study was to prepare uniformly and homogeneously distributed dosage forms of very low-dose drugs using twin screw hot-melt extrusion (HME) and to investigate the distribution of drugs using instrumental analyses. For the feasibility of HME method, a very low amount of coumarin-6, a fluorescent dye, was used to visualize distribution images using confocal laser scanning microscope (CLSM). Limaprost, tamsulosin and glimepiride were then used as low-dose model drugs to study the applicability of HME for content uniformity and distribution behaviors. Hydrophilic thermosensitive polymers with low melting point, such as Poloxamer188 and polyethylene glycol (PEG) 6000, were chosen as carriers. The melt extrusion was carried out around 50C, at which both carriers were easily dissolved but model drugs remained in solid form. The physicochemical properties of the hot-melt extrudates, including differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD) and Fourier transform infrared spectroscopy (FT-IR), were measured. Content uniformity of the drugs was also checked by HPLC. CLSM imaging showed that model drugs were well distributed throughout the hot-melt extrudate, giving better content uniformity with low batch-to-batch variations compared with simple physical mixtures. DSC, PXRD and FT-IR data showed that there was no interaction or interference between model drugs and thermosensitive polymers. The current HME methods could be used to prepare uniformly distributed and reproducible solid dosage forms containing very low dose drugs for further pharmaceutical applications. PMID:24157343

  12. 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.

  13. 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

  14. 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

  15. eDrugCalc: an online self-assessment package to enhance medical students' drug dose calculation skills

    PubMed Central

    McQueen, Daniel S; Begg, Michael J; Maxwell, Simon R J

    2010-01-01

    AIMS Dose calculation errors can cause serious life-threatening clinical incidents. We designed eDrugCalc as an online self-assessment tool to develop and evaluate calculation skills among medical students. METHODS We undertook a prospective uncontrolled study involving 1727 medical students in years 15 at the University of Edinburgh. Students had continuous access to eDrugCalc and were encouraged to practise. Voluntary self-assessment was undertaken by answering the 20 questions on six occasions over 30 months. Questions remained fixed but numerical variables changed so each visit required a fresh calculation. Feedback was provided following each answer. RESULTS Final-year students had a significantly higher mean score in test 6 compared with test 1 [16.6, 95% confidence interval (CI) 16.2, 17.0 vs. 12.6, 95% CI 11.9, 13.4; n = 173, P < 0.0001 Wilcoxon matched pairs test] and made a median of three vs. seven errors. Performance was highly variable in all tests with 2.7% of final-year students scoring < 10/20 in test 6. Graduating students in 2009 (30 months' exposure) achieved significantly better scores than those in 2007 (only 6 months): mean 16.5, 95% CI 16.0, 17.0, n = 184 vs. 15.1, 95% CI 14.5, 15.6, n = 187; P < 0.0001, MannWhitney test. Calculations based on percentage concentrations and infusion rates were poorly performed. Feedback showed that eDrugCalc increased confidence in calculating doses and was highly rated as a learning tool. CONCLUSIONS Medical student performance of dose calculations improved significantly after repeated exposure to an online formative dose-calculation package and encouragement to develop their numeracy. Further research is required to establish whether eDrugCalc reduces calculation errors made in clinical practice. PMID:20840441

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

    PubMed Central

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

    2011-01-01

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

  17. 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,…

  18. 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

  19. 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

  20. 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

  1. 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.

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

    PubMed Central

    Winters, Ken

    2013-01-01

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

  3. 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.

  4. 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 providers workflow. PMID:23763856

  5. 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.

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

    PubMed

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

    2008-09-01

    This exploratory study examines the links between drug use and high-risk sexual practices and HIV in vulnerable drug-using populations in South Africa, including commercial sex workers (CSWs), men who have sex with men (MSM), injecting drug users (IDUs) and non-injecting drug users who are not CSWs or MSM (NIDUs). A rapid assessment ethnographic study was undertaken using observation, mapping, key informant interviews and focus groups in known 'hotspots' for drug use and sexual risk in Cape Town, Durban and Pretoria. Key informant (KI) and focus group interviews involved drug users and service providers. Purposeful snowball sampling and street intercepts were used to recruit drug users. Outcome measures included drug-related sexual HIV risk behaviour, and risk behaviour related to injection drug use, as well as issues related to service use. HIV testing of drug-using KIs was conducted using the SmartCheck Rapid HIV-1 Antibody Test. Non-injection drug use (mainly cannabis, methaqualone, crack cocaine and crystal methamphetamine) and injection drug use (mainly heroin) was occurring in these cities. Drug users report selling sex for money to buy drugs, and CSWs used drugs before, during and after sex. Most (70%) of the drug-using KIs offered HIV testing accepted and 28% were positive, with rates highest among CSWs and MSM. IDUs reported engaging in needle sharing and needle disposal practices that put them and others at risk for contracting HIV. There was a widespread lack of awareness about where to access HIV treatment and preventive services, and numerous barriers to accessing appropriate HIV and drug-intervention services were reported. Multiple risk behaviours of vulnerable populations and lack of access to HIV prevention services could accelerate the diffusion of HIV. Targeted interventions could play an important role in limiting the spread of HIV in and through these under-reached and vulnerable populations. PMID:18979044

  7. Imaging cellular distribution of Bcl inhibitors using small molecule drug conjugates.

    PubMed

    Giedt, Randy J; Sprachman, Melissa M; Yang, Katherine S; Weissleder, Ralph

    2014-11-19

    Overexpression of anti-apoptotic proteins such as Bcl-2 is a cellular mechanism to evade apoptosis; consequently, Bcl-2 inhibitors are being developed as anticancer agents. In this work, we have synthesized a fluorescent version of ABT-199 in an effort to visualize a drug surrogate by high resolution imaging. We show that this fluorescent conjugate has comparable Bcl-2 binding efficacy and cell line potency to the parent compound and can be used as an imaging agent in several cancer cell types. We anticipate that this agent will be a valuable tool for studying the single-cell distribution and pharmacokinetics of ABT-199 as well the broader group of BH3-mimetics. PMID:25333750

  8. 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

  9. Evolutionary conservation of human drug targets in organisms used for environmental risk assessments.

    PubMed

    Gunnarsson, Lina; Jauhiainen, Alexandra; Kristiansson, Erik; Nerman, Olle; Larsson, D G Joakim

    2008-08-01

    Pharmaceuticals are typically found in very low concentrations in the aquatic environment. Accordingly, environmental effects clearly assigned to residual drugs are consistent with high affinity interactions with conserved targets in affected wildlife species rather than with a general toxic effect. Thus, evolutionarily well-conserved targets in a given species are associated with an increased risk. In this study orthologs for 1318 human drug targets were predicted in 16 species of which several are relevant for ecotoxicity testing. The conservation of different functional categories of targets was also analyzed. Zebrafish had orthologs to 86% of the drug targets while only 61% were conserved in Daphnia and 35% in green alga. The predicted presence and absence of orthologs agrees well with published experimental data on the potential for specific drug target interaction in various species. Based on the conservation of targets we propose that aquatic environmental risk assessments for human drugs should always include comprehensive studies on aquatic vertebrates. Furthermore, individual targets, especially enzymes, are well conserved suggesting that tests on evolutionarily distant organisms would be highly relevant for certain drugs. We propose that the results can guide environmental risk assessments by improving the possibilities to identify species sensitive to certain types of pharmaceuticals or to other contaminants that act through well defined mechanisms of action. Moreover, we suggest that the results can be used to interpret the relevance of existing ecotoxicity data. PMID:18754513

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

    PubMed

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

    2010-05-01

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

  11. 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

  12. 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

  13. 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

  14. Inter-expert agreement of seven criteria in causality assessment of adverse drug reactions

    PubMed Central

    Arimone, Yannick; Miremont-Salam, Ghada; Haramburu, Franoise; Molimard, Mathieu; Moore, Nicholas; Fourrier-Rglat, Annie; Bgaud, Bernard

    2007-01-01

    What is already known about this subject In pharmacovigilance, many methods have been proposed for causality assessment of adverse drug reactions. Expert judgement is commonly used to evaluate the causal relationship between a drug treatment and the occurrence of an adverse event. This form of judgement relies either explicitly or implicitly on causality criteria. What this study adds Our study compares the judgements of five senior experts using global introspection about drug causation and seven causality criteria on a random set of putative adverse drug reactions. Even if previous publications have shown poor agreement between experts using global introspection, few have compared judgements of well trained pharmacologists, familiar with using a standardized causality assessment method. Aims To evaluate agreement between five senior experts when assessing seven causality criteria and the probability of drug causation. Methods A sample of 31 adverse event-drug pairs was constituted. For each pair, five experts separately assessed (i) the probability of drug causation, which was secondarily divided into seven causality levels: ruled out (00.05), unlikely (0.060.25), doubtful (0.260.45), indeterminate (0.460.55), plausible (0.560.75), likely (0.760.95), and certain (0.961); and (ii) seven causality criteria. To test discrepancies between experts, the kappa index was used. Results The agreement of the five experts was very poor (kappa = 0.05) for the probability of drug causation. Among the seven levels of causality, only doubtful showed a significant rate of agreement (kappa = 0.32, P < 0.001). For all criteria, the kappa index was significant except for the item risk(s) factor(s) (kappa = 0.09). Agreement between experts was good (0.64, P < 0.001) only for the criterion reaction at site of application or toxic plasma concentration of the drug or validated test. However, the rate of agreement with kappa indices of the causality criteria ranged from 0.12 to 0.38. Conclusions This study confirms that in the absence of an operational procedure, agreement between experts is low. This should be considered when designing a causality assessment method. In particular, criteria inducing a low level of agreement should have their weight reduced. PMID:17711539

  15. 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

  16. 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

  17. Trends in HCV prevalence, risk factors and distribution of viral genotypes in injecting drug users: findings from two cross-sectional studies.

    PubMed

    Oliveira, M L A; Yoshida, C F T; Telles, P R; Hacker, M A; Oliveira, S A N; Miguel, J C; do O, K M R; Bastos, F I

    2009-07-01

    In the last decade, a declining prevalence of HCV infection has been described in injecting drug users (IDUs) in different countries. This study is the first to assess temporal trends in drug-injecting patterns, HCV infection rates and viral genotype distribution in 770 Brazilian IDUs, recruited by two cross-sectional studies (1994-1997 and 1999-2001). A substantial decline in the prevalence of HCV infection was found over the years (75% in 1994 vs. 20.6% in 2001, P<0.001) that may be a consequence of the significant reduction in the overall frequencies of drug injection and needle-sharing, as well as the participation of IDUs in initiatives aimed at reducing drug-related harm. No trend was found in terms of viral genotype distribution. Despite the favourable scenario, preventive measures must be maintained, especially in vulnerable subgroups such as young or new injectors, where risky behaviours through direct and indirect sharing practices remain common. PMID:19144250

  18. 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.

  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 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...

  20. 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...

  1. A Guide to Multicultural Drug Abuse Prevention: Needs Assessment. Series Booklet.

    ERIC Educational Resources Information Center

    Harrison-Burns, Bettye; And Others

    This guide is designed to help planners of drug abuse prevention programs for minority groups to assess the specific needs of their communities. Covered are: (1) sources of and methods of acquiring statistical and background information; (2) community survey techniques; (3) developing problem statements; (4) choosing a remedy; (5) writing a

  2. 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…

  3. 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

  4. 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.

  5. 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

  6. 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.

  7. 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

  8. 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.

