Science.gov

Sample records for assessing drug distribution

  1. Microdialysis versus other techniques for the clinical assessment of in vivo tissue drug distribution.

    PubMed

    Brunner, Martin; Langer, Oliver

    2006-01-01

    Quantification of target site pharmacokinetics (PK) is crucial for drug discovery and development. Clinical microdialysis (MD) has increasingly been employed for the description of drug distribution and receptor phase PK of the unbound fraction of various analytes. Costs for MD experiments are comparably low and given suitable analytics, target tissue PK of virtually any drug molecule can be quantified. The major limitation of MD stems from the fact that organs such as brain, lung or liver are not readily accessible without surgery. Recently, non-invasive imaging techniques, i.e. positron emission tomography (PET) or magnetic resonance spectroscopy (MRS), have become available for in vivo drug distribution assessment and allow for drug concentration measurements in practically every human organ. Spatial resolution of MRS imaging, however, is low and although PET enables monitoring of regional drug concentration differences with a spatial resolution of a few millimetres, discrimination between bound and unbound drug or parent compound and metabolite is difficult. Radiotracer development is furthermore time and labour intensive and requires special expertise and radiation exposure and costs originating from running a PET facility cannot be neglected. The recent complementary use of MD and imaging has permitted to exploit individual strengths of these diverse techniques. In conclusion, MD and imaging techniques have provided drug distribution data that have so far not been available. Used alone or in combination, these methods may potentially play an important role in future drug research and development with the potential to serve as translational tools for clinical decision making.

  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. [Benefit assessment of drugs].

    PubMed

    Kaiser, Thomas; Vervölgyi, V; Wieseler, B

    2015-03-01

    In Germany, new drugs are subject to a benefit assessment at the time of their market access. This "early benefit assessment" is the method primarily used for the benefit assessment of pharmaceuticals in Germany. While for the authorization of a drug a positive risk-benefit ratio is sufficient, early benefit assessment examines whether the new drug has an added benefit compared with other therapies, and thus differs significantly from authorization. For the evaluation, the manufacturer is required to submit a dossier, which must contain all the relevant studies. Early benefit assessment is very transparent in international comparisons, because all the relevant data and the evaluation report will be published. The assessment is carried out with regard to the evidence-based standard of care (the "appropriate comparator"). If the new drug is found to have an additional benefit, the extent of this added benefit is assessed. In addition, groups of patients should be identified with the particular extent of the added benefit. Therefore, subgroup analyses have to be carried out frequently. Often, for new drugs, only registration studies are available. General requirements for such studies (e.g., placebo comparison, endpoints) and decisions regarding the approval process (e.g., dosage regimens) can affect the level of confidence of these studies in the benefit assessment. Joint scientific advice by regulatory authorities and HTA (health technology assessment) agencies are provided to solve this problem. However, this is not possible without additional expense for the pharmaceutical companies. PMID:25566842

  5. Patterns of Drug Distribution: Implications and Issues#

    PubMed Central

    Johnson, Bruce D.

    2007-01-01

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

  6. Distributed road assessment system

    DOEpatents

    Beer, N. Reginald; Paglieroni, David W

    2014-03-25

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

  7. 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.

  8. 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

  9. 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

  10. 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.

  11. 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

  12. 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

  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.

  14. Optimizing distribution of pandemic influenza antiviral drugs.

    PubMed

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

    2015-02-01

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

  15. 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)...

  16. 21 CFR 1310.10 - Removal of the exemption of drugs distributed under the Federal Food, Drug and Cosmetic Act.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

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

  17. 21 CFR 1310.10 - Removal of the exemption of drugs distributed under the Food, Drug and Cosmetic Act.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

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

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

    Code of Federal Regulations, 2011 CFR

    2011-04-01

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

  19. Exploration of Heterogeneity in Distributed Research Network Drug Safety Analyses

    ERIC Educational Resources Information Center

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

    2014-01-01

    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…

  20. 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.

  1. Physiochemical property space distribution among human metabolites, drugs and toxins

    PubMed Central

    2009-01-01

    Background The current approach to screen for drug-like molecules is to sieve for molecules with biochemical properties suitable for desirable pharmacokinetics and reduced toxicity, using predominantly biophysical properties of chemical compounds, based on empirical rules such as Lipinski's "rule of five" (Ro5). For over a decade, Ro5 has been applied to combinatorial compounds, drugs and ligands, in the search for suitable lead compounds. Unfortunately, till date, a clear distinction between drugs and non-drugs has not been achieved. The current trend is to seek out drugs which show metabolite-likeness. In identifying similar physicochemical characteristics, compounds have usually been clustered based on some characteristic, to reduce the search space presented by large molecular datasets. This paper examines the similarity of current drug molecules with human metabolites and toxins, using a range of computed molecular descriptors as well as the effect of comparison to clustered data compared to searches against complete datasets. Results We have carried out statistical and substructure functional group analyses of three datasets, namely human metabolites, drugs and toxin molecules. The distributions of various molecular descriptors were investigated. Our analyses show that, although the three groups are distinct, present-day drugs are closer to toxin molecules than to metabolites. Furthermore, these distributions are quite similar for both clustered data as well as complete or unclustered datasets. Conclusion The property space occupied by metabolites is dissimilar to that of drugs or toxin molecules, with current drugs showing greater similarity to toxins than to metabolites. Additionally, empirical rules like Ro5 can be refined to identify drugs or drug-like molecules that are clearly distinct from toxic compounds and more metabolite-like. The inclusion of human metabolites in this study provides a deeper insight into metabolite/drug/toxin-like properties and

  2. Assessing Specificity of Anticancer Drugs In Vitro

    PubMed Central

    Kluwe, Lan

    2016-01-01

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

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

    PubMed

    Berkland, Cory; Kipper, Matt J; Narasimhan, Balaji; Kim, Kyekyoon Kevin; Pack, Daniel W

    2004-01-01

    A thorough understanding of the factors affecting drug release mechanisms from surface-erodible polymer devices is critical to the design of optimal delivery systems. Poly(sebacic anhydride) (PSA) microspheres were loaded with three model drug compounds (rhodamine B, p-nitroaniline and piroxicam) with a range of polarities (water solubilities). The drug release profiles from monodisperse particles of three different sizes were compared to release from polydisperse microspheres. Each of the model drugs exhibited different release mechanisms. Drug distribution within the polymer was investigated by laser scanning confocal microscopy and scanning electron microscopy. Rhodamine, the most hydrophilic compound investigated, was localized strongly toward the microsphere surface, while the much more hydrophobic compound, piroxicam, distributed more evenly. Furthermore, all three compounds were most uniformly distributed in the smallest microspheres, most likely due to the competing effects of drug diffusion out of the nascent polymer droplets and the precipitation of polymer upon solvent extraction, which effectively "traps" the drug in the polymer matrix. The differing drug distributions were manifested in the drug release profiles. Rhodamine was released very quickly independent of microsphere size. Thus, extended release profiles may not be obtainable if the drug strongly redistributes in the microspheres. The release of p-nitroaniline was more prolonged, but still showed little dependence on microsphere size. Hence, when water-soluble drugs are encapsulated with hydrophobic polymers, it may be difficult to tailor release profiles by controlling microsphere size. The piroxicam-loaded microspheres exhibit the most interesting release profiles, showing that release duration can be increased by decreasing microsphere size, resulting in a more uniform drug distribution. PMID:14684277

  4. 21 CFR 203.50 - Requirements for wholesale distribution of prescription drugs.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 4 2010-04-01 2010-04-01 false Requirements for wholesale distribution of prescription drugs. 203.50 Section 203.50 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) DRUGS: GENERAL PRESCRIPTION DRUG MARKETING Wholesale Distribution §...

  5. An integrated drug prescription and distribution system: challenges and opportunities.

    PubMed

    Lanssiers, R; Everaert, E; De Win, M; Van De Velde, R; De Clercq, H

    2002-01-01

    Using the hospital's drug prescription and distribution system as a guide, benefits and drawbacks of a medical activity management system that is tightly integrated with the supply chain management of a hospital will be discussed from the point of view of various participating healthcare actors. PMID:15058416

  6. 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 §...

  7. 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 §...

  8. 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 §...

  9. 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 §...

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

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

  12. Structural Biomechanics Modulate Intramuscular Distribution of Locally Delivered Drugs

    PubMed Central

    Wu, Peter I-Kung; Edelman, Elazer R.

    2008-01-01

    As local drug delivery continues to emerge as a clinical force, so does understanding of its potentially narrow therapeutic window. Classic molecular transport studies are of value but do not typically account for the local nature of drug transport or the regional dynamic function in target tissues like muscle that may undergo cyclical and variable mechanical motion and loading. We examine the impact of dynamic architecture on intramuscular drug distribution. We designed a tissue mounting technique and mechanical loading system that uniquely enables pharmacokinetics investigations in association with control of muscle biomechanics while preserving physiologic tissue architecture. The system was validated and used to elucidate the influence of architecture and controlled cyclic strain on intramuscular drug distribution. Rat soleus muscles underwent controlled deformations within a drug delivery chamber that preserved in vivo physiology. Penetration of 1 mM 20 kDa FITC-dextran at planar surfaces of the soleus increased significantly from 0.52 ± 0.09 mm under 80 min of static (0%) strain to 0.81 ± 0.09 mm under cyclic (3 Hz, 0–20% peak-to-peak) strain, demonstrating the driving effect of cyclic loading on transport. Penetration at curved margins was 1.57- and 2.53-fold greater than at planar surfaces under static and cyclic strain, respectively, and was enhanced 1.6-fold more by cyclic strain, revealing architecturally dictated spatial heterogeneity in transport and modulation of motion dynamics. Architectural geometry and dynamics modulate the impact of mechanical loading on local drug penetration and intramuscular distribution. Future work will use the biomechanical test system to investigate mechanisms underlying transport effects of specific loading regimens. It is hoped that this work will initiate a broader understanding of intramuscular pharmacokinetics and guide local drug delivery strategies. PMID:18706562

  13. 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.

  14. Assessment of the consistency among three drug compendia in listing and ranking of drug-drug interactions

    PubMed Central

    Nikolić, Božana S.; Ilić, Maja S.

    2013-01-01

    Inconsistent information about drug-drug interactions can cause variations in prescribing, and possibly increase the incidence of morbidity and mortality. The aim of this study was to assess whether there is an inconsistency in drug-drug interaction listing and ranking in three authoritative, freely accessible online drug information sources: The British National Formulary; The Compendium about Drugs Licensed for Use in the United Kingdom (the Electronic Medicines Compendium) and the Compendium about Drugs Licensed for Use in the United States (the DailyMed). Information on drug-drug interactions for thirty drugs which have a high or medium potential for interactions have been selected for analysis. In total, 1971 drug-drug interactions were listed in all three drug information sources, of these 992 were ranked as the interactions with the potential of clinical significance. Comparative analysis identified that 63.98% of interactions were listed in only one drug information source, and 66.63% of interactions were ranked in only one drug information source. Only 15.12% listed and 11.19% ranked interactions were identified in all three information sources. Intraclass correlation coefficient indicated a weak correlation among the three drug information sources in listing (0.366), as well as in ranking drug interactions (0.467). This study showed inconsistency of information on drug-drug interaction for the selected drugs in three authoritative, freely accessible online drug information sources. The application of a uniform methodology in assessment of information, and then the presentation of information in a standardized format is required to prevent and adequately manage drug-drug interactions. PMID:24289762

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

    PubMed

    Daniel, Władysława A

    2003-02-01

    Distribution of a drug in the body is dependent on its permeation properties, the blood flow rates in various tissues, and on plasma and tissue uptake. The distribution of drugs in vivo is largely determined by uptake competitions between blood and tissues, as well as competitions among individual tissues. Basic lipophilic drugs are characterized by extensive accumulation in tissues, which leads to a high volume of distribution. Nonspecific binding to cellular membranes and uptake by acidic compartments (mainly lysosomes) are responsible for such a distribution pattern. Lysosomal trapping is an important mechanism of distribution of basic psychotropic drugs; however, the tissue distribution of the aliphatic-type phenothiazine neuroleptic promazine, tricyclic antidepressants (TADs) and selective serotonin reuptake inhibitors (SSRIs) depends more on phospholipid binding than on lysosomal trapping, whereas in the case thioridazine and perazine, lysosomal trapping is as important for the tissue uptake as is phospholipid binding. Neuroleptics and antidepressants mutually inhibit their lysosomal uptake. A decrease in the intralysosomal drug concentrations in vivo leads to a shift of the drug from organs abundant in lysosomes (lungs, liver and kidneys) to those poor in these organella, e.g., the heart, which may be of clinical importance (cardiotoxicity). The brain is not a homogenous organ, i.e., the phospholipid pattern and density of lysosomes vary in its different regions. Therefore, the contribution of the two mechanisms (lysosomal trapping and tissue binding) to total drug uptake is different in areas of the brain. Both lysosomal trapping and binding to cellular elements for psychotropics are higher in the grey matter and neurons than in the white matter and astrocytes, respectively. Lysosomal trapping and distribution interactions of psychotropics take place mainly in neurons. A decrease (via a distributive interaction) in the concentration of psychotropics in

  16. 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…

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

    PubMed

    Meyer, Markus R; Maurer, Hans H

    2011-02-01

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

  18. 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.