  9. Assessing drug-induced dyskinesia in the clinic, the laboratory and the natural environment of patients.

    PubMed

    Carignan, Benoit; Daneault, Jean-Franois; Duval, Christian

    2011-01-01

    The assessment of drug-induced dyskinesia (DID) in Parkinson's disease represents a formidable challenge for clinicians and researchers alike. The present review describes the current assessment tools used in the clinic, where different scales have been developed for monitoring levels of DID in patients. We also review laboratory tools used to assess the quantity and characteristics of DID. Finally, we review assessment methods currently in development for monitoring DID and voluntary mobility in the natural living environment of patients. Here, we discuss the strengths and weaknesses of these tools as it pertains to their efficacy in assessing the quantity of DID, its characteristics, as well as its impact on the quality of life of patients. Finally, we discuss ongoing challenges and research questions that may guide future development of assessment methods aimed at monitoring DID and its impact on daily lives of patients. PMID:23939342

  10. Patient understanding of drug risks: an evaluation of medication guide assessments

    PubMed Central

    Knox, Caitlin; Hampp, Christian; Willy, Mary; Winterstein, Almut G.; Dal Pan, Gerald

    2016-01-01

    Purpose When a Medication Guide (MG) is part of Risk Evaluation and Mitigation Strategy (REMS), manufacturers assess the effectiveness of MGs through patient surveys, which have not undergone systematic evaluation. We aimed to characterize knowledge rates from these patient surveys, describe their design and respondent characteristics, and explore predictors of acceptable knowledge rates. Methods We analyzed MG assessments submitted to the Food and Drug Administration from September 2008 through June 2012. We evaluated the prevalence of specific characteristics, and calculated knowledge rates, whereby we defined acceptable knowledge when ? 80% of respondents correctly answered questions about the primary drug risk. Univariate logistic models were used to investigate the predictors of acceptable knowledge rates. Results We analyzed the first completed MG assessment for each drug with a patient survey, resulting in 66 unique MG assessments. The mean knowledge rate was 63.8%, with 20 MG assessments (30.3%) achieving the 80% threshold. Compared to assessments that did not reach acceptable knowledge rates, those that did were more likely associated with additional REMS elements (e.g. Elements to Assure Safe Use or Communication Plans). Other factors, including mean age, reading or understanding the MG, and being offered or accepting counseling were not associated with knowledge rates. There was considerable variation in the design of MG assessments. Conclusions Most MG assessments did not reach the 80% knowledge threshold, but those associated with additional interventions were more likely to achieve it. Our study highlights the need to improve patient-directed information and the methods of assessing it. PMID:25808393

  11. 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...

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

    PubMed

    Stern, L

    1981-11-01

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

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

    PubMed Central

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

    2013-01-01

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

  14. 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

  15. 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, Rgis; 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

  16. 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.

  17. Reliability of the Roussel Uclaf Causality Assessment Method for Assessing Causality in Drug-Induced Liver Injury*

    PubMed Central

    Rochon, James; Protiva, Petr; Seeff, Leonard B.; Fontana, Robert J.; Liangpunsakul, Suthat; Watkins, Paul B.; Davern, Timothy; McHutchison, John G.

    2013-01-01

    The Roussel Uclaf Causality Assessment Method (RUCAM) was developed to quantify the strength of association between a liver injury and the medication implicated as causing the injury. However, its reliability in a research setting has never been fully explored. The aim of this study was to determine test-retest and interrater reliabilities of RUCAM in retrospectively-identified cases of drug induced liver injury. The Drug-Induced Liver Injury Network is enrolling well-defined cases of hepatotoxicity caused by isoniazid, phenytoin, clavulanate/amoxicillin, or valproate occurring since 1994. Each case was adjudicated by three reviewers working independently; after an interval of at least 5 months, cases were readjudicated by the same reviewers. A total of 40 drug-induced liver injury cases were enrolled including individuals treated with isoniazid (nine), phenytoin (five), clavulanate/amoxicillin (15), and valproate (11). Mean standard deviation age at protocol-defined onset was 44.8 19.5 years; patients were 68% female and 78% Caucasian. Cases were classified as hepatocellular (44%), mixed (28%), or cholestatic (28%). Test-retest differences ranged from ?7 to +8 with complete agreement in only 26% of cases. On average, the maximum absolute difference among the three reviewers was 3.1 on the first adjudication and 2.7 on the second, although much of this variability could be attributed to differences between the enrolling investigator and the external reviewers. The test-retest reliability by the same assessors was 0.54 (upper 95% confidence limit = 0.77); the interrater reliability was 0.45 (upper 95% confidence limit = 0.58). Categorizing the RUCAM to a five-category scale improved these reliabilities but only marginally. Conclusion The mediocre reliability of the RUCAM is problematic for future studies of drug-induced liver injury. Alternative methods, including modifying the RUCAM, developing drug-specific instruments, or causality assessment based on expert opinion, may be more appropriate. PMID:18798340

  18. 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...

  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. 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...

  1. 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...

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

    PubMed

    Costello, James C; Heiser, Laura M; Georgii, Elisabeth; Gnen, 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

    2014-12-01

    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. A risk-based bioanalytical strategy for the assessment of antibody immune responses against biological drugs.

    PubMed

    Shankar, Gopi; Pendley, Charles; Stein, Kathryn E

    2007-05-01

    Bioanalytical assessments of anti-drug antibodies (ADAs) provide an understanding of the immunogenicity of biological drug molecules. The potential to induce ADAs after treatment with biologics is a safety issue that has become an important consideration in the development of biologics and a critical aspect of regulatory filings. US and European regulatory agencies are recommending that sponsors study immunogenicity using a risk-based approach, encouraging sponsors to formulate and implement their own risk management plans and to conduct discussions with the agencies when necessary. It follows from this that the greater the safety risks of ADAs, the more diligently one should clarify the immunogenicity of the product. Here we propose a general strategy to broadly assign immunogenicity risk levels to biological drug products, and present risk level-based 'fit-for-purpose' bioanalytical schemes for the investigations of treatment-related ADAs in clinical and nonclinical studies. PMID:17483842

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

    PubMed Central

    Costello, James C; Heiser, Laura M; Georgii, Elisabeth; Gnen, 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

  5. 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

  6. 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.

  7. 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

  8. 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

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

    PubMed

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

    2011-03-01

    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 scales in nonclinical correctional samples. The current study examined evidence of convergent and discriminant validity for the substance abuse scales on the PAI in a large, nonclinical sample of offenders. The net sample for the current study consisted of 1,120 federal inmates. Both the drug abuse and alcohol scales showed good convergent validity through high correlations with relevant proximal and distal indicators of substance use across multiple measures from several data sources. Discriminant validity was established as neither scale showed any "erroneous" correlations after controlling for the other scale. Implications for future research and practice are discussed. PMID:20484714

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

    PubMed

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

    2010-02-01

    Laser-evoked potentials (LEPs) are brain responses to laser radiant heat pulses and reflect the activation of Adelta 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

  11. 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

  12. 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.

  13. Subjective health literacy and older adults' assessment of direct-to-consumer prescription drug ads.

    PubMed

    An, Soontae; Muturi, Nancy

    2011-01-01

    Older adults are increasingly the intended target of direct-to-consumer (DTC) prescription drug ads, but limited evidence exists as to how they assess the educational value of DTC ads and, more importantly, whether their assessment depends on their level of health literacy. In-person interviews of 170 older adults revealed that those with low subjective health literacy evaluated the educational value of DTC ads significantly lower than did those with high subjective health literacy. The results prompt us to pay more scholarly attention to determining how effectively DTC ads convey useful medical information, particularly to those with limited health literacy. PMID:21951255

  14. Herbal interactions on absorption of drugs: Mechanisms of action and clinical risk assessment.

    PubMed

    Colalto, Cristiano

    2010-09-01

    Many herbal medications are used to treat diseases but while they are often efficacious, their safety is rarely considered by physicians or users. One particular safety concern is the risk of interactions with drugs, which often lead to toxicity or loss of therapeutic efficacy. In order to assess this risk, it is important to consider all potential mechanisms of pharmacokinetic interference. A large number of in vivo and invitro experiments and clinical studies have cast light on the possible effects of botanical products and phytochemicals on the many enzymes and transporters involved in gastrointestinal drug absorption. This review gives an overview and assessment of the most widely sold herbal medicinal products, including liquorice, garlic, ginger, ginkgo, green tea, St. John's wort, saw palmetto, turmeric, valerian, milk thistle and echinacea, on the basis of the available scientific evidence. Sound knowledge of the mechanisms of herb-drug interactions is essential for clinical risk assessment, in turn vital to healthcare practitioners in their efforts to reduce minimise risk and ensure that taking herbal medicinal products is as safe as possible. PMID:20399862

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

    PubMed

    Guastaferro, Wendy P

    2012-08-01

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

  16. [HTA-Perspective: Challenges in the early assessment of new oncological drugs].

    PubMed

    Wild, Claudia; Nachtnebel, Anna

    2013-01-01

    Oncologic drug therapies have gained wide attention in the context of health policy priority setting for serious and socially significant diseases with high human and monetary costs. Due to uncertainties and scepticism about the actual therapeutic importance of newly approved oncology products, an early assessment programme was already established in Austria in 2007. The assessment of new oncology products is thereby faced with special challenges, since study populations are frequently not representative or the study design is laid out in such a manner that a definitive assessment of patient-relevant endpoints is not possible (cross-overs after interim assessments, surrogate parameters as primary endpoints, uncontrolled studies or those with unrealistic comparators, invalidated post-hoc identified biomarkers). On account of these major uncertainties, even the European Medicines Agency (EMA) is already contemplating multi-stage, "adaptive" approvals, and national reimbursement institutions are increasingly working with outcome-oriented, conditional reimbursement. (As supplied by publisher). PMID:23663907

  17. 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

  18. 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

  19. 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.

  20. 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.

  1. 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 mPas), 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 mPas) quickly leached out onto the surface of the tablet, while the high-viscosity-grade HPMC (4000 mPas) 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

  2. 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

  3. Are zebrafish larvae suitable for assessing the hepatotoxicity potential of drug candidates?

    PubMed

    Mesens, Natalie; Crawford, Alexander D; Menke, Aswin; Hung, Pham Duc; Van Goethem, Freddy; Nuyts, Rik; Hansen, Erik; Wolterbeek, Andre; Van Gompel, Jacky; De Witte, Peter; Esguerra, Camila V

    2015-09-01

    Drug-induced liver injury (DILI) is poorly predicted by single-cell-based assays, probably because of the lack of physiological interactions with other cells within the liver. An intact whole liver system such as one present in zebrafish larvae could provide added value in a screening strategy for DILI; however, the possible occurrence of other organ toxicities and the immature larval stage of the zebrafish might complicate accurate and fast analysis. We investigated whether expression analysis of liver-specific fatty acid binding protein 10a (lfabp10a) was an appropriate endpoint for assessing hepatotoxic effects in zebrafish larvae. It was found that expression analysis of lfabp10a was a valid marker, as after treatment with hepatotoxicants, dose-response curves could be obtained and statistically significant abnormal lfabp10 expression levels correlated with hepatocellular histopathological changes in the liver. However, toxicity in other vital organs such as the heart could impact liver outgrowth and thus had to be assessed concurrently. Whether zebrafish larvae were suitable for assessing human relevant drug-induced hepatotoxicity was assessed with hepatotoxicants and non-hepatotoxicants that have been marketed for human use and classified according to their mechanism of toxicity. The zebrafish larva showed promising predictivity towards a number of mechanisms and was capable of distinguishing between hepatotoxic and non-hepatotoxic chemical analogues, thus implying its applicability as a potential screening model for DILI. PMID:25663337

  4. 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

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

    PubMed

    Tthfalusi, Lszlo; Endrnyi, Lszl; Chow, Shein-Chung

    2014-05-01

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

  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. 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... HUMAN SERVICES Food and Drug Administration 21 CFR Part 514 Antimicrobial Animal Drug Sales...

  8. 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

  9. 2 CFR 182.210 - To whom must I distribute my drug-free workplace statement?

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... workplace statement? 182.210 Section 182.210 Grants and Agreements OFFICE OF MANAGEMENT AND BUDGET GOVERNMENTWIDE GUIDANCE FOR GRANTS AND AGREEMENTS Reserved GOVERNMENTWIDE REQUIREMENTS FOR DRUG-FREE WORKPLACE... my drug-free workplace statement? You must require that a copy of the statement described in ...

  10. 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

  11. 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

  12. 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

  13. 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

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

    PubMed

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

    2012-01-01

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

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

    PubMed

    Klahci, 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

  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. ASSESSMENT AND IMPLICATIONS OF BACTERIAL REGROWTH IN WATER DISTRIBUTION SYSTEMS

    EPA Science Inventory

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

  18. 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

  19. 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

  20. 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

  1. Exposure time independent summary statistics for assessment of drug dependent cell line growth inhibition

    PubMed Central

    2014-01-01

    Background In vitro generated dose-response curves of human cancer cell lines are widely used to develop new therapeutics. The curves are summarised by simplified statistics that ignore the conventionally used dose-response curves dependency on drug exposure time and growth kinetics. This may lead to suboptimal exploitation of data and biased conclusions on the potential of the drug in question. Therefore we set out to improve the dose-response assessments by eliminating the impact of time dependency. Results First, a mathematical model for drug induced cell growth inhibition was formulated and used to derive novel dose-response curves and improved summary statistics that are independent of time under the proposed model. Next, a statistical analysis workflow for estimating the improved statistics was suggested consisting of 1) nonlinear regression models for estimation of cell counts and doubling times, 2) isotonic regression for modelling the suggested dose-response curves, and 3) resampling based method for assessing variation of the novel summary statistics. We document that conventionally used summary statistics for dose-response experiments depend on time so that fast growing cell lines compared to slowly growing ones are considered overly sensitive. The adequacy of the mathematical model is tested for doxorubicin and found to fit real data to an acceptable degree. Dose-response data from the NCI60 drug screen were used to illustrate the time dependency and demonstrate an adjustment correcting for it. The applicability of the workflow was illustrated by simulation and application on a doxorubicin growth inhibition screen. The simulations show that under the proposed mathematical model the suggested statistical workflow results in unbiased estimates of the time independent summary statistics. Variance estimates of the novel summary statistics are used to conclude that the doxorubicin screen covers a significant diverse range of responses ensuring it is useful for biological interpretations. Conclusion Time independent summary statistics may aid the understanding of drugs action mechanism on tumour cells and potentially renew previous drug sensitivity evaluation studies. PMID:24902483

  2. 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...

  3. URBAN WATER SYSTEM PATHOGEN ASSESSMENT: SIGNIFICANCE OF DISTRIBUTION BIOFILMS

    EPA Science Inventory

    Quantitative microbial risk assessment (QMRA), while not new to science is now providing a fundamental role in framing water guidelines internationally as well as identifying research gaps to be filled. Professor Ashbolt has been instrumental in working QMRA concepts into WHO gui...

  4. URBAN WATER SYSTEM PATHOGEN ASSESSMENTS: SIGNIFICANCE OF DISTRIBUTION BIOFILMS

    EPA Science Inventory

    Quantitative microbial risk assessment (QMRA), while not new to science is now providing a fundamental role in framing water guidelines internationally as well as identifying research gaps to be filled. Professor Ashbolt has been instrumental in working QMRA concepts into WHO gui...

  5. 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

  6. 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.

  7. 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

  8. 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

  9. 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.

  10. 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 individuals 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.

  11. Textural Analysis of Nuclear Mitotic Apparatus Antigen (NuMA) Spatial Distribution in Interphase Nuclei from Human Drug-Resistant CEM Lymphoblasts

    PubMed Central

    Rafki?Beljebbar, Naima; Liautaud?Roger, Franoise; Ploton, Dominique; Dufer, Jean

    1999-01-01

    In tumour cell lines, the resistance of cancer cells to a variety of structurally unrelated chemotherapeutic drugs is termed multidrug?resistance or MDR. We reported previously that MDR leukemic cells displayed nuclear texture changes, as assessed by image cytometry. The nature of these changes remained uncertain but they could be associated with alterations of the nuclear matrix which could serve an important role in DNA organization and chromatin structure. Therefore, we have compared the textural features observed in G0/G1 nuclei from human leukemic CEM cells and their MDR variant CEM?VLB, after staining of either DNA by Feulgen method or nuclear matrix by immunodetection of NuMA antigen on DNase treated samples. Chromatin or NuMA distributions within the nucleus were evaluated by image cytometry. Changes in textural parameters indicate that modifications of NuMA distribution observed in MDR cells are parallel to those observed at the whole chromatin level (i.e., a more decondensed and coarse texture with increase of Energy and Long?run sections and decrease of Contrast and Short?run sections). Moreover, Optical Densities measurements indicate that MDR cells seem to contain less NuMA, a datum confirmed by immunoblotting of nuclear proteins. In conclusion, chromatin changes observed by image cytometry in drug?resistant human leukemic CEM cells appear associated with modifications of the nuclear matrix structure. PMID:10609561

  12. [Patient-relevant outcomes and surrogates in the early benefit assessment of drugs: first experiences].

    PubMed

    Kvitkina, Tatjana; ten Haaf, Anette; Reken, Stefanie; McGauran, Natalie; Wieseler, Beate

    2014-01-01

    The Act on the Reform of the Market for Medicinal Products (AMNOG) became effective in Germany on January 1, 2011. Since then, the assessment of the added benefit of new drugs versus a therapeutic standard on the basis of dossiers submitted by pharmaceutical companies has been required by law. The Federal Joint Committee (G-BA) generally commissions the Institute for Quality and Efficiency in Health Care (IQWiG) with this task. The added benefit is primarily to be demonstrated on the basis of patient-relevant outcomes. The aim of this paper is to describe the feasibility of the early benefit assessment on the basis of patient-relevant outcomes by systematically characterising the outcomes available in company dossiers and comparing the companies' and IQWiG's evaluations regarding patient relevance and surrogate validity. Dossier assessments published between October 2011 and June 2012 were used for this purpose. The outcomes available and the respective evaluations were extracted and compared. 12 out of 22 submitted dossiers contained sufficient data to assess outcomes; all 12 assessable dossiers provided data on patient-relevant outcomes. Data on mortality and adverse events were available in all dossiers, except that one dossier did not contain adverse event data on the relevant subpopulation. In contrast, data on morbidity and health-related quality of life were available in 8 and 7 dossiers, respectively. Of a total of 214 outcomes extracted by IQWiG, 124 patient-relevant and 3 surrogate outcomes were included in IQWiG's assessment (companies: a total of 183 outcomes included, of which 172 were patient-relevant and 11 were surrogates). The first experiences with AMNOG have shown that in principle an early benefit assessment of drugs based on patient-relevant outcomes is feasible. The companies' and IQWiG's evaluations regarding patient relevance and surrogate validity of outcomes partly deviated from each other. By increasingly considering patient-relevant outcomes in approval studies, pharmaceutical companies can create the necessary data basis for the early benefit assessment. PMID:25523852

  13. 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 doctors 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

  14. 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

  15. 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

  16. 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

  17. 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.

  18. 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.

  19. 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

  20. 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.

  1. 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

  2. Assessing the distribution of sedimentary C40 carotenoids through time.

    PubMed

    French, K L; Rocher, D; Zumberge, J E; Summons, R E

    2015-03-01

    A comprehensive marine biomarker record of green and purple sulfur bacteria (GSB and PSB, respectively) is required to test whether anoxygenic photosynthesis represented a greater fraction of marine primary productivity during the Precambrian than the Phanerozoic, as current models of ocean redox evolution suggest. For this purpose, we analyzed marine rock extracts and oils from the Proterozoic to the Paleogene for C40 diagenetic products of carotenoid pigments using new analytical methods. Gas chromatography coupled with tandem mass spectrometry provides a new perspective on the temporal distributions of carotenoid biomarkers for phototrophic sulfur bacteria, specifically okenane, chlorobactane, and paleorenieratane. According to conventional paleoredox interpretations, this revised stratigraphic distribution of the GSB and PSB biomarkers implies that the shallow sunlit surface ocean (<24 m) became sulfidic more frequently in the geologic past than was previously thought. We reexamine whether there is evidence supporting a planktonic source of GSB and PSB pigments in marine systems or whether additional factors are required to explain the marine phototrophic sulfur bacteria record. To date, planktonic GSB and PSB and their pigments have been identified in restricted basins and lakes, but they have yet to be detected in the unrestricted, transiently sulfidic, marine systems. Based on modern observations, additional environmental factors, including basin restriction, microbial mats, or sediment transport, may be required to fully explain GSB and PSB carotenoids in the geologic record. PMID:25631735

  3. Personalized Risk Assessment of Drug-Related Harm Is Associated with Health Outcomes

    PubMed Central

    Jones, Andrea A.; Vila-Rodriguez, Fidel; Panenka, William J.; Leonova, Olga; Strehlau, Verena; Lang, Donna J.; Thornton, Allen E.; Wong, Hubert; Barr, Alasdair M.; Procyshyn, Ric M.; Smith, Geoffrey N.; Buchanan, Tari; Krajden, Mel; Krausz, Michael; Montaner, Julio S.; MacEwan, G. William; Nutt, David J.; Honer, William G.

    2013-01-01

    Background The Independent Scientific Committee on Drugs (ISCD) assigned quantitative scores for harm to 20 drugs. We hypothesized that a personalized, ISCD-based Composite Harm Score (CHS) would be associated with poor health outcomes in polysubstance users. Methods A prospective community sample (n=293) of adults living in marginal housing was assessed for substance use. The CHS was calculated based on the ISCD index, and the personal substance use characteristics over four weeks. Regression models estimated the association between CHS and physical, psychological, and social health outcomes. Results Polysubstance use was pervasive (95.8%), as was multimorbid illness (median 3, possible range 012). The median CHS was 2845 (interquartile range 18653977). Adjusting for age and sex, every 1000-unit CHS increase was associated with greater mortality (odds ratio [OR] 1.47, 95% confidence interval [CI] 1.072.01, p = 0.02), and persistent hepatitis C infection (OR 1.29, 95% CI 1.021.67, p = 0.04). The likelihood of substance-induced psychosis increased 1.39-fold (95% CI 1.131.67, p = 0.001). The amount spent on drugs increased 1.51-fold (1.401.62, p < 0.001) and the odds of having committed a crime increased 1.74-fold (1.462.10, p < 0.001). Multimorbid illness increased 1.43-fold (95% CI 1.261.63, p < 0.001). Conclusions Greater CHS predicts poorer physical, psychological, and social health, and may be a useful quantitative, personalized measure of risk for drug-related harm. PMID:24223192

  4. 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

  5. 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

  6. 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

  7. 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

  8. 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

  9. 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…

  10. 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

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

    PubMed

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

    2010-05-01

    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

  12. 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.

  13. 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

  14. 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...

  15. 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.

  16. 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.

  17. 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

  18. 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.

  19. 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 agencys 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

  20. Phospholipid vesicle-based permeation assay and EpiSkin in assessment of drug therapies destined for skin administration.

    PubMed

    Engesland, Andr; kalko-Basnet, Nataa; Flaten, Gril Eide

    2015-03-01

    Cost-effective and efficient methods for permeability screening are crucial during early development of drugs, drug formulations, and cosmeceuticals. Alternatives to animal experiments are impelled for both economical and ethical reasons. The aim of this study was to determine the ability of the phospholipid vesicle-based permeation assay (PVPA) to assess the effect of different formulations on drug permeability and thus establish its utility in formulation development. Three model drugs were tested in solutions and as liposomal formulations. The permeability results for the PVPA models were compared with the results for the reconstructed human skin model, EpiSkin(). The drugs were ranked based on their estimated penetration potentials, and the results were in accordance with what was expected considering the physicochemical properties of the drugs. PVPAs (E-80, ceramide, cholesterol, cholesteryl sulfate, and palmitic acid) was able to distinguish between drug solutions and liposomal formulations; however, EpiSkin() detected only small differences between the drugs in solution and formulations. In contrast with EpiSkin(), which is limited by a 3-day testing window, PVPA barriers can be stored frozen for up to 2 weeks or even up to 16 months, depending on their compositions. The PVPA models are thus more cost effective and efficient than the EpiSkin() model for permeability screening during early drug development. PMID:25558045

  1. Assessment of a Candidate Marker Constituent Predictive of a Dietary SubstanceDrug 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 substancedrug 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 vitroin 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 concentrationtime 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 M; 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 substancedrug interactions to help prioritize new and existing drugs for more advanced (dynamic) modeling and simulation and clinical assessment. PMID:25253884

  2. Assessment of a candidate marker constituent predictive of a dietary substance-drug interaction: case study with grapefruit juice and CYP3A4 drug substrates.

    PubMed

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

    2014-12-01

    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 M; 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

  3. 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.

  4. 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

  5. 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.

  6. 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

  7. 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

  8. 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

  9. 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

  10. 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.