  19. 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... guidance for industry entitled ``Compliance Policy on Reporting Drug Sample Distribution Information Under... availability of a draft guidance for industry entitled ``Compliance Policy on Reporting Drug...

  20. The pKa Distribution of Drugs: Application to Drug Discovery

    PubMed Central

    Manallack, David T.

    2007-01-01

    The acid-base dissociation constant (pKa) of a drug is a key physicochemical parameter influencing many biopharmaceutical characteristics. While this has been well established, the overall proportion of non-ionizable and ionizable compounds for drug-like substances is not well known. Even less well known is the overall distribution of acid and base pKa values. The current study has reviewed the literature with regard to both the proportion of ionizable substances and pKa distributions. Further to this a set of 582 drugs with associated pKa data was thoroughly examined to provide a representative set of observations. This was further enhanced by delineating the compounds into CNS and non-CNS drugs to investigate where differences exist. Interestingly, the distribution of pKa values for single acids differed remarkably between CNS and non-CNS substances with only one CNS compound having an acid pKa below 6.1. The distribution of basic substances in the CNS set also showed a marked cut off with no compounds having a pKa above 10.5. The pKa distributions of drugs are influenced by two main drivers. The first is related to the nature and frequency of occurrence of the functional groups that are commonly observed in pharmaceuticals and the typical range of pKa values they span. The other factor concerns the biological targets these compounds are designed to hit. For example, many CNS targets are based on seven transmembrane G protein-coupled receptors (7TM GPCR) which have a key aspartic acid residue known to interact with most ligands. As a consequence, amines are mostly present in the ligands that target 7TM GPCR’s and this influences the pKa profile of drugs containing basic groups. For larger screening collections of compounds, synthetic chemistry and the working practices of the chemists themselves can influence the proportion of ionizable compounds and consequent pKa distributions. The findings from this study expand on current wisdom in pKa research and have

  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. Designer drugs 2015: assessment and management.

    PubMed

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

    2015-03-25

    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.

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

    PubMed

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

    2005-02-01

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

  4. Assessing drug target association using semantic linked data.

    PubMed

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

    2012-01-01

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

  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. 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

  7. Assessing illicit drug use among adults with schizophrenia

    PubMed Central

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

    2012-01-01

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

  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

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

    PubMed Central

    Hanrahan, Conor T.; Cole, Sabrina W.

    2014-01-01

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

  10. 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...

  11. 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...

  12. Risk-benefit assessment of tocolytic drugs.

    PubMed

    Wischnik, A

    1991-01-01

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

  13. [In Vitro and in Vivo Assessments of Drug-induced Hepatotoxicity and Drug Metabolism in Humans].

    PubMed

    Sanoh, Seigo

    2015-01-01

    Drug-induced hepatotoxicity is of concern in drug discovery and development. Reactive metabolites generated by drug metabolizing enzymes in the liver contribute to the induction of hepatotoxicity. Therefore, drug-induced hepatotoxicity, drug metabolism, and pharmacokinetics were evaluated in vitro and in vivo in this pre-clinical study. First, hepatotoxicity was tested in vitro using three-dimensional hepatocyte cultures. Hepatocyte spheroids formed in the three-dimensional culture systems maintain various liver functions such as the expression of drug metabolizing enzymes. High dose exposure to acetaminophen (APAP) induces hepatotoxicity because of the formation of reactive metabolites by CYP. Using fluorescence imaging, we observed that cell viability and glutathione levels were reduced in hepatocyte spheroids exposed to APAP mediated by the metabolic activation of CYP. On the other hand, there are species differences in the expression of drug metabolizing enzymes and metabolite profiles between animals and humans. Therefore, chimeric mice transfected with human hepatocytes were used for the in vivo assessment of metabolic profiles in humans. We found that drug metabolism and pharmacokinetics mediated by CYP and non-CYP enzymes, such as UDP-glucuronosyltransferase and aldehyde oxidase, in chimeric mice with humanized liver were similar to those in humans. The combination of in vitro and in vivo assessments using spheroids and chimeric mice with humanized liver, respectively, during the screening of drug candidates may help to reveal hepatotoxicity induced by the formation of metabolites. PMID:26521876

  14. 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

  15. 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

  16. 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

  17. 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

  18. Assessment of cognitive safety in clinical drug development

    PubMed Central

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

    2016-01-01

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

  19. 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

  20. Assessing dose rate distributions in VMAT plans

    NASA Astrophysics Data System (ADS)

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

    2016-04-01

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

  1. 77 FR 44177 - Antimicrobial Animal Drug Sales and Distribution Reporting

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-07-27

    ... HUMAN SERVICES Food and Drug Administration 21 CFR Part 514 Antimicrobial Animal Drug Sales and... changes to its regulations relating to records and reports for approved new animal drugs. FDA is considering revisions to this regulation to incorporate the requirements of section 105 of the Animal...

  2. Convection-enhanced drug delivery of interleukin-4 Pseudomonas exotoxin (PRX321): increased distribution and magnetic resonance monitoring.

    PubMed

    Mardor, Y; Last, D; Daniels, D; Shneor, R; Maier, S E; Nass, D; Ram, Z

    2009-08-01

    Convection-enhanced drug delivery (CED) enables achieving a drug concentration within brain tissue and brain tumors that is orders of magnitude higher than by systemic administration. Previous phase I/II clinical trials using intratumoral convection of interleukin-4 Pseudomonas exotoxin (PRX321) have demonstrated an acceptable safety and toxicity profile with promising signs of therapeutic activity. The present study was designed to assess the distribution efficiency and toxicity of this PRX321 using magnetic resonance imaging (MRI) and to test whether reformulation with increased viscosity could enhance drug distribution. Convection of low- [0.02% human serum albumin (HSA)] and high-viscosity (3% HSA) infusates mixed with gadolinium-diethylenetriamine pentaacetic acid and PRX321 were compared with low- and high-viscosity infusates without the drug, in normal rat brains. MRI was used for assessment of drug distribution and detection of early and late toxicity. Representative brain samples were subjected to histological examination. Distribution volumes calculated from the magnetic resonance images showed that the average distribution of 0.02% HSA was larger than that of 0.02% HSA with PRX321 by a factor of 1.98 (p < 0.02). CED of 3.0% HSA, with or without PRX321, tripled the volume of distribution compared with 0.02% HSA with PRX321 (p < 0.015). No drug-related toxicity was detected. These results suggest that the impeded convection of the PRX321 infusate used in previous clinical trials can be reversed by increasing infusate viscosity and lead to tripling of the volume of distribution. This effect was not associated with any detectable toxicity. A similar capability to reverse impeded convection was also demonstrated in a CED model using acetic acid. These results will be implemented in an upcoming phase IIb PRX321 CED trial with a high-viscosity infusate.

  3. Solubility and dissolution profile assessment in drug discovery.

    PubMed

    Sugano, Kiyohiko; Okazaki, Arimichi; Sugimoto, Shohei; Tavornvipas, Sumitra; Omura, Atsushi; Mano, Takashi

    2007-08-01

    The purposes of the review are to: a) Provide a comprehensible introduction of the-state-of-the-art sciences of solubility and dissolution, b) introduce typical technologies to assess solubility and dissolution, and c) propose the best practice strategy. The theories of solubility and dissolution required in drug discovery were reviewed especially from the view point of oral absorption. The physiological conditions in the gastrointestinal fluid in humans and animals were then briefly summarized. Technologies to assess solubility and dissolution in drug discovery were then introduced. Recently, these technologies have been improved by the laboratory automation and computational technologies. Finally, the strategies to apply these technologies for a drug discovery project were discussed.

  4. 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

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

    PubMed

    Svennebring, Andreas Mats

    2016-01-01

    1. New equations have been developed from an updated version of Øie-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.

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

    PubMed

    Saldías, César; Velásquez, 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 (ɛ-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 (ζ), 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

  7. A Zebrafish Thrombosis Model for Assessing Antithrombotic Drugs.

    PubMed

    Zhu, Xiao-Yu; Liu, Hong-Cui; Guo, Sheng-Ya; Xia, Bo; Song, Ru-Shun; Lao, Qiao-Cong; Xuan, Yao-Xian; Li, Chun-Qi

    2016-08-01

    Thrombosis is a leading cause of death and the development of effective and safe therapeutic agents for thrombotic diseases has been proven challenging. In this study, taking advantage of the transparency of larval zebrafish, we developed a larval zebrafish thrombosis model for drug screening and efficacy assessment. Zebrafish at 2 dpf (days post fertilization) were treated with phenylhydrazine (PHZ) and a testing drug for 24 h. Tested drugs were administered into the zebrafish either by direct soaking or circulation microinjection. Antithrombotic efficacy was quantitatively evaluated based on our previously patented technology characterized as an image analysis of the heart red blood cells stained with O-dianisidine staining. Zebrafish at 2 dpf treated with PHZ at a concentration of 1.5 μM for a time period of 24 h were determined as the optimum conditions for the zebrafish thrombosis model development. Induced thrombosis in zebrafish was visually confirmed under a dissecting stereomicroscope and quantified by the image assay. All 6 human antithrombotic drugs (aspirin, clopidogrel, diltiazem hydrochloride injection, xuanshuantong injection, salvianolate injection, and astragalus injection) showed significant preventive and therapeutic effects on zebrafish thrombosis (p < 0.05, p < 0.01, & p < 0.001) in this zebrafish thrombosis model. The larval zebrafish thrombosis model developed and validated in this study could be used for in vivo thrombosis studies and for rapid screening and efficacy assessment of antithrombotic drugs. PMID:27333081

  8. 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

  9. 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…

  10. 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.

  11. 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)

  12. 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

  13. 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.

  14. 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-Sánchez, Rubén

    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.

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

    PubMed

    Łotysz, Sławomir

    2014-01-01

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

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

    PubMed

    Łotysz, Sławomir

    2014-01-01

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

  17. 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

  18. 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.

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

    PubMed

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

    2016-03-01

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

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

    PubMed

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

    2016-03-01

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

  1. Impact of drug administration route on drug delivery and distribution into the lung: an imaging mass spectrometry approach.

    PubMed

    Zecchi, Riccardo; Trevisani, Marcello; Pittelli, Maria; Pedretti, Pamela; Manni, Maria Elena; Pieraccini, Giuseppe; Pioselli, Barbara; Amadei, Francesco; Moneti, Gloriano; Catinella, Silvia

    2013-01-01

    During the last decade, significant technological improvements in mass spectrometry have had a great impact on drug discovery. The development of matrix-assisted laser desorption/ionization imaging mass spectrometry (MALDI-IMS) has set a new frontier for the study of the distribution of endogenous and exogenous molecules present within a tissue. MALDI-IMS is a surface sampling technique that allows not only the detection of multiple analytes but also gives the spatial distribution of those analytes. Active compounds for pulmonary disease need an optimal and well-studied delivery into the lungs, in order to assure distribution with greater penetration into the peripheral or the alveolar region of the lung to maximize the therapeutic effects. IMS is very useful in the field of drug discovery, showing drug delivery and distribution in the body and organs. In this study, we present a comparison between two different ways of carrying out pulmonary drug administration: inhalation of a nebulized aerosol of aqueous drug solutions and intratracheal administration, which is much simpler, not expensive and commonly used during in vivo screening. Tiotropium bromide is a long-acting anticholinergic medicine used for maintenance treatment of chronic obstructive pulmonary disease. In the present work, tiotropium was administered by nebulization and by intratracheal instillation to guinea pigs at doses able to induce significant anti-bronchoconstrictive activity. Lung samples were dissected, frozen, cryosectioned and coated with matrix (α-hydroxy-cinnamic acid). IMS analyses were performed using a MALDI-LTQ-Orbitrap XL. Using this technique we were able to compare different distributions of the drug depending on the method of administration.