  11. Predictive accuracy of the Miller assessment for preschoolers in children with prenatal drug exposure.

    PubMed

    Fulks, Mary-Ann L; Harris, Susan R

    2005-01-01

    The Miller Assessment for Preschoolers (MAP) is a standardized test purported to identify preschool-aged children at risk for later learning difficulties. We evaluated the predictive validity of the MAP Total Score, relative to later cognitive performance and across a range of possible cut-points, in 37 preschool-aged children with prenatal drug exposure. Criterion measures were the Wechsler Preschool & Primary Scale of Intelligence-Revised (WPPSI-R), Test of Early Reading Ability-2, Peabody Picture Vocabulary Test-Revised, and Developmental Test of Visual Motor Integration. The highest predictive accuracy was demonstrated when the WPPSI-R was the criterion measure. The 14th percentile cutoff point demonstrated the highest predictive accuracy across all measures. PMID:15760822

  12. 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

  13. 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

  14. 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

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

    PubMed

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

    2013-07-01

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

  16. 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.

  17. 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.

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

    PubMed

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

    2014-04-01

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

  19. Gold island films as biocompatible SERS substrates for imaging of the intracellular distribution of anticancer drugs

    NASA Astrophysics Data System (ADS)

    Sockalingum, Ganesh D.; Beljebbar, Abdelilah; Morjani, Hamid; Manfait, Michel

    1998-04-01

    Highly reproducible and stable surface gold island films exhibiting long-range enhancement have been investigated and characterized as compatible for biological systems. These surface-enhanced Raman scattering (SERS) substrates allowed the non-invasive detection of micromolar concentrations of antitumor drugs using red and near-infrared excitations. Thus, good quality SERS spectra of dimethylcrocetin (DMCRT) in a single living HL60 cell have been recorded on these substrates using red excitation, without any noticeable perturbation of the cell integrity. Comparison of these spectra with FT-Raman data obtained in HL60 cells on one hand, and with FT-SERS data of the DMCRT-retinoic acid receptor (RAR) complex on the other, shows practically the same spectral profiles. However, it should be noted that with the red laser the spectrum gives additional information on the cellular components. Similarity between the signal of DMCRT-treated K562 cells and the free drug is explained by either an absence of RAR in this cell line or a lack of binding.

  20. 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

  1. 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

  2. Assessment of recovery in the hemiparkinson rat: drug-induced rotation is inadequate.

    PubMed

    Castaeda, Eddie; Fleming, Sheila; Paquette, Melanie A; Boat, Kim; Moffett, John; Stachowiak, Ewa K; Bloom, David C; Stachowiak, Michal K

    2005-03-31

    Recovery from apomorphine-induced rotational behavior was compared to sensorimotor and motor function in hemiparkinsonian rats receiving intrastriatal grafts of astrocytes expressing recombinant tyrosine hydroxylase (TH) or control beta-galactosidase (beta-gal). Rats received unilateral intranigral infusions of 6-hydroxydopamine (6-OHDA). Animals with large lesions, as determined by apomorphine-induced rotation, received grafts of astrocytes into the denervated striatum. Behavioral recovery was assessed on days 14-16 post-transplantation using apomorphine-induced rotation, somatosensory neglect, and reaching for pellets using the Montoya staircase method. Rats that received transplants of TH-transfected astrocytes showed a 34% decrease in rotational behavior, but no consistent recovery of somatosensory neglect or skilled reaching. Post-mortem histological analyses revealed survival of grafted astrocytes in host striatum and expression of TH at 17 days post-transplantation. We suggest that TH-expressing astrocytes may reverse post-synaptic dopamine (DA) receptor supersensitivity; however, sensorimotor and motor abilities are not restored due to a failure by TH-expressing astrocytes to reestablish dopaminergic circuitry. The present results demonstrate the need to utilize a variety of sensory and motor behavioral tests that cohesively provide greater interpretability than a single behavioral measure used in isolation, such as drug-induced rotational behavior, to assess the efficacy of experimental gene therapies. PMID:15811387

  3. 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

  4. 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

  5. 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.

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

    PubMed Central

    2013-01-01

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

  7. 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

  8. 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

  9. 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

  10. 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 companys 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

  11. 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

  12. Experience with external quality assessment of drugs of abuse testing in the Lombardy Region in Italy.

    PubMed

    Cassani, Mario; Giuliani, Lucia; Amigoni, Maurizio; Buratta, Antonietta; Marocchi, Alessandro

    2002-02-01

    Following up previous experience with External Quality Assessment (EQA) and Proficiency Testing Programs (PTP) on drugs of abuse (DoA) testing in Italy and in other European countries, the government of the Lombardy Region, first among Italian regions, established in 1995 a compulsory EQA scheme for laboratories authorized to perform these tests. The purpose of the present work is the description of the program and the overall evaluation of the results obtained in the first three annual cycles (1995-1998). During each annual cycle laboratories received 22 urine samples; some samples were collected from patients ("real samples") and some were "spiked" urine samples. Both types of samples could contain the following substances/classes of substances: opiates, cocaine, cannabinoids, methadone, buprenorphine, benzodiazepines, barbiturates. Type A laboratories used an immunological screening method; they expressed the results as concentrations. Type B laboratories, authorized to perform screening methods followed by confirmatory techniques, searched for and identified single substances and provided an interpretation on possibly taken drugs. During the study period the laboratories produced about 21,000 analytical results. Among them, false-negative results were 0.9% of true positives, and false-positive results were 0.7% of true negatives. Performance using the spiked samples was better than using real samples, and performance of type B laboratories better than that of type A. The results obtained during the program are consistent with those of other quality control programs. This program, in addition, has provided information on the status of DoA testing in the Lombardy region's laboratories, in particular on their analytical performance, on the quality of interpretation of results and on a degree of improvement achieved during the program. PMID:11939489

  13. A methodology for technical and financial assessment of distributed generation in the US

    SciTech Connect

    Curtiss, P.; Kreider, J.; Cohen, D.

    1999-07-01

    Traditionally, distributed power generation technologies have been considered to help reduce or eliminate the need for grid-connected electricity. It has been difficult, however, to assess the economic benefits of such technologies due to a lack of computer tools and data related to operating characteristics. This paper discusses a method for performing such as assessment based on electrical and thermal building loads, existing utility rate structures, standard economic parameters, tangible benefits from distributed resource and T and D benefits, and different control techniques. The paper concludes with an example showing the dependency of the internal rate of return on some of the input parameters.

  14. 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

  15. Use of the cassette-dosing approach to assess brain penetration in drug discovery.

    PubMed

    Liu, Xingrong; Ding, Xiao; Deshmukh, Gauri; Liederer, Bianca M; Hop, Cornelis E C A

    2012-05-01

    The objective of the present study was to examine the cassette dosing method in determination of brain-to-plasma concentration ratio (area under the concentration-time profiles for plasma/area under the concentration-time profiles for brain, K(p)). Eleven model compounds, amprenavir, citalopram, digoxin, elacridar, imatinib, (3S,6S,12aS)-1,2,3,4,6,7,12,12a-octahydro-9-methoxy-6-(2-methylpropyl)-1,4-dioxopyrazino[1',2':1,6]pyrido[3,4-b]indole-3-propanoic acid 1,1-dimethylethyl ester (Ko143), loperamide, prazosin, quinidine, sulfasalazine, and verapamil, were selected to compare their K(p) determined from discrete dosing in wild-type mice and their K(p) from cassette dosing in wild-type, Mdr1a/1b(-/-), Bcrp1(-/-), and Mdr1a/1b(-/-)/Bcrp1(-/-) mice at 1 to 3 mg/kg. The mice brain and plasma were collected at 0.25, 1, and 3 h and were analyzed using high-performance liquid chromatography-tandem mass spectrometry methods. The K(p) determined from discrete dosing versus cassette dosing in the wild-type mice were within 2-fold for all the compounds except sulfasalazine and Ko143. The brain concentrations of sulfasalazine and Ko143 and the plasma concentrations of Ko143 were below the lower limit of quantitation. In addition, the K(p) values estimated by mass spectrometry responses, namely the ratio of compound peak area to internal standard peak area, were within 2-fold of the K(p) observed from the actual concentrations. Furthermore, the ratios of K(p) in Mdr1a/1b(-/-), Bcrp1(-/-), and Mdr1a/1b(-/-)/Bcrp1(-/-) mice versus the K(p) in the wild-type mice from cassette dosing were consistent with the ones reported in the literature where the compounds were dosed discretely. These results demonstrate that drug-drug interactions at the blood-brain barrier are unlikely at a subcutaneous dose of 1 to 3 mg/kg and support the use of the cassette dosing approach to assess brain penetration in drug discovery. PMID:22328585

  16. 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

  17. Quantitative PCR analysis and protein distribution of drug transporter genes in the rat cochlea.

    PubMed

    Manohar, Senthilvelan; Jamesdaniel, Samson; Ding, Dalian; Salvi, Richard; Seigel, Gail M; Roth, Jerome A

    2016-02-01

    Membrane transporters can be major determinants in the targeting and effectiveness of pharmaceutical agents. A large number of biologically important membrane transporters have been identified and localized to a variety of tissues, organs and cell types. However, little is known about the expression of key membrane transporters in the inner ear, a promising site for targeted therapeutics, as well as a region vulnerable to adverse drug reactions and environmental factors. In this study, we examined the levels of endogenous membrane transporters in rat cochlea by targeted PCR array analysis of 84 transporter genes, followed by validation and localization in tissues by immunohistochemistry. Our studies indicate that several members of the SLC, VDAC and ABC membrane transporter families show high levels of expression, both at the RNA and protein levels in the rat cochlea. Identification and characterization of these membrane transporters in the inner ear have clinical implications for both therapeutic and cytotoxic mechanisms that may aid in the preservation of auditory function. PMID:26626361

  18. Relevance of Campus Climate for Alcohol and Other Drug Use among LGBTQ Community College Students: A Statewide Qualitative Assessment

    ERIC Educational Resources Information Center

    Manning, Patricia; Pring, Lauren; Glider, Peggy

    2012-01-01

    Literature suggests that individuals who identify as LGBTQ may engage in more alcohol and other drug (AOD) use/abuse than others. Little data is available about these populations on college campuses where AOD use may be seen as part of the general campus climate and culture. This article will describe a qualitative needs assessment conducted on 10

  19. 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

  20. 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

  1. Preclinical Development of an anti-5T4 Antibody-Drug Conjugate: Pharmacokinetics in Mice, Rats, and NHP and Tumor/Tissue Distribution in Mice.

    PubMed

    Leal, Mauricio; Wentland, JoAnn; Han, Xiaogang; Zhang, Yanhua; Rago, Brian; Duriga, Nicole; Spriggs, Franklin; Kadar, Eugene; Song, Wei; McNally, James; Shakey, Quazi; Lorello, Leslie; Lucas, Judy; Sapra, Puja

    2015-11-18

    The pharmacokinetics of an antibody (huA1)-drug (auristatin microtubule disrupting MMAF) conjugate, targeting 5T4-expressing cells, were characterized during the discovery and development phases in female nu/nu mice and cynomolgus monkeys after a single dose and in S-D rats and cynomolgus monkeys from multidose toxicity studies. Plasma/serum samples were analyzed using an ELISA-based method for antibody and conjugate (ADC) as well as for the released payload using an LC-MS/MS method. In addition, the distribution of the Ab, ADC, and released payload (cys-mcMMAF) was determined in a number of tissues (tumor, lung, liver, kidney, and heart) in two tumor mouse models (H1975 and MDA-MB-361-DYT2 models) using similar LBA and LC-MS/MS methods. Tissue distribution studies revealed preferential tumor distribution of cys-mcMMAF and its relative specificity to the 5T4 target containing tissue (tumor). Single dose studies suggests lower CL values at the higher doses in mice, although a linear relationship was seen in cynomolgus monkeys at doses from 0.3 to 10 mg/kg with no evidence of TMDD. Evaluation of DAR (drug-antibody ratio) in cynomolgus monkeys (at 3 mg/kg) indicated that at least half of the payload was still on the ADC 1 to 2 weeks after IV dosing. After multiple doses, the huA1 and conjugate data in rats and monkeys indicate that exposure (AUC) increases with increasing dose in a linear fashion. Systemic exposure (as assessed by Cmax and AUC) of the released payload increased with increasing dose, although exposure was very low and its pharmacokinetics appeared to be formation rate limited. The incidence of ADA was generally low in rats and monkeys. We will discuss cross species comparison, relationships between the Ab, ADC, and released payload exposure after multiple dosing, and insights into the distribution of this ADC with a focus on experimental design as a way to address or bypass apparent obstacles and its integration into predictive models. PMID:26180901

  2. 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

  3. 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…

  4. 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.

  5. 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 stimulusinduced 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

  6. Motivational determinants of illicit drug use: an assessment of underlying dimensions and their relationship to behavior.

    PubMed

    Butler, M C; Gunderson, E K; Bruni, J R

    1981-02-01

    Principal components analysis was used to delineate motivational patterns associated with illicit drug use in a population of U.S. Navy enlisted men (n = 867) undergoing drug rehabilitation. Patients indicated which of 31 reasons for drug use were associated with various drugs. Four components emerged from this analysis, labeled Insight-Seeking, Therapeutic Needs, Sentience, and Pleasure-Seeking. Higher order factor analysis revealed the presence of a general factor, labeled General Sensation-Seeking. Multiple regression procedures were used to relate the derived dimensions to actual drug use behavior. The significant relationships observed among the factor analytic patterns in predicting overall drug involvement were shown to lead to increased explanation concerning interrelationships among personality needs and social resources. The findings suggested a number of hypotheses pertaining to increased understanding of motivational patterns underlying initiation and continuation of illicit drug use. PMID:7275378

  7. 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

  8. 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...

  9. 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...

  10. 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…

  11. 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

  12. 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

  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. 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.

  15. 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

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

    PubMed

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

    2008-08-01

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

  17. 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

  18. 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

  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. Completeness assessment of type II active pharmaceutical ingredient drug master files under generic drug user fee amendment: review metrics and common incomplete items.

    PubMed

    Zhang, Huyi; Li, Haitao; Song, Wei; Shen, Diandian; Skanchy, David; Shen, Kun; Lionberger, Robert A; Rosencrance, Susan M; Yu, Lawrence X

    2014-09-01

    Under the Generic Drug User Fee Amendments (GDUFA) of 2012, Type II active pharmaceutical ingredient (API) drug master files (DMFs) must pay a user fee and pass a Completeness Assessment (CA) before they can be referenced in an Abbreviated New Drug Application (ANDA), ANDA amendment, or ANDA prior approval supplement (PAS). During the first year of GDUFA implementation, from October 1, 2012 to September 30, 2013, approximately 1,500 Type II API DMFs received at least one cycle of CA review and more than 1,100 Type II DMFs were deemed complete and published on FDA's "Available for Reference List". The data from CA reviews were analyzed for factors that influenced the CA review process and metrics, as well as the areas of DMF submissions which most frequently led to an incomplete CA status. The metrics analysis revealed that electronic DMFs appear to improve the completeness of submission and shorten both the review and response times. Utilizing the CA checklist to compile and proactively update the DMFs improves the chance for the DMFs to pass the CA in the first cycle. However, given that the majority of DMFs require at least two cycles of CA before being deemed complete, it is recommended that DMF fees are paid 6 months in advance of the ANDA submissions in order to avoid negatively impacting the filling status of the ANDAs. PMID:25034968

  1. 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

  2. Drug biokinetic and toxicity assessments in rat and human primary hepatocytes and HepaRG cells within the EU-funded Predict-IV project.

    PubMed

    Mueller, Stefan O; Guillouzo, Andr; Hewitt, Philip G; Richert, Lysiane

    2015-12-25

    The overall aim of Predict-IV (EU-funded collaborative project #202222) was to develop improved testing strategies for drug safety in the late discovery phase. One major focus was the prediction of hepatotoxicity as liver remains one of the major organ leading to failure in drug development, drug withdrawal and has a poor predictivity from animal experiments. In this overview we describe the use and applicability of the three cell models employed, i.e., primary rat hepatocytes, primary human hepatocytes and the human HepaRG cell line, using four model compounds, chlorpromazine, ibuprofen, cyclosporine A and amiodarone. This overview described the data generated on mode of action of liver toxicity after long-term repeat-dosing. Moreover we have quantified parent compound and its distribution in various in vitro compartments, which allowed us to develop biokinetic models where we could derive real exposure concentrations in vitro. In conclusion, the complex data set enables quantitative measurements that proved the concept that we can define human relevant free and toxic exposure levels in vitro. Further compounds have to be analyzed in a broader concentration range to fully exploit these promising results for improved prediction of hepatotoxicity and hazard assessment for humans. PMID:25952325

  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. Assessing spatiotemporal patterns of multidrug-resistant and drug-sensitive tuberculosis in a South American setting.

    PubMed

    Lin, H; Shin, S; Blaya, J A; Zhang, Z; Cegielski, P; Contreras, C; Asencios, L; Bonilla, C; Bayona, J; Paciorek, C J; Cohen, T

    2011-11-01

    We examined the spatiotemporal distribution of laboratory-confirmed multidrug-resistant tuberculosis (MDR TB) cases and that of other TB cases in Lima, Peru with the aim of identifying mechanisms responsible for the rise of MDR TB in an urban setting. All incident cases of TB in two districts of Lima, Peru during 2005-2007 were included. The spatiotemporal distributions of MDR cases and other TB cases were compared with Ripley's K statistic. Of 11,711 notified cases, 1187 received drug susceptibility testing and 376 were found to be MDR. Spatial aggregation of patients with confirmed MDR disease appeared similar to that of other patients in 2005 and 2006; however, in 2007, cases with confirmed MDR disease were found to be more tightly grouped. Subgroup analysis suggests the appearance of resistance may be driven by increased transmission. Interventions should aim to reduce the infectious duration for those with drug-resistant disease and improve infection control. PMID:21205434

  5. 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.

  6. Rapid assessment of drug response in cancer cells using microwell array and molecular imaging

    PubMed Central

    Wang, Min S.; Luo, Zhen; Nitin, Nitin

    2015-01-01

    Selection of personalized chemotherapy regimen for individual patients has significant potential to improve chemotherapy efficacy and to reduce the deleterious effects of ineffective chemotherapy drugs. In this study, a rapid and high-throughput in vitro drug response assay was developed using a combination of microwell array and molecular imaging. The microwell array provided high-throughput analysis of drug response, which was quantified based on the reduction in intracellular uptake (2-[N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino]-2-deoxy-d-glucose) (2-NBDG). Using this synergistic approach, the drug response measurement was completed within 4 h, and only a couple thousand cells were needed for quantification. The broader application of this microwell molecular imaging approach was demonstrated by evaluating the drug response of two cancer cell lines, cervical (HeLa) and bladder (5637) cancer cells, to two distinct classes of chemotherapy drugs (cisplatin and paclitaxel). This approach did not require an extended cell culturing period, and the quantification of cellular drug response was 416 times faster compared with other cell-microarray drug response studies. Moreover, this molecular imaging approach had comparable sensitivity to traditional cell viability assays, i.e., the MTT assay and propidium iodide labeling of cellular nuclei;and similar throughput results as flow cytometry using only 1,0002,000 cells. Given the simplicity and robustness of this microwell molecular imaging approach, it is anticipated that the assay can be adapted to quantify drug responses in a wide range of cancer cells and drugs and translated to clinical settings for a rapid in vitro drug response using clinically isolated samples. PMID:24760393

  7. Rapid assessment of drug response in cancer cells using microwell array and molecular imaging.

    PubMed

    Wang, Min S; Luo, Zhen; Nitin, Nitin

    2014-07-01

    Selection of personalized chemotherapy regimen for individual patients has significant potential to improve chemotherapy efficacy and to reduce the deleterious effects of ineffective chemotherapy drugs. In this study, a rapid and high-throughput in vitro drug response assay was developed using a combination of microwell array and molecular imaging. The microwell array provided high-throughput analysis of drug response, which was quantified based on the reduction in intracellular uptake (2-[N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino]-2-deoxy-D-glucose) (2-NBDG). Using this synergistic approach, the drug response measurement was completed within 4 h, and only a couple thousand cells were needed for quantification. The broader application of this microwell molecular imaging approach was demonstrated by evaluating the drug response of two cancer cell lines, cervical (HeLa) and bladder (5637) cancer cells, to two distinct classes of chemotherapy drugs (cisplatin and paclitaxel). This approach did not require an extended cell culturing period, and the quantification of cellular drug response was 4-16 times faster compared with other cell-microarray drug response studies. Moreover, this molecular imaging approach had comparable sensitivity to traditional cell viability assays, i.e., the MTT assay and propidium iodide labeling of cellular nuclei;and similar throughput results as flow cytometry using only 1,000-2,000 cells. Given the simplicity and robustness of this microwell molecular imaging approach, it is anticipated that the assay can be adapted to quantify drug responses in a wide range of cancer cells and drugs and translated to clinical settings for a rapid in vitro drug response using clinically isolated samples. PMID:24760393

  8. 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, Jrgen; 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

  9. 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

  10. 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

  11. 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

  12. 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.

  13. Rational assessment of the interaction profile of cerivastatin supports its low propensity for drug interactions.

    PubMed

    Mck, W

    1998-01-01

    Pharmacokinetic drug-drug interactions influence drug efficacy, tolerability, and compliance. Such interactions are both more common and of more clinical relevance than often appreciated. The US Food and Drug Administration and the European Agency for the Evaluation of Medicinal Products have recently issued guidelines setting out in vitro and in vivo investigations to be conducted during drug development. These guidelines reflect the increasing interest of public health authorities in this topic. Cerivastatin is a novel, potent HMG-CoA reductase inhibitor that effectively reduces serum cholesterol levels at low daily doses. It is completely absorbed after oral administration, undergoes moderate first-pass metabolism and high plasma protein binding, and is cleared exclusively via hepatic cytochrome P450 (CYP). Unlike other drugs of its class, cerivastatin has a dual metabolic pathway, with the involvement of more than one CYP isozyme. Metabolites are cleared via both biliary and renal excretion. On the basis of this pharmacokinetic profile and a knowledge of the target population, the formal in vivo interaction programme for cerivastatin investigated many important potential cerivastatin drug-drug interactions. Cerivastatin appears to lack clinically relevant interactions with digoxin, warfarin, antacid, cimetidine, nifedipine, omeprazole, erythromycin and itraconazole. PMID:9740537

  14. 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,

  15. 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…

  16. 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,…

  17. 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

  18. In-line assessment of pulmonary drug delivery using light obscuration.

    PubMed

    Kusmartseva, O; Kattige, A S; Price, R; Smith, P R

    2004-10-15

    A candidate optical technology for characterisation of the value and quality of the drug dose delivered to a patient from an inhaler is examined. The theoretical reasoning behind the design of this technology is presented with reference to the optical scattering of the drug cloud. A technical implementation is presented; based upon the light obscuration signature, observed in the delivery path during drug delivery. Dose evaluation studies are reported, performed on different types of drug formulations using regulatory testing procedures and the proposed optical sensing system. Further applications of this technology are discussed in relation to the identification and evaluation of inhaler-drug formulation combinations, which are most suitable for particular patients. PMID:15494227

  19. Establishment of an in vitro assay for assessing the effects of drugs on the liver stages of Plasmodium vivax malaria.

    PubMed

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

    2010-01-01

    Plasmodium vivax (Pv) is the second most important human malaria parasite. Recent data indicate that the impact of Pv malaria on the health and economies of the developing world has been dramatically underestimated. Pv has a unique feature in its life cycle. Uninucleate sporozoites (spz), after invasion of human hepatocytes, either proceed to develop into tens of thousands of merozoites within the infected hepatocytes or remain as dormant forms called hypnozoites, which cause relapses of malaria months to several years after the primary infection. Elimination of malaria caused by Pv will be facilitated by developing a safe, highly effective drug that eliminates Pv liver stages, including hypnozoites. Identification and development of such a drug would be facilitated by the development of a medium to high throughput assay for screening drugs against Pv liver stages. We undertook the present pilot study to (1) assess the feasibility of producing large quantities of purified, vialed, cryopreserved Pv sporozoites and (2) establish a system for culturing the liver stages of Pv in order to assess the effects of drugs on the liver stages of Pv. We used primaquine (PQ) to establish this assay model, because PQ is the only licensed drug known to clear all Pv hepatocyte stages, including hypnozoites, and the effect of PQ on Pv hepatocyte stage development in vitro has not previously been reported. We report that we have established the capacity to reproducibly infect hepatoma cells with purified, cyropreserved Pv spz from the same lot, quantitate the primary outcome variable of infected hepatoma cells and demonstrate the inhibitory activity of primaquine on the infected hepatoma cells. We have also identified small parasite forms that may be hypnozoites. These data provide the foundation for finalizing a medium throughput, high content assay to identify new drugs for the elimination of all Pv liver stages. PMID:21151554

  20. Undersampling power-law size distributions: effect on the assessment of extreme natural hazards

    USGS Publications Warehouse

    Geist, Eric L.; Parsons, Thomas E.