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

    PubMed Central

    2015-01-01

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

  3. Distribution system reliability assessment using hierarchical Markov modeling

    SciTech Connect

    Brown, R.E.; Gupta, S.; Christie, R.D.; Venkata, S.S.; Fletcher, R.

    1996-10-01

    Distribution system reliability assessment is concerned with power availability and power quality at each customer`s service entrance. This paper presents a new method, termed Hierarchical Markov Modeling (HMM), which can perform predictive distribution system reliability assessment. HMM is unique in that it decomposes the reliability model based on system topology, integrated protection systems, and individual protection devices. This structure, which easily accommodates the effects of backup protection, fault isolation, and load restoration, is compared to simpler reliability models. HMM is then used to assess the reliability of an existing utility distribution system and to explore the reliability impact of several design improvement options.

  4. Physics and instrumentation for imaging in-vivo drug distribution.

    PubMed

    Singh, M; Waluch, V

    2000-03-15

    Several imaging methods are currently available to measure drugs noninvasively. Of these, two techniques are today central to such measurements: nuclear imaging and magnetic resonance imaging/spectroscopy (MRI and MRS). While other methods, such as optical techniques, are rapidly gaining in interest, they have not yet attained the degree of development that makes them effective in measuring drugs in living systems, except in a small number of examples. The following introduction provides some basic elements of the potential and the limitations of both nuclear imaging and MRI/MRS techniques, methods that will be used in the studies described in the articles in this issue. However, and for those desiring to gain a better understanding of both methods, the reader is advised to consult much more extensive reviews and books describing such methods. A suggested list of books and articles on Nuclear Imaging and MRI/MRS is given.

  5. 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,…

  6. 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)...

  7. 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...

  8. 28 CFR 83.210 - To whom must I distribute my drug-free workplace statement?

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 28 Judicial Administration 2 2010-07-01 2010-07-01 false To whom must I distribute my drug-free 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...

  9. 38 CFR 48.210 - To whom must I distribute my drug-free workplace statement?

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 38 Pensions, Bonuses, and Veterans' Relief 2 2010-07-01 2010-07-01 false To whom must I distribute 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 ASSISTANCE) Requirements for Recipients...

  10. 40 CFR 36.210 - To whom must I distribute my drug-free workplace statement?

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 40 Protection of Environment 1 2010-07-01 2010-07-01 false To whom must I distribute my drug-free 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...

  11. 22 CFR 210.210 - To whom must I distribute my drug-free workplace statement?

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 22 Foreign Relations 1 2010-04-01 2010-04-01 false To whom must I distribute my drug-free 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...

  12. 22 CFR 133.210 - To whom must I distribute my drug-free workplace statement?

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 22 Foreign Relations 1 2010-04-01 2010-04-01 false To whom must I distribute my drug-free 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...

  13. 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 statement? 26.210 Section 26.210 National Defense Department of Defense OFFICE OF THE SECRETARY OF DEFENSE DoD GRANT AND AGREEMENT REGULATIONS GOVERNMENTWIDE REQUIREMENTS FOR DRUG-FREE WORKPLACE (FINANCIAL ASSISTANCE) Requirements for...

  14. 15 CFR 29.210 - To whom must I distribute my drug-free workplace statement?

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 15 Commerce and Foreign Trade 1 2010-01-01 2010-01-01 false To whom must I distribute my drug-free 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...

  15. 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.

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

    PubMed

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

    2015-01-23

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

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

    PubMed

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

    2012-05-10

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

  18. Distribution of methamphetamine and amphetamine in drug abusers' head hair.

    PubMed

    Lee, Sooyeun; Han, Eunyoung; Park, Yonghoon; Choi, Hwakyung; Chung, Heesun

    2009-09-10

    In order to aid the interpretation of hair results from methamphetamine (MA) abusers the MA and amphetamine (AP) concentrations in 2070 hair samples were statistically evaluated. The MA and AP concentrations in hair were put into three groups arbitrarily representing low, medium and high ranges and the metabolite-to-parent drug ratios of each group were examined. The concentration ranges proposed here were also applied to the interpretation of five authentic cases. The low, medium and high ranges of MA were 0.5-4.2, 4.2-24.5 and 24.5-608.9 ng/mg and those of AP were 0.1-0.4, 0.4-1.7 and 1.7-41.4 ng/mg. The AP-to-MA ratios showed large variation but a tendency that it decreased as the MA ranges increased. This evaluation was very useful to presume the severity of individuals' MA abuse and to provide law enforcement agencies more understandable information. It could also facilitate the court's decision regarding specific circumstances surrounding the drug-related crimes.

  19. DISTRIBUTION OF DOXORUBICIN IN RATS UNDERGOING ULTRASONIC DRUG DELIVERY

    PubMed Central

    Staples, Bryant J.; Pitt, William G.; Roeder, Beverly L.; Husseini, Ghaleb A.; Rajeev, Deepthi; Schaalje, G. Bruce

    2015-01-01

    Ultrasound increases efficacy of drugs delivered from micelles, but the pharmacokinetics have not been studied previously. In this study, ultrasound was used to deliver doxorubicin sequestered in micelles in an in vivo rat model with bilateral leg tumors. One of two frequencies with identical mechanical index and intensity was delivered for 15 minutes to one tumor immediately after systemic injection of micellar doxorubicin. Pharmacokinetics in myocardium, liver, skeletal muscle, and tumors were measured for one week. When applied in combination with micellar doxorubicin, the ultrasoincated tumor had higher doxorubicin concentrations at 30 minutes, compared to bilateral noninsonated controls. Initially, concentrations were highest in heart and liver, but within 24 hours they decreased significantly. From 24 hours to 7 days, concentrations remained highest in tumors, regardless of whether they received ultrasound or not. Comparison of insonated and noninsonated tumors showed 50% more doxorubicin in the insonated tumor at 30 minutes post-treatment. Four weekly treatment produced additional doxorubicin accumulation in the myocardium but not in liver, skeletal leg muscle, or tumors compared to single treatment. Controls showed that neither ultrasound nor the empty carrier impacted tumor growth. This study shows that US causes more release of drug at the targeted tumor. PMID:20166203

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

    PubMed

    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.

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

    ERIC Educational Resources Information Center

    Sarvela, Paul D.; And Others

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

  2. Truncated shifted pareto distribution in assessing size distribution of oil and gas fields

    SciTech Connect

    Houghton, J.C.

    1988-11-01

    The truncated shifted Pareto (TSP) distribution, a variant of the two-parameter Pareto distribution, in which one parameter is added to shift the distribution right and left and the right-hand side is truncated, is used to model size distributions of oil and gas fields for resource assessment. Assumptions about limits to the left-hand and right-hand side reduce the number of parameters to two. The TSP distribution has advantages over the more customary lognormal distribution because it has a simple analytic expression, allowing exact computation of several statistics of interest, has a J-shape, and has more flexibility in the thickness of the right-hand tail. Oil field sizes from the Minnelusa play in the Powder River Basin, Wyoming and Montana, are used as a case study. Probability plotting procedures allow easy visualization of the fit and help the assessment.

  3. Use of the truncated shifted Pareto distribution in assessing size distribution of oil and gas fields

    USGS Publications Warehouse

    Houghton, J.C.

    1988-01-01

    The truncated shifted Pareto (TSP) distribution, a variant of the two-parameter Pareto distribution, in which one parameter is added to shift the distribution right and left and the right-hand side is truncated, is used to model size distributions of oil and gas fields for resource assessment. Assumptions about limits to the left-hand and right-hand side reduce the number of parameters to two. The TSP distribution has advantages over the more customary lognormal distribution because it has a simple analytic expression, allowing exact computation of several statistics of interest, has a "J-shape," and has more flexibility in the thickness of the right-hand tail. Oil field sizes from the Minnelusa play in the Powder River Basin, Wyoming and Montana, are used as a case study. Probability plotting procedures allow easy visualization of the fit and help the assessment. ?? 1988 International Association for Mathematical Geology.

  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. Analysis on distribution features and drug resistance of clinically isolated Acinetobacter baumannii

    PubMed Central

    Ren, Guangming; Zhou, Min; Ding, Ning; Zhou, Ning; Li, Qingling

    2016-01-01

    The aim of the present study was to examine the clinical distribution and drug resistance of Acinetobacter baumannii infection, and provide evidence of clinical medication as well as the prophylaxis for the treatment of drug resistance bacteria. In total, 306 Acinetobacter baumanniis selected from routine culture were collected between January 2012 and December 2013, to analyze the distributions among clinical specimens and wards and their drug resistance state. Of the 306 Acinetobacter baumanniis, the main distribution of specimens was sputum, accounting for 77.78%. The distribution of administrative office was dominated by intensive care unit with a proportion of 40.0% in 2012, which rapidly increased to 60.9% in 2013, followed by neurosurgery, respiration medicine and orthopedics with proportions of 23, 12 and 9.0% in 2012 and 9.71, 8.74 and 3.88% in 2013, respectively. The Acinetobacter baumannii's drug resistance rate of Tazobactam and Piperacillin was increased from 68.0% in 2012 to 71.36% in 2013. At the same time, the drug resistance rate of imipenem was enhanced from 66.0% in 2012 to 72.81% in 2013. By 2013, the drug resistance rates of penbritin, ceftizoxime, cefotetan and macrodantin reached ≤100%. In conclusion, Acinetobacter baumannii mainly causes respiratory tract infection with severe drug resistance. The drug resistance of Acinetobacter baumannii was mainly manifested as multidrug resistance or even pan-drug resistance with an obvious increasing trend of tolerance. Thus, it is necessary to prevent and treat nosocomial infection, to minimize usage of antibiotics and to standardize medical operating, to reduce the increase in persistence. PMID:27602085

  6. 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.

  7. 78 FR 36787 - Rechanneling the Current Cardiac Risk Paradigm: Arrhythmia Risk Assessment During Drug...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-06-19

    ... From the Federal Register Online via the Government Publishing Office DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration Rechanneling the Current Cardiac Risk Paradigm: Arrhythmia... the Current Cardiac Risk Paradigm: Arrhythmia Risk Assessment During Drug Development Without...

  8. 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)

  9. [Supervision of distribution and use of veterinary drugs in Schleswig-Holstein].

    PubMed

    Bettin, U

    1996-07-01

    By means of drug related legislation the endowment and limits of veterinary medicines surveillance are demonstrated. The distribution of veterinary pharmaceutical products is organised in wide area structures, both in legal and illegal employment. Thus powerful monitoring can only be established by co-operation of all involved institutions. In advance, a concentration of duties in a few administrations with supraregional authorisation can take place, in particular shown here for the organisation of the recommended institutions in Schleswig-Holstein. A catalogue of typical violations und neglects indicates areas of problems at various levels of veterinary drug trade (production, distribution, pharmacy, veterinarian). A report about the performance and results of the surveillance of drug applications in animal production demonstrates the conjoint consummation of drug control in farms and specimen control on living and slaughtered animals.

  10. 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 (§...

  11. 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 (§...

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

    PubMed Central

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

    2016-01-01

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

  13. 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

  14. Open drug scenes and drug-related public nuisance: a visual rapid assessment research study in Dublin, Ireland.

    PubMed

    Van Hout, Marie Claire; Bingham, Tim

    2013-01-01

    The research was undertaken at a time of increasing public concerns for drug- and alcohol-related public nuisance in the city center of Dublin, Ireland. Rapid Assessment Research was conducted involving qualitative interviewing with drug service users; business, transport, community, voluntary, and statutory stakeholders (n = 61); and an environmental mapping exercise. The interplay between homelessness, loitering, an influx of drug users via city metro systems, transient open drug scenes, street drinking, drug injecting, intimidation, knife crime, and prescribed medication abuse was evident. Potential strategies to address drug and alcohol related public nuisance are advised to include the relocation of treatment services, targeted harm reduction initiatives, urban regeneration, improved community rehabilitation pathways, and heightened policing intensity.

  15. MR-based assessment of body fat distribution and characteristics.

    PubMed

    Baum, Thomas; Cordes, Christian; Dieckmeyer, Michael; Ruschke, Stefan; Franz, Daniela; Hauner, Hans; Kirschke, Jan S; Karampinos, Dimitrios C

    2016-08-01

    The assessment of body fat distribution and characteristics using magnetic resonance (MR) methods has recently gained significant attention as it further extends our pathophysiological understanding of diseases including obesity, metabolic syndrome, or type 2 diabetes mellitus, and allows more detailed insights into treatment response and effects of lifestyle interventions. Therefore, the purpose of this study was to review the current literature on MR-based assessment of body fat distribution and characteristics. PubMed search was performed to identify relevant studies on the assessment of body fat distribution and characteristics using MR methods. T1-, T2-weighted MR Imaging (MRI), Magnetic Resonance Spectroscopy (MRS), and chemical shift-encoding based water-fat MRI have been successfully used for the assessment of body fat distribution and characteristics. The relationship of insulin resistance and serum lipids with abdominal adipose tissue (i.e. subcutaneous and visceral adipose tissue), liver, muscle, and bone marrow fat content have been extensively investigated and may help to understand the underlying pathophysiological mechanisms and the multifaceted obese phenotype. MR methods have also been used to monitor changes of body fat distribution and characteristics after interventions (e.g. diet or physical activity) and revealed distinct, adipose tissue-specific properties. Lastly, chemical shift-encoding based water-fat MRI can detect brown adipose tissue which is currently the focus of intense research as a potential treatment target for obesity. In conclusion, MR methods reliably allow the assessment of body fat distribution and characteristics. Irrespective of the promising findings based on these MR methods the clinical usefulness remains to be established.

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

    PubMed Central

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

    2008-01-01

    Background The emergence of drug resistance is a major problem in malaria control. For mathematical modelling of the transmission and spread of drug resistance the determinant parameters need to be identified and measured. The underlying hypothesis is that mutations associated with drug resistance incur fitness costs to the parasite in absence of drug pressure. The distribution of drug resistance haplotypes in different subsets of the host population was investigated. In particular newly acquired haplotypes after radical cure were characterized and compared to haplotypes from persistent infections. Methods Mutations associated with antimalarial drug resistance were analysed in parasites from children, adults, and new infections occurring after treatment. Twenty-five known single nucleotide polymorphisms from four Plasmodium falciparum genes associated with drug resistance were genotyped by DNA chip technology. Results Haplotypes were found to differ between subsets of the host population. A seven-fold mutated haplotype was significantly reduced in adults compared to children and new infections, whereas parasites harbouring fewer mutations were more frequent in adults. Conclusion The reduced frequency of highly mutated parasites in chronic infections in adults is likely a result of fitness costs of drug resistance that increases with number of mutations and is responsible for reduced survival of mutant parasites. PMID:18460212

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

    PubMed

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

    2014-05-01

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

  18. 7 CFR 1230.73 - Uses of distributed assessments.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... its distribution of assessments pursuant to § 1230.72, as well as any proceeds from the investment of such funds pending their use, for financing plans and projects and the administrative expenses incurred....72, as well as any proceeds from the investment of such funds pending their use, for financing...

  19. 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...

  20. 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...

  1. Positron emission tomography (PET) for assessing aerosol deposition of orally inhaled drug products.

    PubMed

    Dolovich, Myrna B; Bailey, Dale L

    2012-12-01

    The topical distribution of inhaled therapies in the lung can be viewed using radionuclides and imaging. Positron emission tomography (PET) is a three-dimensional functional imaging technique providing quantitatively accurate localization of the quantity and distribution of an inhaled or injected PET radiotracer in the lung. A series of transaxial slices through the lungs are obtained, comparable to an X-ray computed tomography (CT) scan. Subsequent reformatting allows coronal and sagittal images of the distribution of radioactivity to be viewed. This article describes procedures for administering [(18)F]-fluorodeoxyglucose aerosol to human subjects for the purpose of determining dose and distribution following inhalation from an aerosol drug delivery device (ADDD). The advantages of using direct-labeled PET drugs in the ADDD are discussed with reference to the literature. The methods for designing the inhalation system, determining proper radiation shielding, calibration, and validation of administered radioactivity, scanner setup, and data handling procedures are described. Obtaining an X-ray CT or radionuclide transmission scan to provide accurate geometry of the lung and also correct for tissue attenuation of the PET radiotracer is discussed. Protocols for producing accurate images, including factors that need to be incorporated into the data calibration, are described, as well as a proposed standard method for partitioning the lung into regions of interest. Alternate methods are described for more detailed assessments. Radiation dosimetry/risk calculations for the procedures are appended, as well as a sample data collection form and spreadsheet for calculations. This article should provide guidance for those interested in using PET to determine quantity and distribution of inhaled therapeutics. PMID:23215847

  2. An assessment of drug testing within the construction industry.

    PubMed

    Gerber, Jonathan K; Yacoubian, George S

    2002-01-01

    Drug testing in the workplace has gone from virtual nonexistence to widespread employer acceptance during the past two decades. This growth is particularly significant for the construction industry. High rates of alcohol and other drug use, coupled with the high-risk, safety-sensitive nature of the industry, have prompted the development of a variety of drug surveillance and prevention strategies. Despite this growing vigilance, no scholarly works have examined the impact of drug-related policies in the construction industry. To address this limitation, we investigate the efficacy of workplace drug-testing programs in reducing injury incident rates and workers' compensation experience-rating modification factors (MODs) within the construction industry. Analyses indicate that companies with drug-testing programs experienced a 51 percent reduction in incident rates within two years of implementation. Moreover, companies that drug test their employees experienced a significant reduction in their MODs. Policy implications are discussed in light of the current findings.

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

    PubMed

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

    2016-01-15

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

  4. 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...

  5. 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...

  6. 29 CFR 1472.210 - To whom must I distribute my drug-free workplace statement?

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 29 Labor 4 2011-07-01 2011-07-01 false To whom must I distribute my drug-free workplace statement? 1472.210 Section 1472.210 Labor Regulations Relating to Labor (Continued) FEDERAL MEDIATION AND... who will be engaged in the performance of any Federal award....

  7. Melting Point Distribution Analysis of Globally Approved and Discontinued Drugs: A Research for Improving the Chance of Success of Drug Design and Discovery.

    PubMed

    Mao, Fei; Kong, Qingya; Ni, Wei; Xu, Xiang; Ling, Dazheng; Lu, Zhengyu; Li, Jian

    2016-08-01

    The melting point (MP), an easily accessible physical parameter, has considerable potential for the judgment of drug-like properties. However, to the best of our knowledge, there are no useful guidelines for understanding the relationship between the MP and drug-like properties. To this end, we have constructed the largest MP database (experimental value) of globally approved drugs (3164 organic small-molecule drugs) and discontinued drugs (417 organic small-molecule drugs) and subsequently extracted six subdatabases from the whole approved database and two subdatabases from the discontinued database. The MP distribution statistics and analysis of approved drugs reveal five noteworthy observations; moreover, the MP distribution statistics and analysis of discontinued drugs further supplement these criteria. In addition, the comparison of molecular weight (MW) versus MP and Clog P versus MP distributions of different classes of approved drugs indicated that the MWs and Clog P values of most drugs in the optimal MP range were not more than 500 and 5, respectively, implying the MP distribution criterion was in accordance with Lipinski's rule of five.

  8. Melting Point Distribution Analysis of Globally Approved and Discontinued Drugs: A Research for Improving the Chance of Success of Drug Design and Discovery.

    PubMed

    Mao, Fei; Kong, Qingya; Ni, Wei; Xu, Xiang; Ling, Dazheng; Lu, Zhengyu; Li, Jian

    2016-08-01

    The melting point (MP), an easily accessible physical parameter, has considerable potential for the judgment of drug-like properties. However, to the best of our knowledge, there are no useful guidelines for understanding the relationship between the MP and drug-like properties. To this end, we have constructed the largest MP database (experimental value) of globally approved drugs (3164 organic small-molecule drugs) and discontinued drugs (417 organic small-molecule drugs) and subsequently extracted six subdatabases from the whole approved database and two subdatabases from the discontinued database. The MP distribution statistics and analysis of approved drugs reveal five noteworthy observations; moreover, the MP distribution statistics and analysis of discontinued drugs further supplement these criteria. In addition, the comparison of molecular weight (MW) versus MP and Clog P versus MP distributions of different classes of approved drugs indicated that the MWs and Clog P values of most drugs in the optimal MP range were not more than 500 and 5, respectively, implying the MP distribution criterion was in accordance with Lipinski's rule of five. PMID:27547646

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

    PubMed

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

    2015-10-01

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

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

    PubMed Central

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

    2015-01-01

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

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

    PubMed

    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. 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

  13. 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.

  14. Comparative Genomic Assessment of Novel Broad-Spectrum Targets for Antibacterial Drugs

    PubMed Central

    White, Thomas A.

    2004-01-01

    Single and multiple resistance to antibacterial drugs currently in use is spreading, since they act against only a very small number of molecular targets; finding novel targets for anti-infectives is therefore of great importance. All protein sequences from three pathogens (Staphylococcus aureus, Mycobacterium tuberculosis and Escherichia coli O157:H7 EDL993) were assessed via comparative genomics methods for their suitability as antibacterial targets according to a number of criteria, including the essentiality of the protein, its level of sequence conservation, and its distribution in pathogens, bacteria and eukaryotes (especially humans). Each protein was scored and ranked based on weighted variants of these criteria in order to prioritize proteins as potential novel broad-spectrum targets for antibacterial drugs. A number of proteins proved to score highly in all three species and were robust to variations in the scoring system used. Sensitivity analysis indicated the quantitative contribution of each metric to the overall score. After further analysis of these targets, tRNA methyltransferase (trmD) and translation initiation factor IF-1 (infA) emerged as potential and novel antimicrobial targets very worthy of further investigation. The scoring strategy used might be of value in other areas of post-genomic drug discovery. PMID:18629165

  15. Validation of a preclinical model for assessment of drug efficacy in melanoma

    PubMed Central

    Delyon, Julie; Varna, Mariana; Feugeas, Jean-Paul; Sadoux, Aurélie; Yahiaoui, Saliha; Podgorniak, Marie-Pierre; Leclert, Geoffroy; Dorval, Sarra Mazouz; Dumaz, Nicolas; Janin, Anne

    2016-01-01

    The aim of personalized medicine is to improve our understanding of the disease at molecular level and to optimize therapeutic management. In this context, we have developed in vivo and ex vivo preclinical strategies evaluating the efficacy of innovative drugs in melanomas. Human melanomas (n = 17) of different genotypes (mutated BRAF, NRAS, amplified cKIT and wild type) were successfully engrafted in mice then amplified by successive transplantations. The exhaustive characterization of patient-derived xenografts (PDX) at genomic level (transcriptomic and CGH arrays) revealed a similar distribution pattern of genetic abnormalities throughout the successive transplantations compared to the initial patient tumor, enabling their use for mutation-specific therapy strategies. The reproducibility of their spontaneous metastatic potential in mice was assessed in 8 models. These PDXs were used for the development of histoculture drug response assays (ex vivo) for the evaluation of innovative drug efficacy (BRAF and MEK inhibitors). The pharmacological effects of BRAF and MEK inhibitors were similar between PDX-derived histocultures and their corresponding PDX, on 2 models of BRAF and NRAS-mutated melanomas. These models constitute a validated, effective tool for preclinical investigation of new therapeutic agents, and improve therapeutic strategies in the treatment of metastatic melanoma. PMID:26909610

  16. 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.

  17. 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.

  18. 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, Véronique

    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

  19. 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

  20. Assessment of non-linear combination effect terms for drug-drug interactions.

    PubMed

    Koch, Gilbert; Schropp, Johannes; Jusko, William J

    2016-10-01

    Drugs interact with their targets in different ways. A diversity of modeling approaches exists to describe the combination effects of two drugs. We investigate several combination effect terms (CET) regarding their underlying mechanism based on drug-receptor binding kinetics, empirical and statistical summation principles and indirect response models. A list with properties is provided and the interrelationship of the CETs is analyzed. A method is presented to calculate the optimal drug concentration pair to produce the half-maximal combination effect. This work provides a comprehensive overview of typically applied CETs and should shed light into the question as to which CET is appropriate for application in pharmacokinetic/pharmacodynamic models to describe a specific drug-drug interaction mechanism. PMID:27638639

  1. 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…

  2. 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.

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

    PubMed

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

    2015-11-30

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

  4. 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

  5. Distributed electrical generation technologies and methods for their economic assessment

    SciTech Connect

    Kreider, J.F.; Curtiss, P.S.