    2014-01-01

    The effect of undersampling on estimating the size of extreme natural hazards from historical data is examined. Tests using synthetic catalogs indicate that the tail of an empirical size distribution sampled from a pure Pareto probability distribution can range from having one-to-several unusually large events to appearing depleted, relative to the parent distribution. Both of these effects are artifacts caused by limited catalog length. It is more difficult to diagnose the artificially depleted empirical distributions, since one expects that a pure Pareto distribution is physically limited in some way. Using maximum likelihood methods and the method of moments, we estimate the power-law exponent and the corner size parameter of tapered Pareto distributions for several natural hazard examples: tsunamis, floods, and earthquakes. Each of these examples has varying catalog lengths and measurement thresholds, relative to the largest event sizes. In many cases where there are only several orders of magnitude between the measurement threshold and the largest events, joint two-parameter estimation techniques are necessary to account for estimation dependence between the power-law scaling exponent and the corner size parameter. Results indicate that whereas the corner size parameter of a tapered Pareto distribution can be estimated, its upper confidence bound cannot be determined and the estimate itself is often unstable with time. Correspondingly, one cannot statistically reject a pure Pareto null hypothesis using natural hazard catalog data. Although physical limits to the hazard source size and by attenuation mechanisms from source to site constrain the maximum hazard size, historical data alone often cannot reliably determine the corner size parameter. Probabilistic assessments incorporating theoretical constraints on source size and propagation effects are preferred over deterministic assessments of extreme natural hazards based on historic data.

  1. 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

  2. Assessing the potential impact of non-proprietary drug copies on quality of medicine and treatment in patients with relapsing multiple sclerosis: the experience with fingolimod

    PubMed Central

    Correale, Jorge; Chiquete, Erwin; Milojevic, Snezana; Frider, Nadina; Bajusz, Imre

    2014-01-01

    Background Fingolimod is a once-daily oral treatment for relapsing multiple sclerosis, the proprietary production processes of which are tightly controlled, owing to its susceptibility to contamination by impurities, including genotoxic impurities. Many markets produce nonproprietary medicines; assessing their efficacy and safety is difficult as regulators may approve nonproprietary drugs without bioequivalence data, genotoxic evaluation, or risk management plans (RMPs). This assessment is especially important for fingolimod given its solubility/bioavailability profile, genotoxicity risk, and low-dose final product (0.5 mg). This paper presents an evaluation of the quality of proprietary and nonproprietary fingolimod variants. Methods Proprietary fingolimod was used as a reference substance against which eleven nonproprietary fingolimod copies were assessed. The microparticle size distribution of each compound was assessed by laser light diffraction, and inorganic impurity content by sulfated ash testing. Heavy metals content was quantified using inductively coupled plasma optical emission spectrometry, and levels of unspecified impurities by high-performance liquid chromatography. Solubility was assessed in a range of solvents at different pH values. Key information from the fingolimod RMP is also presented. Results Nonproprietary fingolimod variants exhibited properties out of proprietary or internationally accepted specifications, including differences in particle size distribution and levels of impurities such as heavy metals. For microparticle size and heavy metals, all tested fingolimod copies were out-of-specification by several-fold magnitudes. Proprietary fingolimod has a well-defined RMP, highlighting known and potential mid- to long-term safety risks, and risk-minimization and pharmacovigilance procedures. Conclusion Nonproprietary fingolimod copies produced by processes less well controlled than or altered from proprietary production processes may reduce product reproducibility and quality, potentially presenting risks to patients. Safety data and risk-minimization strategies for proprietary fingolimod may not apply to the nonproprietary fingolimod copies evaluated here. Market authorization of nonproprietary fingolimod copies should require an appropriate RMP to minimize risks to patients. PMID:25028537

  3. 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

  4. 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.

  5. 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

  6. 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

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

    PubMed

    Odano, N; Ishida, T

    2005-01-01

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

  8. Cell-based systems to assess nuclear receptor activation and their use in drug development.

    PubMed

    Raucy, Judy L; Lasker, Jerome M

    2013-02-01

    The evolution of scientific information relating to the regulation of xenobiotic disposition has extended to the discovery of an intricate group of receptor systems now recognized as master regulators. These ligand-activated transcription factors are commonly designated as "nuclear receptors", and include CAR (NR1I3), PXR (NR1I2), PPAR (NR1C1, NR1C2, and NR1C3) and AhR (HLHE76). As regulators of gene expression, activation of these receptors can elicit a plethora of drug-drug interactions. The aforementioned nuclear receptors bind a wide range of structurally-unrelated ligands, such as steroid hormones, bile acids, and small drug-type molecules. A pivotal nuclear receptor with regards to regulation of drug-drug interactions is the pregnane X receptor (PXR). Gene expression profiling has demonstrated that PXR regulates over 60 human genes that are involved not only in physiological functions but also in the metabolism of xenobiotics. Moreover, chemical library screening suggests that about 10% of the compounds comprising the U. S. Food and Drug Administration 1 and 2, Sigma-Aldrich LOPAC collection, Biomol, and Tocris/TimTec bioactive collection libraries exhibit some form of PXR binding. For these reasons, efficient, rapid and economical systems have been developed to identify nuclear receptor ligands. Cell-based assays encompassing transiently and stably-transfected cells and mammalian two-hybrid systems are currently being employed by the pharmaceutical industry to screen compounds for binding to and/or activation of nuclear receptors. Overall, these systems have the ability to predict in vivo responses to receptor activation that culminate in drug-drug interactions and adverse drug effects. PMID:23330544

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

    NASA Astrophysics Data System (ADS)

    Barnes, P. R.; Vandyke, 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. 2, the range was larger: from a few percent to near 80% for a case where costly investments were deferred. In general, additional savings of at least 10 to 20% can be expected by integrating at the distribution level. Wind energy systems were found to be economical in good wind resource regions, whereas photovoltaic systems costs are presently a factor of 2.5 too expensive under the most favorable conditions.

  10. 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.

  11. 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).

  12. 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.

  13. 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

  14. 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

  15. Distribution of CCR5 genotypes and HLA Class I B alleles in HIV-1 infected and uninfected injecting drug users from Rio de Janeiro, Brazil.

    PubMed

    Teixeira, Sylvia Lopes Maia; Bastos, Francisco Incio; Hacker, Mariana A; Morgado, Mariza Gonalves

    2009-07-01

    Host genetic factors play an important role in the HIV epidemic dynamics, and have been considered in studies assessing susceptibility/resistance to HIV-1 infection as well as clinical evolution. Class I and Class II HLA alleles have been associated with the heterogeneity of HIV-1 infection susceptibility, as protective or risk factors for HIV-1 transmission. Moreover, a 32-base pair deletion in the HIV-1 CCR5 gene-coding region confers resistance to HIV-1 infection in homozygous individuals for the deleted allele. In this study, DNA samples from HIV-1 infected and uninfected injecting drug users (IDUs) from Rio de Janeiro were PCR amplified to determine CCR5 genotypes based on the presence of the CCR5Delta32 mutation and typed for the HLA-B locus, in an attempt to assess possible associations between these genetic factors and susceptibility/resistance to HIV-1 infection. The distribution of CCR5 genotypes between the two IDU groups did not differ. The homozygous mutant genotype Delta32/Delta32 was not found in this study. Except for HLA-B*45 (4.0% vs. 3.0%; p=0.04) and for B*51 (12.1% vs. 4.4%; p=0.002), no statistically significant differences were made evident when analyzing the frequencies of each HLA-B allele between Caucasian and non-Caucasian IDUs. The most frequent HLA-B alleles were B*15; B*35; B*44 and B*51. Although some differences in the allele frequencies could be observed between the two IDU groups, none of these was statistically significant. Therefore, no putative association between these genetic markers and susceptibility/resistance to HIV-1 infection could be made evident in the present study. So far, the assessment of genetic markers among the IDU population has been restricted to North American, European, and Asian studies and this report represents a pioneer descriptive study of the distribution of CCR5 genotypes and HLA-B alleles in Rio de Janeiro, Brazil. PMID:19460331

  16. 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.

  17. 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.

  18. A modified Marple-type cascade impactor for assessing aerosol particle size distributions in workplaces.

    PubMed

    Wu, Yi-Hsuan; Vincent, James H

    2007-10-01

    Knowledge of the particle size distributions for workplace aerosols is invaluable in the assessment of aerosol-related health effects. Cascade impactors have been widely used for obtaining such information, including a small number that have been developed as personal samplers of the type that can be used for the assessment of the exposures of individual workers. Common limitations for most samplers of this type have been that (a) the aspiration efficiency has not been well defined (leading to biases in particle size distribution measurement), and (b) the range of particle size has been constrained by particle bounce in impactors for particle sizes beyond about 20 micro m. This article describes a modification of the Marple personal cascade impactor that addresses these limitations. The sampler has a new entry whose aspiration efficiency is known and a new top stage that employs porous plastic foam filtration media and significantly extends the particle size range of the instrument. The new instrument is referred to as the modified-Marple sampler. A numerical simulation was performed to investigate the ability of the new instrument to accurately retrieve particle size distributions over the range typical of aerosols found in workplaces. The retrieval process was carried out using a simple inversion algorithm of the "zeroth-order" type. The results are presented in terms of the ability of the new sampler to retrieve the masses contained in the inhalable, thoracic, and respirable fractions. They suggest that the more narrowly distributed the particle size distribution, the more restricted the ability to accurately retrieve the particle size distribution. However, for most aerosols of the type encountered in the real world of industrial hygiene, the modified-Marple sampler provides particle size information of sufficient quality for most practical purposes. PMID:17763071

  19. Assessment of dye distribution in sensitized solar cells by microprobe techniques

    NASA Astrophysics Data System (ADS)

    Barreiros, M. A.; Corregidor, V.; Alves, L. C.; Guimares, 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 ?m thickness). These results are consistent with the EPMA/EDS maps obtained.

  20. An assessment of drug-drug interactions: the effect of desvenlafaxine and duloxetine on the pharmacokinetics of the CYP2D6 probe desipramine in healthy subjects.

    PubMed

    Patroneva, Albena; Connolly, Sandra M; Fatato, Penny; Pedersen, Ron; Jiang, Qin; Paul, Jeffrey; Guico-Pabia, Christine; Isler, Jennifer A; Burczynski, Michael E; Nichols, Alice I

    2008-12-01

    A number of antidepressants inhibit the activity of the cytochrome P450 2D6 enzyme system, which can lead to drug-drug interactions. Based on its metabolic profile, desvenlafaxine, administered as desvenlafaxine succinate, a new serotonin-norepinephrine reuptake inhibitor, is not expected to have an impact on activity of CYP2D6. This single-center, randomized, open-label, four-period, crossover study was undertaken to evaluate the effect of multiple doses of desvenlafaxine (100 mg/day, twice the recommended therapeutic dose for major depressive disorder in the United States) and duloxetine (30 mg b.i.d.) on the pharmacokinetics (PK) of a single dose of desipramine (50 mg). A single dose of desipramine was given first to assess its PK. Desvenlafaxine or duloxetine was then administered, in a crossover design, so that steady-state levels were achieved; a single dose of desipramine was then coadministered. The geometric least-square mean ratios (coadministration versus desipramine alone) for area under the plasma concentration versus time curve (AUC) and peak plasma concentrations (C(max)) of desipramine and 2-hydroxydesipramine were compared using analysis of variance. Relative to desipramine alone, increases in AUC and C(max) of desipramine associated with duloxetine administration (122 and 63%, respectively) were significantly greater than those associated with desvenlafaxine (22 and 19%, respectively; P < 0.001). Duloxetine coadministered with desipramine was also associated with a decrease in 2-hydroxydesipramine C(max) that was significant compared with the small increase seen with desvenlafaxine and desipramine (-24 versus 9%; P < 0.001); the difference between changes in 2-hydroxydesipramine AUC did not reach statistical significance (P = 0.054). Overall, desvenlafaxine had a minimal impact on the PK of desipramine compared with duloxetine, suggesting a lower risk for CYP2D6-mediated drug interactions. PMID:18809731

  1. 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

  2. Assessing drug and metabolite detection in liver tissue by UV-MALDI and IR-MALDESI mass spectrometry imaging coupled to FT-ICR MS

    PubMed Central

    Barry, Jeremy A.; Groseclose, M. Reid; Robichaud, Guillaume; Castellino, Stephen; Muddiman, David C.