    2000-07-01

    A confluence of events in the electrical generation and transmission industry has produced a new paradigm for distributed electrical generation and distribution in the US Electrical deregulation, reluctance of traditional utilities to commit capital to large central plants and transmission lines, and a suite of new, efficient generation hardware have all combined to bring this about. Persistent environmental concerns have further stimulated several new approaches. In this paper the authors describe the near term distributed generation technologies and their differentiating characteristics along with their readiness for the US market. In order to decide which approaches are well suited to a specific project, an assessment methodology is needed. A technically sound approach is therefore described and example results are given.

  6. Identifying adverse drug event information in clinical notes with distributional semantic representations of context.

    PubMed

    Henriksson, Aron; Kvist, Maria; Dalianis, Hercules; Duneld, Martin

    2015-10-01

    For the purpose of post-marketing drug safety surveillance, which has traditionally relied on the voluntary reporting of individual cases of adverse drug events (ADEs), other sources of information are now being explored, including electronic health records (EHRs), which give us access to enormous amounts of longitudinal observations of the treatment of patients and their drug use. Adverse drug events, which can be encoded in EHRs with certain diagnosis codes, are, however, heavily underreported. It is therefore important to develop capabilities to process, by means of computational methods, the more unstructured EHR data in the form of clinical notes, where clinicians may describe and reason around suspected ADEs. In this study, we report on the creation of an annotated corpus of Swedish health records for the purpose of learning to identify information pertaining to ADEs present in clinical notes. To this end, three key tasks are tackled: recognizing relevant named entities (disorders, symptoms, drugs), labeling attributes of the recognized entities (negation, speculation, temporality), and relationships between them (indication, adverse drug event). For each of the three tasks, leveraging models of distributional semantics - i.e., unsupervised methods that exploit co-occurrence information to model, typically in vector space, the meaning of words - and, in particular, combinations of such models, is shown to improve the predictive performance. The ability to make use of such unsupervised methods is critical when faced with large amounts of sparse and high-dimensional data, especially in domains where annotated resources are scarce.

  7. Identifying adverse drug event information in clinical notes with distributional semantic representations of context.

    PubMed

    Henriksson, Aron; Kvist, Maria; Dalianis, Hercules; Duneld, Martin

    2015-10-01

    For the purpose of post-marketing drug safety surveillance, which has traditionally relied on the voluntary reporting of individual cases of adverse drug events (ADEs), other sources of information are now being explored, including electronic health records (EHRs), which give us access to enormous amounts of longitudinal observations of the treatment of patients and their drug use. Adverse drug events, which can be encoded in EHRs with certain diagnosis codes, are, however, heavily underreported. It is therefore important to develop capabilities to process, by means of computational methods, the more unstructured EHR data in the form of clinical notes, where clinicians may describe and reason around suspected ADEs. In this study, we report on the creation of an annotated corpus of Swedish health records for the purpose of learning to identify information pertaining to ADEs present in clinical notes. To this end, three key tasks are tackled: recognizing relevant named entities (disorders, symptoms, drugs), labeling attributes of the recognized entities (negation, speculation, temporality), and relationships between them (indication, adverse drug event). For each of the three tasks, leveraging models of distributional semantics - i.e., unsupervised methods that exploit co-occurrence information to model, typically in vector space, the meaning of words - and, in particular, combinations of such models, is shown to improve the predictive performance. The ability to make use of such unsupervised methods is critical when faced with large amounts of sparse and high-dimensional data, especially in domains where annotated resources are scarce. PMID:26291578

  8. 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...

  9. 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...

  10. 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...

  11. 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...

  12. 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...

  13. 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

  14. Assessing risks of changing sterile drug manufacturing sites.

    PubMed

    Langille, Stephen E; Campbell, Cliff

    2010-01-01

    This article summarizes a recently completed research assignment conducted on behalf of the Food and Drug Administration's (FDA) Office of Pharmaceutical Science. The assignment addressed the issue of changing sterile drug manufacturing sites from the point of view of both synthetic and biotech drug products. The article is intended to provide readers with an overview of the assignment and to summarize a recommended approach whereby the use of a comparability protocol can satisfy the FDA's review expectations on the one hand, and facilitate streamlined compliance and faster product to market by manufacturers on the other.

  15. 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

  16. 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 (AUCτ) 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 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 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

  17. Melting Point Distribution Analysis of Globally Approved and Discontinued Drugs: A Research for Improving the Chance of Success of Drug Design and Discovery

    PubMed Central

    Mao, Fei; Kong, Qingya; Ni, Wei; Xu, Xiang; Ling, Dazheng; Lu, Zhengyu

    2016-01-01

    Abstract The melting point (MP), an easily accessible physical parameter, has considerable potential for the judgment of drug‐like properties. However, to the best of our knowledge, there are no useful guidelines for understanding the relationship between the MP and drug‐like properties. To this end, we have constructed the largest MP database (experimental value) of globally approved drugs (3164 organic small‐molecule drugs) and discontinued drugs (417 organic small‐molecule drugs) and subsequently extracted six subdatabases from the whole approved database and two subdatabases from the discontinued database. The MP distribution statistics and analysis of approved drugs reveal five noteworthy observations; moreover, the MP distribution statistics and analysis of discontinued drugs further supplement these criteria. In addition, the comparison of molecular weight (MW) versus MP and Clog P versus MP distributions of different classes of approved drugs indicated that the MWs and Clog P values of most drugs in the optimal MP range were not more than 500 and 5, respectively, implying the MP distribution criterion was in accordance with Lipinski's rule of five. PMID:27547646

  18. 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.

  19. 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

  20. Challenges in the clinical assessment of novel tuberculosis drugs.

    PubMed

    Dooley, Kelly E; Phillips, Patrick P J; Nahid, Payam; Hoelscher, Michael

    2016-07-01

    To tackle the global TB epidemic effectively, novel treatment strategies are critically needed to shorten the duration of TB therapy and treat drug-resistant TB. Drug development for TB, stymied for decades, has enjoyed a renaissance over the past several years. However, the development of new TB regimens is hindered by the limitations in our understanding and use of preclinical models; the paucity of accurate, early surrogate markers of cure, and challenges in untangling the individual contributions of drugs to multidrug regimens in a complex, multi-compartment disease. Lack of profit motive, advocacy, and imagination has contributed mightily to the dearth of drugs we have on the shelf to treat this ancient disease. Areas that will speed the development of new regimens for TB include novel murine and in vitro pharmacodynamics models, clinical endpoints that are not culture-based, innovative clinical trial designs, and an infusion of much-needed funding. PMID:26827911

  1. An analytical solution for the model of drug distribution and absorption in small intestine

    NASA Astrophysics Data System (ADS)

    Mingyu, Xu

    1990-11-01

    According to the physiological and anatomical characteristics of small intestine, neglecting the effect of its motility on the distribution and absorption of drug and nutrient, Y. Miyamoto et al.[1] proposed a model of two-dimensional laminar flow in a circular porous tube with permeable wall and calculated the concentration profile of drug by numerical analysis. In this paper, we give a steady state analytical solution of the above model including deactivation term. The obtained results are in agreement with the results of their numerical analysis. Moreover the analytical solution presented in this paper reveals the relation among the physiological parameters of the model and describes the basic absorption rule of drug and nutrient through the intestinal wall and hence provides a theoretical basis for determining the permeability and reflection coefficient through in situ experiments.

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

    PubMed Central

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

    2015-01-01

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

  3. Cerebrospinal fluid uptake and peripheral distribution of centrally acting drugs: relation to lipid solubility.

    PubMed

    Ochs, H R; Greenblatt, D J; Abernethy, D R; Arendt, R M; Gerloff, J; Eichelkraut, W; Hahn, N

    1985-06-01

    In an anaesthetized dog model, serum kinetics and CSF entry were determined after i.v. administration of the following 8 drugs: salicylic acid (as acetylsalicylic acid), antipyrine, acetaminophen (paracetamol), lidocaine (lignocaine), trimipramine, amitriptyline, haloperidol, and imipramine. Kinetic variables were evaluated in relation to in-vitro lipophilicity, measured by the reverse-phase high-pressure liquid chromatographic (HPLC) retention index. After correction for individual values of serum binding (determined as the CSF: serum ratio at equilibrium), in-vivo volume of distribution was highly correlated with HPLC retention (r = 0.92). Conversely, the time of peak CSF concentration and the CSF entry half-life were negatively correlated with HPLC retention (r = -0.83 and -0.63, respectively). Thus lipophilicity is a physiochemical property which has an influence on the peripheral distribution of drugs as well as their rate of entry into CSF. PMID:2862269

  4. Time Varying Apparent Volume of Distribution and Drug Half-Lives Following Intravenous Bolus Injections.

    PubMed

    Wesolowski, Carl A; Wesolowski, Michal J; Babyn, Paul S; Wanasundara, Surajith N

    2016-01-01

    We present a model that generalizes the apparent volume of distribution and half-life as functions of time following intravenous bolus injection. This generalized model defines a time varying apparent volume of drug distribution. The half-lives of drug remaining in the body vary in time and become longer as time elapses, eventually converging to the terminal half-life. Two example fit models were substituted into the general model: biexponential models from the least relative concentration error, and gamma variate models using adaptive regularization for least relative error of clearance. Using adult population parameters from 41 studies of the renal glomerular filtration marker 169Yb-DTPA, simulations of extracellular fluid volumes of 5, 10, 15 and 20 litres and plasma clearances of 40 and 100 ml/min were obtained. Of these models, the adaptively obtained gamma variate models had longer times to 95% of terminal volume and longer half-lives.

  5. Time Varying Apparent Volume of Distribution and Drug Half-Lives Following Intravenous Bolus Injections

    PubMed Central

    Wesolowski, Carl A.; Wesolowski, Michal J.; Babyn, Paul S.

    2016-01-01

    We present a model that generalizes the apparent volume of distribution and half-life as functions of time following intravenous bolus injection. This generalized model defines a time varying apparent volume of drug distribution. The half-lives of drug remaining in the body vary in time and become longer as time elapses, eventually converging to the terminal half-life. Two example fit models were substituted into the general model: biexponential models from the least relative concentration error, and gamma variate models using adaptive regularization for least relative error of clearance. Using adult population parameters from 41 studies of the renal glomerular filtration marker 169Yb-DTPA, simulations of extracellular fluid volumes of 5, 10, 15 and 20 litres and plasma clearances of 40 and 100 ml/min were obtained. Of these models, the adaptively obtained gamma variate models had longer times to 95% of terminal volume and longer half-lives. PMID:27403663

  6. Time Varying Apparent Volume of Distribution and Drug Half-Lives Following Intravenous Bolus Injections.

    PubMed

    Wesolowski, Carl A; Wesolowski, Michal J; Babyn, Paul S; Wanasundara, Surajith N

    2016-01-01

    We present a model that generalizes the apparent volume of distribution and half-life as functions of time following intravenous bolus injection. This generalized model defines a time varying apparent volume of drug distribution. The half-lives of drug remaining in the body vary in time and become longer as time elapses, eventually converging to the terminal half-life. Two example fit models were substituted into the general model: biexponential models from the least relative concentration error, and gamma variate models using adaptive regularization for least relative error of clearance. Using adult population parameters from 41 studies of the renal glomerular filtration marker 169Yb-DTPA, simulations of extracellular fluid volumes of 5, 10, 15 and 20 litres and plasma clearances of 40 and 100 ml/min were obtained. Of these models, the adaptively obtained gamma variate models had longer times to 95% of terminal volume and longer half-lives. PMID:27403663

  7. Assessing introduction risk using species' rank-abundance distributions.

    PubMed

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

    2015-01-22

    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

  8. 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

  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. Core Concepts Involving Adverse Psychotropic Drug Effects: Assessment, Implications, and Management.

    PubMed

    Goldberg, Joseph F; Ernst, Carrie L

    2016-09-01

    Adverse effects from psychiatric drugs can profoundly influence treatment adherence and outcomes. Good care involves addressing adverse effects no differently than any other component of treatment. Knowledge about adverse effect assessment and management fosters a proper context that helps clinicians not sacrifice a drug's potential therapeutic benefits because of greater concerns about its tolerability. This article provides an overview of basic concepts related to the assessment and management of suspected adverse effects from psychotropic drugs. Key points are discussed regarding clinical, pharmacogenetic, pharmacokinetic, and pharmacodynamic risk factors for treatment-emergent adverse effects, alongside recommendations for their systematic assessment. PMID:27514295

  11. 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.

  12. Industrial Power Distribution System Reliability Assessment utilizing Markov Approach

    NASA Astrophysics Data System (ADS)

    Guzman-Rivera, Oscar R.

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

  13. Drug-to-antibody ratio (DAR) and drug load distribution by hydrophobic interaction chromatography and reversed phase high-performance liquid chromatography.

    PubMed

    Ouyang, Jun

    2013-01-01

    Hydrophobic interaction chromatography (HIC) is the method of choice for determination of the drug-to-antibody ratio (DAR) and drug load distribution for cysteine (Cys)-linked antibody-drug conjugates (ADCs). The drug-loaded species are resolved based on the increasing hydrophobicity with the least hydrophobic, unconjugated form eluting first and the most hydrophobic, 8-drug form eluting last. The area percentage of a peak represents the relative distribution of the particular drug-loaded ADC species. The weighted average DAR is then calculated using the percentage peak area information and the drug load numbers. Reversed phase high-performance liquid chromatography (RP-HPLC) offers an orthogonal method to obtain DAR for Cys-linked ADCs. The method involves, first, a reduction reaction to completely dissociate the heavy and light chains of the ADC, then separation of the light and heavy chains and their corresponding drug-loaded forms on an RP column. The percentage peak area from integration of the light chain and heavy chain peaks, combined with the assigned drug load for each peak, is used to calculate the weighted average DAR.

  14. 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 3.98±0.13, 3.90±0.22, 29.3±2.2, 0.66±0.04 1.78±0.30, 4.08±0.50, with (2-hydroxyethyl)-β-cyclodextrin, (2-hydroxypropyl)-β-cyclodextrin, 2,6-di-O-methyl-β-cyclodextrin, hepta-kis(2,3,6-tri-O-methyl)-β-cyclodextrin, α-cyclodextrin, β-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

  15. Influence of ammonium chloride on the tissue distribution of anticholinergic drugs in rats.

    PubMed

    Ishizaki, J; Yokogawa, K; Nakashima, E; Ohkuma, S; Ichimura, F

    1998-07-01

    Ammonium chloride (NH4Cl) increases lysosomal pH and thereby abolishes intralysosomal accumulation of drugs. Its effect on the tissue distribution of biperiden and trihexyphenidyl in rats has been investigated. The tissue-plasma concentration ratios (Kp) of these drugs in various tissues were determined by infusion studies at steady-state in the presence or absence of NH4Cl. Treatment with NH4Cl reduced the Kp values for both drugs, causing the largest reduction in Kp in the lung (52.1 to 11.8 for biperiden and 59.5 to 18.9 for trihexyphenidyl; ratios of decrease 0.77 and 0.68, respectively), followed by the heart and kidneys, with relatively small reductions in the brain, gut, muscle and fat. Subcellular fractionation studies in the lung indicated that the subcellular fraction-plasma concentration ratio of each drug at the steady state (K(p,sf)) was reduced by treatment with NH4Cl, with the largest decrease in the post-nuclear fraction (ratio of decrease 0.82 for biperiden and 0.74 for trihexyphenidyl), followed by the nucleus, microsomes and supernatant, in that order. A strong correlation was found between the ratio of decrease in K(p,sf) after NH4Cl treatment and the specific activity of acid phosphatases, a marker of lysosomes, in each fraction (biperiden, r = 0.948; trihexyphenidyl, r = 0.945). These results suggest that acidic organelles contribute significantly to the distribution kinetics of anticholinergic drugs.

  16. 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

  17. 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...

  18. 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…

  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. 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...

  1. 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

  2. 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

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

    PubMed Central

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

    2015-01-01

    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

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

    ERIC Educational Resources Information Center

    Blair, Louis H.; Sessler, John

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

  5. Prioritising anticancer drugs for environmental monitoring and risk assessment purposes.

    PubMed

    Booker, Victoria; Halsall, Crispin; Llewellyn, Neville; Johnson, Andrew; Williams, Richard

    2014-03-01

    Anticancer drugs routinely used in chemotherapy enter wastewater through the excretion of the non-metabolised drug following administration to patients. This study considers the consumption and subsequent behaviour and occurrence of these chemicals in aquatic systems, with the aim of prioritising a selection of these drugs which are likely to persist in the environment and hence be considered for environmental screening programmes. Accurate consumption data were compiled from a hospital survey in NW England and combined with urinary excretion rates derived from clinical studies. Physical-chemical property data were compiled along with likely chemical fate and persistence during and after wastewater treatment. A shortlist of 15 chemicals (from 65) was prioritised based on their consumption, persistency and likelihood of occurrence in surface waters and supported by observational studies where possible. The ecological impact of these 'prioritised' chemicals is uncertain as the measured concentrations in surface waters generally fall below standard toxicity thresholds. Nonetheless, this prioritised sub-list should prove useful for developing environmental screening programmes. PMID:24369294

  6. Preclinical Assessment of the Anticancer Drug Response of Plexiform Neurofibroma Tissue Using Primary Cultures

    PubMed Central

    Mautner, Victor-F.; Friedrich, Reinhard E.; Kluwe, Lan

    2015-01-01

    Background and Purpose Individualized drug testing for tumors using a strategy analogous to antibiotic tests for infectious diseases would be highly desirable for personalized and individualized cancer care. Methods Primary cultures containing tumor and nontumor stromal cells were utilized in a novel strategy to test drug responses with respect to both efficacy and specificity. The strategy tested in this pilot study was implemented using four primary cultures derived from plexiform neurofibromas. Responses to two cytotoxic drugs (nilotinib and imatinib) were measured by following dose-dependent changes in the proportions of tumor and nontumor cells, determined by staining them with cell-type-specific antibodies. The viability of the cultured cells and the cytotoxic effect of the drugs were also measured using proliferation and cytotoxicity assays. Results The total number of cells decreased after the drug treatment, in accordance with the observed reduction in proliferation and increased cytotoxic effect upon incubation with the two anticancer drugs. The proportions of Schwann cells and fibroblasts changed dose-dependently, although the patterns of change varied between the tumor samples (from different sources) and between the two drugs. The highly variable in vitro drug responses probably reflect the large variations in the responses of tumors to therapies between individual patients in vivo. Conclusions These preliminary results suggest that the concept of assessing in vitro drug responses using primary cultures is feasible, but demands the extensive further development of an application for preclinical drug selection and drug discovery. PMID:25851896

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

    PubMed

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

    2016-06-01

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

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

    PubMed Central

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

    2014-01-01

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

  9. 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.

  10. 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

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

    PubMed

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

    2015-04-21

    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.

  12. Assessment of alcohol and other drug use behaviors in health professions students.

    PubMed

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

    2006-09-01

    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, with 42.6% of respondents reporting one or both. Among nursing respondents, 48.1%, 19.2% and 51.1%, respectively, reported family problems with alcohol, drugs, or one or both. Past-year alcohol use was comparable to undergraduate college students (UCS) nationally (83%); heavy drinking, tobacco and recreational drug use by HPS were lower. Past year drug use was highest among medical students. Marijuana was the predominant illicit drug; medical students and males most often reported use. Health professions educational systems should proactively address student AOD prevention, education and assistance needs.

  13. Trastuzumab emtansine. An inadequately assessed combination of two cytotoxic drugs.

    PubMed

    2014-12-01

    There is no consensus on second-line treatment for women with metastatic or locally advanced breast cancer over-expressing HER-2 protein in whom treatment with a taxane + trastuzumab has failed. Capecitabine is one option. Adding lapatinib does not prolong survival. Trastuzumab emtansine (Kadcyla, Roche) has received EU marketing authorisation for use in this setting. It consists of two covalently bound drugs: trastuzumab, a monoclonal antibody that binds to HER-2 receptors, and DM1, a cytotoxic microtubule inhibitor. DM1 is derived from maytansine, a cytotoxic drug abandoned in the 1980s because it proved to be too toxic after systemic administration. Clinical evaluation of trastuzumab emtansine is based on an unblinded trial versus capecitabine + lapatinib in 991 patients. The use of lapatinib in all patients in the control group is questionable. An interim analysis suggested that overall survival was about 6 months longer with trastuzumab emtansine (30.9 versus 25.1 months). In addition to the adverse effects of trastuzumab (thrombocytopenia, heart failure, etc.), trastuzumab emtansine causes frequent and potentially life-threatening hepatic toxicity, peripheral neuropathy, and urinary tract infections. Trastuzumab emtansine appears to be less toxic to the skin and mucous membranes than the capecitabine + lapatinib combination. DM1 is metabolised by cytochrome P450 isoenzymes CYP3A4 and CYP3A5 and is also a P-glycoprotein substrate, creating a potential risk of multiple pharmacokinetic interactions. Trastuzumab emtansine appears to be teratogenic and embryotoxic. The international nonproprietary name of this drug is easily confused with trastuzumab. In practice, it is best to at least wait for the full results of the only available comparative trial of trastuzumab emtansine before drawing conclusions about its harm-benefit balance and its possible use if it represents a real therapeutic advance. PMID:25629144

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

    PubMed

    Hörn, 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.

  15. Assessing organizational effectiveness in higher education drug prevention consortia.

    PubMed

    Sheldon-Keller, A E; Lloyd-McGarvey, E; Canterbury, R J

    1995-01-01

    Eighty-three consortia of institutions of higher education, organized under funding from the Fund for the Improvement of Post-Secondary Education (FIPSE) Drug Prevention Programs of the Department of Education, were surveyed to measure organizational effectiveness. Generalized satisfaction with the functioning of the consortia was related to the number of active members, the average miles traveled to meetings, satisfaction with performance of task functions, members' roles, the level of trust among members and the level of creativity and innovation in problem-solving. Satisfaction with goal attainment was significantly related to the presence of at least one "internal" goal for the consortium.

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

    PubMed

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

    2006-01-01

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

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

    PubMed

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

    2013-03-25

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

  18. Atom type preferences, structural diversity, and property profiles of known drugs, leads, and nondrugs: a comparative assessment.

    PubMed

    Viswanadhan, Vellarkad N; Rajesh, Hariharan; Balaji, Vitukudi N

    2011-05-01

    A new characterization of known drug, lead, and representative nondrug databases was performed taking into account several properties at the atomic and molecular levels. This characterization included atom type preferences, intrinsic structural diversity (Atom Type Diversity, ATD), and other well-known physicochemical properties, as an approach for rapid assessment of druglikeness for small molecule libraries. To characterize ATD, an elaborate united atom classification, UALOGP (United Atom Log P), with 148 atom types, was developed along with associated atomic physicochemical parameters. This classification also enabled an analysis of atom type and physicochemical property distributions (for calculated log P, molar refractivity, molecular weight, total atom count, and ATD) of drug, lead, and nondrug databases, a reassessment of the Ro5 (Rule of Five) and GVW (Ghose−Viswanadhan−Wendoloski) criteria, and development of new criteria and ranges more accurately reflecting the chemical space occupied by small molecule drugs. A relative druglikeness parameter was defined for atom types in drugs, identifying the most preferred types. The present work demonstrates that drug molecules are constitutionally more diverse relative to nondrugs, while being less diverse than leads.

  19. A Novel Method for Assessing Drug Degradation Product Safety Using Physiologically-Based Pharmacokinetic Models and Stochastic Risk Assessment.

    PubMed

    Nguyen, Hoa Q; Stamatis, Stephen D; Kirsch, Lee E

    2015-09-01

    Patient safety risk due to toxic degradation products is a potentially critical quality issue for a small group of useful drug substances. Although the pharmacokinetics of toxic drug degradation products may impact product safety, these data are frequently unavailable. The objective of this study is to incorporate the prediction capability of physiologically based pharmacokinetic (PBPK) models into a rational drug degradation product risk assessment procedure using a series of model drug degradants (substituted anilines). The PBPK models were parameterized using a combination of experimental and literature data and computational methods. The impact of model parameter uncertainty was incorporated into stochastic risk assessment procedure for estimating human safe exposure levels based on the novel use of a statistical metric called "PROB" for comparing probability that a human toxicity-target tissue exposure exceeds the rat exposure level at a critical no-observed-adverse-effect level. When compared with traditional risk assessment calculations, this novel PBPK approach appeared to provide a rational basis for drug instability risk assessment by focusing on target tissue exposure and leveraging physiological, biochemical, biophysical knowledge of compounds and species. PMID:25900395

  20. A Novel Method for Assessing Drug Degradation Product Safety Using Physiologically-Based Pharmacokinetic Models and Stochastic Risk Assessment.