    2014-01-01

    Determining the distribution of a drug and its metabolites within tissue is a key facet of evaluating drug candidates. Drug distribution can have a significant implication in appraising drug efficacy and potential toxicity. The specificity and sensitivity of mass spectrometry imaging (MSI) make it a perfect complement to the analysis of drug distributions in tissue. The detection of lapatinib as well as several of its metabolites in liver tissue was determined by MSI using infrared matrix-assisted laser desorption electrospray ionization (IR-MALDESI) coupled to high resolving power Fourier transform ion cyclotron resonance (FT-ICR) mass spectrometers. IR-MALDESI required minimal sample preparation while maintaining high sensitivity. The effect of the electrospray solvent composition on IR-MALDESI MSI signal from tissue analysis was investigated and an empirical comparison of IR-MALDESI and UV-MALDI for MSI analysis is also presented. PMID:26056514

  3. Drug Resistance of Enteric Bacteria XIII. Distribution of R Factors in Escherichia coli Strains Isolated from Livestock

    PubMed Central

    Mitsuhashi, Susumu; Hashimoto, Hajime; Suzuki, Kaname

    1967-01-01

    Escherichia coli strains isolated from 151 swine and 108 fowl, which were kept at the Animal Health Center, Maebashi, Japan, were surveyed for drug resistance and distribution of R factors. All of the swine and 38% of the fowl excreted E. coli strains resistant to tetracycline, chloramphenicol, streptomycin, and sulfanilamide, or certain combinations thereof. Among 278 resistant cultures isolated from swine, 13% were found to be resistant to one antibiotic, whereas 87% were resistant to more than one antibiotic. Among these resistant strains, 40% carried R factors which were transferable by the usual conjugal process. The resistance patterns of these R factors included 36% which were singly resistant and 64% which were multiply resistant. Among 54 resistant cultures isolated from fowl, 24% were singly resistant and 76% were multiply resistant. Of the resistant strains from fowl, 22% carried R factors. The resistance patterns of R factors included 50% of the singly resistant type and 50% which were multiply resistant. In spite of feeding with dairy products containing only tetracycline, a high incidence of multiple resistance was observed in the E. coli strains and the R factors isolated from these animals. PMID:4860911

  4. Distribution of drug resistance genotypes in Plasmodium falciparum in an area of limited parasite diversity in Saudi Arabia.

    PubMed

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

    2012-05-01

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

  5. 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

  6. 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

  7. 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

  8. Kinetic modeling of tricarboxylic acid cycle and glyoxylate bypass in Mycobacterium tuberculosis, and its application to assessment of drug targets

    PubMed Central

    Singh, Vivek Kumar; Ghosh, Indira

    2006-01-01

    Background Targeting persistent tubercule bacilli has become an important challenge in the development of anti-tuberculous drugs. As the glyoxylate bypass is essential for persistent bacilli, interference with it holds the potential for designing new antibacterial drugs. We have developed kinetic models of the tricarboxylic acid cycle and glyoxylate bypass in Escherichia coli and Mycobacterium tuberculosis, and studied the effects of inhibition of various enzymes in the M. tuberculosis model. Results We used E. coli to validate the pathway-modeling protocol and showed that changes in metabolic flux can be estimated from gene expression data. The M. tuberculosis model reproduced the observation that deletion of one of the two isocitrate lyase genes has little effect on bacterial growth in macrophages, but deletion of both genes leads to the elimination of the bacilli from the lungs. It also substantiated the inhibition of isocitrate lyases by 3-nitropropionate. On the basis of our simulation studies, we propose that: (i) fractional inactivation of both isocitrate dehydrogenase 1 and isocitrate dehydrogenase 2 is required for a flux through the glyoxylate bypass in persistent mycobacteria; and (ii) increasing the amount of active isocitrate dehydrogenases can stop the flux through the glyoxylate bypass, so the kinase that inactivates isocitrate dehydrogenase 1 and/or the proposed inactivator of isocitrate dehydrogenase 2 is a potential target for drugs against persistent mycobacteria. In addition, competitive inhibition of isocitrate lyases along with a reduction in the inactivation of isocitrate dehydrogenases appears to be a feasible strategy for targeting persistent mycobacteria. Conclusion We used kinetic modeling of biochemical pathways to assess various potential anti-tuberculous drug targets that interfere with the glyoxylate bypass flux, and indicated the type of inhibition needed to eliminate the pathogen. The advantage of such an approach to the assessment of drug targets is that it facilitates the study of systemic effect(s) of the modulation of the target enzyme(s) in the cellular environment. PMID:16887020

  9. 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 literature review. Studies were included if they examined the effect of Zilver paclitaxel drug-eluting stents in de novo or restenotic lesions in above-the-knee arteries. For the budget impact analysis, 3 scenarios were constructed based on different assumptions. Results One randomized controlled trial reported a significantly higher patency rate with Zilver paclitaxel drug-eluting stents for lesions ≤ 14 cm than with angioplasty or bare metal stents. One observational study showed no difference in patency rates between Zilver paclitaxel drug-eluting stents and paclitaxel drug-coated balloons. Zilver paclitaxel drug-eluting stents were associated with a significantly higher event-free survival rate than angioplasty, but the event-free survival rate was similar for Zilver paclitaxel drug-eluting stents and paclitaxel drug-coated balloons. No economic evaluations compared Zilver paclitaxel drug-eluting stents with bare metal stents or angioplasty for peripheral arterial disease. A budget impact analysis showed that the cost savings associated with funding of Zilver paclitaxel drug-eluting stents would be $470,000 to $640,000 per year, assuming that the use of the Zilver paclitaxel drug-eluting stent was associated with a lower risk of subsequent revascularization. Conclusions Based on evidence of low to moderate quality, Zilver paclitaxel drug-eluting stents were associated with a higher patency rate than angioplasty or bare metal stents, and with fewer adverse events than angioplasty. The effectiveness and safety of Zilver paclitaxel drug-eluting stents and paclitaxel drug-coated balloons were similar. PMID:26719778

  10. 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

  11. 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

  12. Assessment of the Dissociation Energetics of Some Selected Ligand Drugs Bound on Human Serum Albumin by Differential Scanning Calorimetry.

    PubMed

    Faroongsarng, Damrongsak

    2016-04-01

    Drug-protein binding may play a role in the thermal energetics of protein denaturation and could lead to the determination of its equilibrium dissociation parameter. The aim of this study was to assess the energetics of a drug that was bound to human serum albumin (HSA) during thermal denaturation. Drugs that were bound at a single high-affinity primary binding site on HSA, including diazepam and ibuprofen, were employed. Commercial HSA was treated with charcoal to remove stabilizers and adjusted to 20% w/v in a pH 7.4 buffered solution. Serial concentrations of individual drugs up to 0.16 mmole/g-protein were added to the cleaned HSA solutions whereas diazepam was added to a commercial HSA solution. Samples were subjected to differential scanning calorimetry (DSC) set to run from 37 to 90°C at 3.0°C/min. Binding of the drug slightly increased the denaturing temperature of the cleaned HSA due to a shift in the equilibrium toward the native protein bound with the drug. Diazepam depressed the denaturing temperature of the commercial HSA by competing with the stabilizers already bound to the primary site of the HSA. This yielded not only the HSA-stabilizer but also the HSA-diazepam type complexes that exhibited a different denaturation process. A rational approximation of the Lumry-Eyring protein denaturation model was used to treat the DSC endotherms. The approximated scheme: [Formula: see text] was successfully fitted to the data. It was used to determine the dissociation parameters for diazepam and ibuprofen bound to the HSA. These results were comparable to those obtained from other methods. PMID:26246411

  13. Computational assessment of drug-induced effects on the electrocardiogram: from ion channel to body surface potentials

    PubMed Central

    Zemzemi, Nejib; Bernabeu, Miguel O; Saiz, Javier; Cooper, Jonathan; Pathmanathan, Pras; Mirams, Gary R; Pitt-Francis, Joe; Rodriguez, Blanca

    2013-01-01

    Background and Purpose Understanding drug effects on the heart is key to safety pharmacology assessment and anti-arrhythmic therapy development. Here our goal is to demonstrate the ability of computational models to simulate the effect of drug action on the electrical activity of the heart, at the level of the ion-channel, cell, heart and ECG body surface potential. Experimental Approach We use the state-of-the-art mathematical models governing the electrical activity of the heart. A drug model is introduced using an ion channel conductance block for the hERG and fast sodium channels, depending on the IC50 value and the drug dose. We simulate the ECG measurements at the body surface and compare biomarkers under different drug actions. Key Results Introducing a 50% hERG-channel current block results in 8% prolongation of the APD90 and 6% QT interval prolongation, hERG block does not affect the QRS interval. Introducing 50% fast sodium current block prolongs the QRS and the QT intervals by 12% and 5% respectively, and delays activation times, whereas APD90 is not affected. Conclusions and Implications Both potassium and sodium blocks prolong the QT interval, but the underlying mechanism is different: for potassium it is due to APD prolongation; while for sodium it is due to a reduction of electrical wave velocity. This study shows the applicability of in silico models for the investigation of drug effects on the heart, from the ion channel to the ECG-based biomarkers. PMID:22946617

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

    PubMed

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

    2011-12-01

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

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

    PubMed Central

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

    2013-01-01

    Background In veterinary parasitology samples are often pooled for a rapid assessment of infection intensity and drug efficacy. Currently, studies evaluating this strategy in large-scale drug administration programs to control human soil-transmitted helminths (STHs; Ascaris lumbricoides, Trichuris trichiura, and hookworm), are absent. Therefore, we developed and evaluated a pooling strategy to assess intensity of STH infections and drug efficacy. Methods/Principal Findings Stool samples from 840 children attending 14 primary schools in Jimma, Ethiopia were pooled (pool sizes of 10, 20, and 60) to evaluate the infection intensity of STHs. In addition, the efficacy of a single dose of mebendazole (500 mg) in terms of fecal egg count reduction (FECR; synonym of egg reduction rate) was evaluated in 600 children from two of these schools. Individual and pooled samples were examined with the McMaster egg counting method. For each of the three STHs, we found a significant positive correlation between mean fecal egg counts (FECs) of individual stool samples and FEC of pooled stool samples, ranging from 0.62 to 0.98. Only for A. lumbricoides was any significant difference in mean FEC of the individual and pooled samples found. For this STH species, pools of 60 samples resulted in significantly higher FECs. FECR for the different number of samples pooled was comparable in all pool sizes, except for hookworm. For this parasite, pools of 10 and 60 samples provided significantly higher FECR results. Conclusion/Significance This study highlights that pooling stool samples holds promise as a strategy for rapidly assessing infection intensity and efficacy of administered drugs in programs to control human STHs. However, further research is required to determine when and how pooling of stool samples can be cost-effectively applied along a control program, and to verify whether this approach is also applicable to other NTDs. PMID:23696905

  16. 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

  17. Modeling 3D soil and sediment distributions for assessing catchment structure and hydrological feedbacks

    NASA Astrophysics Data System (ADS)

    Maurer, Thomas; Brck, 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 'Hhnerwasser' (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.

  18. Assessing the Spatial Scale Effect of Anthropogenic Factors on Species Distribution

    PubMed Central

    Mangiacotti, Marco; Scali, Stefano; Sacchi, Roberto; Bassu, Lara; Nulchis, Valeria; Corti, Claudia

    2013-01-01

    Patch context is a way to describe the effect that the surroundings exert on a landscape patch. Despite anthropogenic context alteration may affect species distributions by reducing the accessibility to suitable patches, species distribution modelling have rarely accounted for its effects explicitly. We propose a general framework to statistically detect the occurrence and the extent of such a factor, by combining presence-only data, spatial distribution models and information-theoretic model selection procedures. After having established the spatial resolution of the analysis on the basis of the species characteristics, a measure of anthropogenic alteration that can be quantified at increasing distance from each patch has to be defined. Then the distribution of the species is modelled under competing hypotheses: H0, assumes that the distribution is uninfluenced by the anthropogenic variables; H1, assumes the effect of alteration at the species scale (resolution); and H2, H3 Hn add the effect of context alteration at increasing radii. Models are compared using the Akaike Information Criterion to establish the best hypothesis, and consequently the occurrence (if any) and the spatial scale of the anthropogenic effect. As a study case we analysed the distribution data of two insular lizards (one endemic and one naturalised) using four alternative hypotheses: no alteration (H0), alteration at the species scale (H1), alteration at two context scales (H2 and H3). H2 and H3 performed better than H0 and H1, highlighting the importance of context alteration. H2 performed better than H3, setting the spatial scale of the context at 1 km. The two species respond differently to context alteration, the introduced lizard being more tolerant than the endemic one. The proposed approach supplies reliably and interpretable results, uses easily available data on species distribution, and allows the assessing of the spatial scale at which human disturbance produces the heaviest effects. PMID:23825669

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

    PubMed Central

    Zhu, Timothy C.; Finlay, Jarod C.; Hahn, Stephen M.