    PubMed

    Nguyen, Hoa Q; Stamatis, Stephen D; Kirsch, Lee E

    2015-09-01

    Patient safety risk due to toxic degradation products is a potentially critical quality issue for a small group of useful drug substances. Although the pharmacokinetics of toxic drug degradation products may impact product safety, these data are frequently unavailable. The objective of this study is to incorporate the prediction capability of physiologically based pharmacokinetic (PBPK) models into a rational drug degradation product risk assessment procedure using a series of model drug degradants (substituted anilines). The PBPK models were parameterized using a combination of experimental and literature data and computational methods. The impact of model parameter uncertainty was incorporated into stochastic risk assessment procedure for estimating human safe exposure levels based on the novel use of a statistical metric called "PROB" for comparing probability that a human toxicity-target tissue exposure exceeds the rat exposure level at a critical no-observed-adverse-effect level. When compared with traditional risk assessment calculations, this novel PBPK approach appeared to provide a rational basis for drug instability risk assessment by focusing on target tissue exposure and leveraging physiological, biochemical, biophysical knowledge of compounds and species.

  1. Performance Assessment of OVERFLOW on Distributed Computing Environment

    NASA Technical Reports Server (NTRS)

    Djomehri, M. Jahed; Rizk, Yehia M.

    2000-01-01

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

  2. Skeletal muscle grids for assessing current distributions from defibrillation shocks.

    PubMed

    Schmidt, J; Gatlin, B; Eason, J; Koomullil, G; Pilkington, T

    1992-01-01

    This paper utilizes a structured and an unstructured grid representation of a torso with an anisotropic skeletal muscle to assess current distributions from defibrillation shocks. The results show that a finite-element solution on an unstructured grid of 400,000 elements (60,000 nodes) achieves comparable current distributions with a finite-difference solution on a structured grid that uses approximately the same number of nodes. Moreover, a finite-element solution on a 65,000-element (10,500 nodes) unstructured grid yielded fractional percent current results within 5% of the finer grids. The structured and unstructured grid models are used to investigate recent interpretations of experimental data that concluded that more than 80% of the total defibrillation current is shunted by the anisotropic skeletal muscle thoracic cage. It is concluded that these interpretations, which were based on a one-dimensional resistive network representation of the three-dimensional defibrillation situation, overestimate by 25% the current shunted by the anisotropic thoracic cage. PMID:1424684

  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. 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…

  5. 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…

  6. 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…

  7. 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 50°C, 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.

  8. Cardiac repolarisation and drug regulation: assessing cardiac safety 10 years after the CPMP guidance.

    PubMed

    Shah, Rashmi R

    2007-01-01

    December 2007 marks the 10-year anniversary of the first regulatory guidance for evaluation of drug-induced QT interval prolongation. A decade on, it seems surprising that this document, which was released by the Committee on Proprietary Medicinal Products, caused such acrimony in the industry. Sponsors now routinely evaluate their new drugs for an effect on cardiac electrophysiology in preclinical studies, in addition to obtaining ECGs in all phases of drug development and conducting a formal thorough QT study in humans.However, concurrently, new concerns have also emerged on broader issues related to the cardiovascular safety of drugs because of their potential to shorten the QT interval as well as to induce proischaemic, profibrotic or prothrombotic effects. Drugs may also have an indirect effect by adversely affecting one or more of the cardiovascular risk factors (e.g. through fluid retention or induction of dyslipidaemia). In addition to peroxisome proliferator-activated receptor agonists and cyclo-oxygenase 2 selective inhibitors, three other drugs, darbepoetin alfa, pergolide and tegaserod, provide a more contemporary regulatory stance on tolerance of cardiovascular risk of drugs and their benefit-risk assessment. This recent, more assertive, risk-averse stance has significant implications for future drug development. These include the routine evaluation of cardiovascular safety for certain classes of drugs. Drugs that are intended for long-term use will almost certainly require long-term clinical evaluation in studies that enrol populations that most closely resemble the ultimate target population. Novel mechanisms of action and biomarkers by themselves are no guarantee of improved safety or benefits. Even some traditional biomarkers have come to be viewed with scepticism. Requirements for more extensive and earlier postmarketing assessment of clinical benefits and rare, but serious risks associated with new medicinal products should create a new standard

  9. Pharmacokinetic drug-drug interaction assessment between LCZ696, an angiotensin receptor neprilysin inhibitor, and hydrochlorothiazide, amlodipine, or carvedilol.

    PubMed

    Hsiao, Hsiu-Ling; Langenickel, Thomas Heiko; Greeley, Michael; Roberts, John; Zhou, Wei; Pal, Parasar; Rebello, Sam; Rajman, Iris; Sunkara, Gangadhar

    2015-11-01

    LCZ696 is a first-in-class angiotensin receptor neprilysin inhibitor in development for treatments of hypertension and heart failure indications. In 3 separate studies, pharmacokinetic drug-drug interactions (DDIs) potential was assessed when LCZ696 was coadministered with hydrochlorothiazide (HCTZ), amlodipine, or carvedilol. The studies used a open-label, single-sequence, 3-period, crossover design in healthy subjects. Blood samples were collected to determine the pharmacokinetic parameters of LCZ696 analytes (AHU377, LBQ657, and valsartan), HCTZ, amlodipine, or carvedilol (R[+]- and S[-]-carvedilol) for statistical analysis. When coadministered LCZ696 with HCTZ, the 90% CIs of the geometric mean ratios of AUCtau,ss of HCTZ and that of LBQ657 were within a 0.80-1.25 interval, whereas HCTZ Cmax,ss decreased by 26%, LBQ657 Cmax,ss increased by 19%, and the AUCtau,ss and Cmax,ss of valsartan increased by 14% and 16%, respectively. Pharmacokinetics of amlodipine, R(+)- and S(-)-carvedilol, or LBQ657 were not altered after coadministration of LCZ696 with amlodipine or carvedilol. Coadministration of LCZ696 400 mg once daily (qd) with HCTZ 25 mg qd, amlodipine 10 mg qd, or carvedilol 25 mg twice a day (bid) had no clinically relevant pharmacokinetic drug-drug interactions. LCZ696, HCTZ, amlodipine, and carvedilol were safe and well tolerated when given alone or concomitantly in the investigated studies. PMID:27137712

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

    PubMed

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

    2013-07-01

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

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

    NASA Astrophysics Data System (ADS)

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

    2010-03-01

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

  12. 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 1–5 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, Mann–Whitney 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

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

    PubMed

    Ponnusankar, S; Tejaswini, M; Chaitanya, M

    2015-01-01

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

  14. 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.

  15. 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,…

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

    PubMed

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

    2013-06-01

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

  17. 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

  18. 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.

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

    PubMed

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

    2016-05-01

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

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

    PubMed

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

    2016-04-01

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

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

    PubMed

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

    2016-04-01

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

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

    PubMed Central

    Simoens, Steven

    2013-01-01

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

  3. Risk assessment for drugs of abuse in the Dutch watercycle.

    PubMed

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

    2013-04-01

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

  4. Causality Assessment in Premarketing Drug Clinical Trials: Regulatory Evolution in the USA and Ongoing Concerns.

    PubMed

    Goldman, Stephen A

    2016-10-01

    Since 1993, how to assess the causality of serious adverse events in premarketing drug clinical trials has undergone sustained regulatory evolution in the USA. In that year, an investigational drug study for chronic hepatitis B virus infection was emergently stopped after a patient suddenly exhibited hepatic failure and lactic acidosis, which later developed, along with pancreatitis and peripheral neuropathy, in several others after drug discontinuation. Five patients eventually died, including three despite emergency liver transplantation. The drug's multisystem toxicity was not predicted by preclinical animal studies, with grave injury to human mitochondria subsequently implicated. A concerned US Food and Drug Administration (FDA) created a task force whose findings would have a lasting impact on the agency's thinking. In 1994, the FDA proposed to amend its investigational new drug reporting requirements largely based on task force recommendations for ways to enhance the likelihood that sponsors and investigators would consider investigational agents as a possible cause of serious adverse events mimicking the underlying disease or concomitant drug toxicity. Then, in its 1997 final rule for expedited safety reporting requirements for drugs and biologics, the FDA advised sponsors that such reporting of serious, unexpected clinical trial cases would be expected when "there is a reasonable suspected causal relationship between the investigational product and the adverse event (i.e., the causal relationship cannot be ruled out)." This last clause was codified into the suspected adverse drug reaction definition in the FDA's 2003 safety reporting requirements for drugs and biologics proposed rule. The negatively received suspected adverse drug reaction and proposed causality standard were not adopted in the FDA's 2010 finalized investigational new drug safety reporting regulations, the agency stating that "'reasonable possibility' means there is evidence to suggest a

  5. Causality Assessment in Premarketing Drug Clinical Trials: Regulatory Evolution in the USA and Ongoing Concerns.

    PubMed

    Goldman, Stephen A

    2016-10-01

    Since 1993, how to assess the causality of serious adverse events in premarketing drug clinical trials has undergone sustained regulatory evolution in the USA. In that year, an investigational drug study for chronic hepatitis B virus infection was emergently stopped after a patient suddenly exhibited hepatic failure and lactic acidosis, which later developed, along with pancreatitis and peripheral neuropathy, in several others after drug discontinuation. Five patients eventually died, including three despite emergency liver transplantation. The drug's multisystem toxicity was not predicted by preclinical animal studies, with grave injury to human mitochondria subsequently implicated. A concerned US Food and Drug Administration (FDA) created a task force whose findings would have a lasting impact on the agency's thinking. In 1994, the FDA proposed to amend its investigational new drug reporting requirements largely based on task force recommendations for ways to enhance the likelihood that sponsors and investigators would consider investigational agents as a possible cause of serious adverse events mimicking the underlying disease or concomitant drug toxicity. Then, in its 1997 final rule for expedited safety reporting requirements for drugs and biologics, the FDA advised sponsors that such reporting of serious, unexpected clinical trial cases would be expected when "there is a reasonable suspected causal relationship between the investigational product and the adverse event (i.e., the causal relationship cannot be ruled out)." This last clause was codified into the suspected adverse drug reaction definition in the FDA's 2003 safety reporting requirements for drugs and biologics proposed rule. The negatively received suspected adverse drug reaction and proposed causality standard were not adopted in the FDA's 2010 finalized investigational new drug safety reporting regulations, the agency stating that "'reasonable possibility' means there is evidence to suggest a

  6. Assessment of Drug Sensitivity of Human Leukaemic Myeloblasts

    PubMed Central

    FalcãO, R. P.; Sonis, S.; MacLennan, I. C. M.; Chassoux, D.; Davies, A. J. S.; Munro, T. R.

    1977-01-01

    The compound 125IUdR can be incorporated in a stable form into the DNA of cells. The isotope is released if labelled cells or their progeny die. Consequently the rate of 125I excretion from mice can be used to follow the fate of labelled cells in vivo. Using these principles we show: (1) Sufficient label can be incorporated in vitro into both fresh and cryopreserved human leukaemic myeloblasts, in non-toxic concentrations, to allow their survival in mice to be estimated by whole-body counting; (2) The release of isotope from labelled cells is sufficiently slow to offer reasonable expectation that this technique can be used for assessing the sensitivity of myeloblasts to cytotoxic agents in vivo (an application described in the second paper in this series, Sonis, Falcão and MacLennon, 1977); (3) The rate of 125Iexcretion from mice injected with myeloblasts from different donors varies. This probably reflects different rates of spontaneous death of injected myeloblasts; (4) Active rejection of myeloblasts starts within 48 h of their injection into mice; (5) Indirect evidence that phagocytic cells may be active agents in myeloblast destruction in mice; (6) Various methods of immunologically depriving mice were assessed to see if they would result in a useful increase in survival of injected human myeloblasts. We conclude that there is little advantage and some limitations in using mice thus deprived; (7) One of the agents used for immunological deprivation—silica powder—markedly decreased the rate of 125I loss from mice injected with labelled killed myeloblasts. This experience emphasizes the importance of including the killed-cell control in this assay. PMID:270372