    2015-01-01

    It is desirable to quantify the distribution of the light fluence rate, the optical properties, the drug concentration, and the tissue oxygenation for photodynamic therapy (PDT) of prostate cancer. We have developed an integrated system to determine these quantities before and after PDT treatment using motorized probes. The optical properties (absorption (?a), transport scattering (?s?), and effective attenuation (?eff) coefficients) of cancerous human prostate were measured in-vivo using interstitial isotropic detectors. Measurements were made at 732 nm before and after motexafin lutetium (MLu) mediated PDT at different locations along each catheter. The light fluence rate distribution was also measured along the catheters during PDT. Diffuse absorption spectroscopy measurement using a white light source allows extrapolation of the distribution of oxygen saturation (StO2), total blood volume ([Hb]t), and MLu concentration. The distribution of drug concentration was also studied using fluorescence from a single optical fiber, and was found to be in good agreement with the values determined by absorption spectroscopy. This study shows significant inter- and intra-prostatic variations in the tissue optical properties and MLu drug distribution, suggesting that a real-time dosimetry measurement and feedback system for monitoring these values during treatment should be considered in future PDT studies. PMID:15896650

  20. GWAMAR: Genome-wide assessment of mutations associated with drug resistance in bacteria

    PubMed Central

    2014-01-01

    Background Development of drug resistance in bacteria causes antibiotic therapies to be less effective and more costly. Moreover, our understanding of the process remains incomplete. One promising approach to improve our understanding of how resistance is being acquired is to use whole-genome comparative approaches for detection of drug resistance-associated mutations. Results We present GWAMAR, a tool we have developed for detecting of drug resistance-associated mutations in bacteria through comparative analysis of whole-genome sequences. The pipeline of GWAMAR comprises several steps. First, for a set of closely related bacterial genomes, it employs eCAMBer to identify homologous gene families. Second, based on multiple alignments of the gene families, it identifies mutations among the strains of interest. Third, it calculates several statistics to identify which mutations are the most associated with drug resistance. Conclusions Based on our analysis of two large datasets retrieved from publicly available data for M. tuberculosis, we identified a set of novel putative drug resistance-associated mutations. As a part of this work, we present also an application of our tool to detect putative compensatory mutations. PMID:25559874

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

    PubMed

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

    2011-05-01

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

  2. Development of blood biomarkers for drug-induced liver injury: an evaluation of their potential for risk assessment and diagnostics.

    PubMed

    Amacher, David E; Schomaker, Shelli J; Aubrecht, Jiri

    2013-12-01

    Drug-induced liver injury (DILI) remains a rare but serious complication in drug therapy that is a primary cause of drug failure during clinical trials. Conventional biomarkers, particularly the serum transaminases and bilirubin, serve as useful indicators of hepatocellular or cholestatic liver injury, respectively, but only after substantial and sometimes irreversible tissue damage. Ideally, more sensitive biomarkers that respond very early before irreversible injury has occurred would offer improved outcomes. Novel biomarkers are initially being developed in animal models exposed to intrinsically hepatotoxic stimuli. However, the eventual translation to human populations, even those with known risk factors that predispose the liver to drug toxicity, would be the fundamental goal. Ultimately, some might even be applicable for the early identification of individuals predisposed to idiosyncratic hepatotoxicity potential. This article reviews recent progress in the discovery and qualification of novel biomarkers for DILI and delineates the path to eventual utilization for risk assessment. Some major categories of plasma or serum biomarkers surveyed include proteins, cytokines, circulating mRNAs, and microRNAs. PMID:23868512

  3. Rapid Assessment Response (RAR) study: drug use, health and systemic risksEmthonjeni Correctional Centre, Pretoria, South Africa

    PubMed Central

    2014-01-01

    Background Correctional centre populations are one of the populations most at risk of contracting HIV infection for many reasons, such as unprotected sex, violence, rape and tattooing with contaminated equipment. Specific data on drug users in correctional centres is not available for the majority of countries, including South Africa. The study aimed to identify the attitudes and knowledge of key informant (KI) offender and correctional centre staff regarding drug use, health and systemic-related problems so as to facilitate the long-term planning of activities in the field of drug-use prevention and systems strengthening in correctional centres, including suggestions for the development of appropriate intervention and rehabilitation programmes. Method A Rapid Assessment Response (RAR) methodology was adopted which included observation, mapping of service providers (SP), KI interviews (staff and offenders) and focus groups (FGs). The study was implemented in Emthonjeni Youth Correctional Centre, Pretoria, South Africa. Fifteen KI staff participants were interviewed and 45 KI offenders. Results Drug use is fairly prevalent in the centre, with tobacco most commonly smoked, followed by cannabis and heroin. The banning of tobacco has also led to black-market features such as transactional sex, violence, gangsterism and smuggling in order to obtain mainly prohibited tobacco products, as well as illicit substances. Conclusion HIV, health and systemic-related risk reduction within the Correctional Service sector needs to focus on measures such as improvement of staff capacity and security measures, deregulation of tobacco products and the development and implementation of comprehensive health promotion programmes. PMID:24708609

  4. Barriers to formal drug abuse treatment in the rural south: a preliminary ethnographic assessment.

    PubMed

    Sexton, Rocky L; Carlson, Robert G; Leukefeld, Carl G; Booth, Brenda M

    2008-06-01

    This article describes barriers to obtaining drug abuse treatment in the rural South using qualitative interviews conducted with 86 illicit stimulant users recruited in rural Arkansas and Kentucky between 2003 and 2005. Fifty-nine (69.0%) of the interviewees had never entered drug abuse treatment. Sixteen (19.0%) participants reported current perceived need for treatment, while seven (8%) were ambivalent about seeking it. Interview data suggest five interrelated categories of barriers to accessing drug abuse treatment: (1) geographical, (2) organizational, (3) economic, (4) social, and (5) psychological. The study findings can inform further examination of rural treatment barriers and have important implications for developing strategies to overcome these obstacles. PMID:18720660

  5. Assessment of the post-prandial distribution of intragastric contents using an automated technique.

    PubMed

    Moraes, Eder R; Troncon, Luiz E A; Herculano, José Ruver L; Secaf, Marie; Oliveira, Ricardo B; Baffa, Oswaldo

    2006-09-01

    The distribution of intragastric contents has been studied using operator-dependent methods. We devised an automated technique for determining post-prandial intragastric distribution of radiolabeled meals, based on the calculation of the 'center of activity' (CA) of the radioactivity contained in the stomach in any given scintigraphic image. Twelve healthy volunteers and eleven functional dyspepsia (FD) patients ingested a liquid meal (320 mL, 450 kcal) labeled with (99m)Technetium-phytate. Images of the stomach were acquired every 5-10 min for 2 h, and counted to determine the percentage of total activity retained in the upper half of the stomach, as visually delineated. Each image was then processed using an algorithm for calculating a CA value representing the average of image-forming points corrected by pixel number. The relative CA position along the main longitudinal axis of the stomach, as defined by a digital 'skeletonizing' process, was expressed in a '0 to 1' scale. In the FD patients, the average of all CA determinations was significantly higher than in the controls (0.56, 0.30-0.80 versus 0.48, 0.33-0.68, p < 0.05) and correlated significantly with proximal stomach retention values assessed by a visual method (R = -0.64, p < 0.001). Assessing post-prandial intragastric distribution by a novel automated method is feasible and yields reliable data, while being much less operator dependent. PMID:16868344

  6. Assessment of the effect of vasodilators on the distribution of cardiac output by whole-body Thallium imaging

    SciTech Connect

    Juni, J.E.; Wallis, J.; Diltz, E.; Nicholas, J.; Lahti, D.; Pitt, B.

    1985-05-01

    Vasodilator therapy (tx) of congestive heart failure (CHF) has been shown to be effective in increasing cardiac output (CO) and lowering vascular resistance. Unfortunately, these hemodynamic effects are not usually accompanied by improved peripheral circulation of exercise capacity. To assess the effect of a new vasodilator, Cl-914, on the redistribution of CO to the peripheral circulation, the authors performed testing whole-body thallium scanning (WB-Th) on 6 patients (pts) with severe CHF. Immediately following i.v. injection of 1.5 mCi Th-201, WB scanning was performed from anterior and posterior views. Regions of interest were defined for the peripheral (P) muscles (legs and arms), central torso (C), and splanchnic bed (S). The geometric mean of activity in these regions was calculated from both views. Each pt was studied before tx and again, after 1 week on tx. Invasive measurements revealed that all pts had significant improvements in resting cardiac output (mean increase 49%) and vascular resistance (mean decrease 30%). Unlike other vasodilators, all CI-914 pts had a significant improvement in treadmill exercise capacity (mean increase 54%). WB-Th revealed a significant shift in CO to the peripheral circulation with P:C increased 33.2% (rho= .001) and P:S increased 29% (rho=.01). Vasoactive drugs may significantly alter the relative distribution of cardiac output. WB-Th scanning provides a simple quantitative means of following such changes.

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

    PubMed Central

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

    2013-01-01

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

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

    PubMed

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

    2012-05-10

    For the first time in Europe hair and urine testing have been applied to assess drugs of abuse consumption in couples undergoing assisted reproductive technology and the eventual association of toxic habits with other lifestyle, health status and sociodemographic factors was also investigated. Couples attending five assisted reproduction centers in Rome were invited to join the study. When they presented at the Centre for the visit, they were asked to answer a structured questionnaire concerning sociodemographic characteristics and lifestyle habits, and at the same time to provide hair and urine samples. Hair and urine testing for drugs of abuse, urinary profile of principal endogenous steroids involved in fertility process (testosterone, epitestosterone, androsterone, etiocholanolone and dehydroepiandrosterone) and of alcohol and tobacco smoke biomarkers were performed with validated methodologies. Of the 594 enrolled individuals (297 couples), 352 (164 couples and 24 single individuals from the couple) completed the questionnaire and gave both hair and urine samples, apart from 3 bald men, who only gave urine samples. Urine testing showed an overall 4.8% (17 individuals) positivity to drugs of abuse: 4.2% to cannabinoids, 1.4% to cocaine and 0.85% to both drugs. Results of 4cm segment hair samples testing matched those from urine samples. Thus, taking together, results of urine and hair testing confirmed repeated use of cannabis, cocaine and both drugs in 3.7, 0.85 and 0.57% examined individuals, respectively. Drug consumers were in a statistically higher percentage active smokers and alcohol drinkers, less prone to physical activity and with a trend towards higher weight than non consumers. Finally, repeated drug consumption was associated with significant lower concentration of urinary testosterone in males and of urinary dehydroepiandrosterone in females. The findings of the present study confirm the suitability of urine testing to disclose recent drugs of abuse consumption and of hair analysis to verify repeated consumption. Association between different toxic habits and sedentary lifestyle is also substantiated by the obtained results in our cohort of couples attending assisted reproduction centers. PMID:22018744

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

    PubMed

    Calfee, J E

    2007-10-01

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

  10. Sustained active ingredient release from drugs: statistical model for random sample assessment in vitro.

    PubMed

    Peil, H; von Storp, L H; Zacharias, H

    1989-11-01

    A method is presented according to which tolerances for active ingredient release from pharmaceutical dosage forms are calculated. The procedure is based on a statistical model. In accordance with this, the mean value is specified as a measure of the amount of active ingredient released, and the standard deviation as a measure of the uniformity of the active ingredient release. The determination of drug release tolerances is standardized. Based on clinically tested samples, changes arising from the manufacture and the storage are taken into account, thus establishing a manufacturing standard. Depending on the information available, a dynamic adaption of drug release tolerances (e.g., during the develop