  7. Drugs.

    ERIC Educational Resources Information Center

    Hurst, Hunter, Ed.; And Others

    1984-01-01

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

  8. Distribution of drug-resistant bacteria and rational use of clinical antimicrobial agents

    PubMed Central

    ZHOU, CHENLIANG; CHEN, XIAOBING; WU, LIWEN; QU, JING

    2016-01-01

    Open wound may lead to infection in patients. Due to overuse of medication, certain bacteria have become resistant to drugs currently available. The aim of the present study was to provide a guide to ameliorate the appropriate and rational use of clinical antimicrobial agents by analyzing the distribution of drug-resistant pathogenic bacteria in patients. Between October 2013 and January 2015, 126 patients were selected at the Department of Orthopedics. Wound secretion samples were collected, and the pathogen bacteria isolated and identified. Identification was performed using an automated identification instrument and the Kirby-Bauer antibiotic method was used to evaluate the bacterial resistance. Of the 126 patients, 118 patients were infected (infection rate, 93.65%). Additionally, 47 strains of gram-positive pathogenic bacteria (39.83%) and 71 strains of pathogenic-gram negative bacteria (60.17%) were identified. The bacteria were most likely to be resistant to penicillin while sensitive to vancomycin and imipenem. Some bacteria were resistant to several antibacterial agents. The results showed that existing risk factors at the Department of Orthopedics were complex and any non-standard procedures were able to cause bacterial infection. There were obvious dissimilarities among infectious bacteria with regard to their sensitivity to various antibacterial agents. Manipulation techniques during the treatment process were performed in a sterile manner and the use of antibacterial agents was required to be strictly in accordance with the results of drug sensitivity tests to provide effective etiologic information and a treatment plan for clinical trials and to reduce the risk of infection by multi-resistant bacteria. PMID:27313667

  9. 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

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

    SciTech Connect

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

    1981-06-01

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

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

    PubMed

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

    2002-09-01

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

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

    PubMed

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

    2011-06-30

    Drug toxicity is a leading cause of attrition of candidate drugs during drug development as well as of withdrawal of drugs post-licensing due to adverse drug reactions in man. These adverse drug reactions cause a broad range of clinically severe conditions including both highly reproducible and dose dependent toxicities as well as relatively infrequent and idiosyncratic adverse events. The underlying risk factors can be split into two groups: (1) drug-related and (2) patient-related. The drug-related risk factors include metabolic factors that determine the propensity of a molecule to form toxic reactive metabolites (RMs), and the RM and non-RM mediated mechanisms which cause cell and tissue injury. Patient related risk factors may vary markedly between individuals, and encompass genetic and non-genetic processes, e.g. environmental, that influence the disposition of drugs and their metabolites, the nature of the adverse responses elicited and the resulting biological consequences. We describe a new strategy, which builds upon the strategies used currently within numerous pharmaceutical companies to avoid and minimize RM formation during drug discovery, and that is intended to reduce the likelihood that candidate drugs will cause toxicity in the human population. The new strategy addresses drug-related safety hazards, but not patient-related risk factors. A common target organ of toxicity is the liver and to decrease the likelihood that candidate drugs will cause liver toxicity (both non-idiosyncratic and idiosyncratic), we propose use of an in vitro Hepatic Liability Panel alongside in vitro methods for the detection of RMs. This will enable design and selection of compounds in discovery that have reduced propensity to cause liver toxicity. In vitro Hepatic Liability is assessed using toxicity assays that quantify: CYP 450 dependent and CYP 450 independent cell toxicity; mitochondrial impairment; and inhibition of the Bile Salt Export Pump. Prior to progression

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

    PubMed

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

    2011-06-30

    Drug toxicity is a leading cause of attrition of candidate drugs during drug development as well as of withdrawal of drugs post-licensing due to adverse drug reactions in man. These adverse drug reactions cause a broad range of clinically severe conditions including both highly reproducible and dose dependent toxicities as well as relatively infrequent and idiosyncratic adverse events. The underlying risk factors can be split into two groups: (1) drug-related and (2) patient-related. The drug-related risk factors include metabolic factors that determine the propensity of a molecule to form toxic reactive metabolites (RMs), and the RM and non-RM mediated mechanisms which cause cell and tissue injury. Patient related risk factors may vary markedly between individuals, and encompass genetic and non-genetic processes, e.g. environmental, that influence the disposition of drugs and their metabolites, the nature of the adverse responses elicited and the resulting biological consequences. We describe a new strategy, which builds upon the strategies used currently within numerous pharmaceutical companies to avoid and minimize RM formation during drug discovery, and that is intended to reduce the likelihood that candidate drugs will cause toxicity in the human population. The new strategy addresses drug-related safety hazards, but not patient-related risk factors. A common target organ of toxicity is the liver and to decrease the likelihood that candidate drugs will cause liver toxicity (both non-idiosyncratic and idiosyncratic), we propose use of an in vitro Hepatic Liability Panel alongside in vitro methods for the detection of RMs. This will enable design and selection of compounds in discovery that have reduced propensity to cause liver toxicity. In vitro Hepatic Liability is assessed using toxicity assays that quantify: CYP 450 dependent and CYP 450 independent cell toxicity; mitochondrial impairment; and inhibition of the Bile Salt Export Pump. Prior to progression

  14. Biometrical issues in the analysis of adverse events within the benefit assessment of drugs.

    PubMed

    Bender, Ralf; Beckmann, Lars; Lange, Stefan

    2016-07-01

    The analysis of adverse events plays an important role in the benefit assessment of drugs. Consequently, results on adverse events are an integral part of reimbursement dossiers submitted by pharmaceutical companies to health policy decision-makers. Methods applied in the analysis of adverse events commonly include simple standard methods for contingency tables. However, the results produced may be misleading if observations are censored at the time of discontinuation due to treatment switching or noncompliance, resulting in unequal follow-up periods. In this paper, we present examples to show that the application of inadequate methods for the analysis of adverse events in the reimbursement dossier can lead to a downgrading of the evidence on a drug's benefit in the subsequent assessment, as greater harm from the drug cannot be excluded with sufficient certainty. Legal regulations on the benefit assessment of drugs in Germany are presented, in particular, with regard to the analysis of adverse events. Differences in safety considerations between the drug approval process and the benefit assessment are discussed. We show that the naive application of simple proportions in reimbursement dossiers frequently leads to uninterpretable results if observations are censored and the average follow-up periods differ between treatment groups. Likewise, the application of incidence rates may be misleading in the case of recurrent events and unequal follow-up periods. To allow for an appropriate benefit assessment of drugs, adequate survival time methods accounting for time dependencies and duration of follow-up are required, not only for time-to-event efficacy endpoints but also for adverse events. © 2016 The Authors. Pharmaceutical Statistics published by John Wiley & Sons Ltd.

  15. 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

  16. 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

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

    PubMed Central

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

    2013-01-01

    Objective Inventory Drug-Taking Situations (IDTS) is a universal instrument used to determine high-risk situations resulting in drug abuse. The aim of this study was to translate this questionnaire to Farsi, and to assess its validity and reliability by applying it to Iranian drug users. Methods As a psychometric study, 300 drug users participated in a treatment program in National Center of Addiction Studies filled in a version of Inventory of Drug Taking Situations. We assessed face and content validity, internal consistency, and reliability based on the completed questionnaires, using test-retest method and confirmatory factor analysis. Results Internal consistency analysis confirmed that all subscales of IDTS were reliable (Cronbach alpha was ranging from 0.7 to 0.81). Analyses indicated that each of the subscales was unifactorial; however, unpleasant emotions had a second eigenvalue that was nearly large enough to be a second factor. Confirmatory factor analysis was used to test the fit of the data to the original version of IDTS. Based on goodness of fit indices, we found that all factors were fitted (χ2/df = 1.43, GFI = 0.98, RMSEA = 0.038). The test-retest reliability was satisfactory(r > 0.6). Conclusion The Farsi version of Inventory of Drug Taking Situations was shown to be a valid and reliable instrument to apply in clinical and research settings in Iran. PMID:24130606

  18. 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

  19. Assessing magnitude probability distribution through physics-based rupture scenarios

    NASA Astrophysics Data System (ADS)

    Hok, Sébastien; Durand, Virginie; Bernard, Pascal; Scotti, Oona

    2016-04-01

    When faced with complex network of faults in a seismic hazard assessment study, the first question raised is to what extent the fault network is connected and what is the probability that an earthquake ruptures simultaneously a series of neighboring segments. Physics-based dynamic rupture models can provide useful insight as to which rupture scenario is most probable, provided that an exhaustive exploration of the variability of the input parameters necessary for the dynamic rupture modeling is accounted for. Given the random nature of some parameters (e.g. hypocenter location) and the limitation of our knowledge, we used a logic-tree approach in order to build the different scenarios and to be able to associate them with a probability. The methodology is applied to the three main faults located along the southern coast of the West Corinth rift. Our logic tree takes into account different hypothesis for: fault geometry, location of hypocenter, seismic cycle position, and fracture energy on the fault plane. The variability of these parameters is discussed, and the different values tested are weighted accordingly. 64 scenarios resulting from 64 parameter combinations were included. Sensitivity studies were done to illustrate which parameters control the variability of the results. Given the weight of the input parameters, we evaluated the probability to obtain a full network break to be 15 %, while single segment rupture represents 50 % of the scenarios. These rupture scenario probability distribution along the three faults of the West Corinth rift fault network can then be used as input to a seismic hazard calculation.

  20. 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...

  1. 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

  2. [Counterfeit drugs in Israel and worldwide. Part II: distribution profile and anti-counterfeiting strategies and actions].

    PubMed

    Furman-Assaf, Sharon; Tamir, Orly; Marom, Eli; Arieli, Mickey; Shemer, Joshua

    2010-07-01

    Counterfeit drugs are a major threat to public health and safety around the world. This review describes the various distribution methods and channels of counterfeit drugs, including the growing use of the internet. National, regional and international efforts to confront this problem are presented, as well as a wide range of technologies that may assist in detection and enforcement. Finally, the Israeli perspective and actions are illustrated.

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

    PubMed Central

    Pettus, Kevin; Sharpe, Samera

    2015-01-01

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

  4. Rapid assessment of drug consumption at Santa Cruz de la Sierra, Bolivia.

    PubMed

    Caris, L; Suarez, R; Covarrubias, G; Fernández, E; Roca, E

    1996-01-01

    The present paper describes a rapid assessment carried out in 1996 at Santa Cruz de la Sierra, Bolivia, with a view to defining the sociocultural groups at risk and gaining insight, through the comments of those interviewed, into their perceptions of the phenomenon of drug abuse, their reasons for abusing drugs, the drugs most frequently abused and the psychological and social factors involved when they enter, remain in and finally leave drug-abusing circles. By using qualitative methodology and techniques it was possible to gain access to the typical world inhabited by the interviewees, and thus to characterize the subjects of the study in the light of their closest social reference points (family, peer group, education and work). Among the conclusions of the study are the following: drug abuse is a complex and dynamic phenomenon that has occurred throughout the society of Santa Cruz, fostered by cultural and economic factors; there is a need for society, and especially the Government, to devise a specific, focused and diversified range of services, both in prevention and in rehabilitation, with integration and participation being key features of such initiatives; and the mechanisms for controlling the production of drugs and drug trafficking need to be strengthened. PMID:9839039

  5. Raman mapping for kinetic analysis of crystallization of amorphous drug based on distributional images.

    PubMed

    Ueda, Hiroshi; Ida, Yasuo; Kadota, Kazunori; Tozuka, Yuichi

    2014-02-28

    The feasibility of Raman mapping for understanding the crystallization mechanism of an amorphous drug was investigated using described images. The crystallization tendency of amorphous indomethacin under dry condition at 30 °C was kinetically evaluated by means of Raman mapping and X-ray powder diffraction (XRPD) with change in the calculated crystallinities. Raman images directly revealed the occurrence of particle size-dependent non-uniform crystallization; slow crystallization of large particles, but fast crystallization of small particles. Kinetic analysis by fitting to the Kolmogorov-Johnson-Mehl-Avrami equation was performed for the crystallization profiles of both Raman mapping and XRPD data. For the Raman mapping data, the distribution of large particles was characterized and examined. The kinetic parameters calculated from the whole Raman image area agreed well with those of XRPD, suggesting accurate prediction of both techniques for the entire crystallization. Raman images revealed the change in the crystallization mechanism for the focused area; the large particles showed a reduced crystallization rate constant and an increase in the dimensional crystal growth exponent. Raman mapping is an attractive tool for quantitative and kinetic investigation of the crystallization mechanism with distributional images.

  6. Challenges and advances in the assessment of the disposition of antibody‐drug conjugates

    PubMed Central

    Iyer, Suhasini

    2015-01-01

    Abstract Antibody‐drug conjugates (ADCs) are a rapidly growing therapeutic platform for the treatment of cancer. ADCs consist of a cytotoxic small molecule drug linked to an antibody to provide targeted delivery of the cytotoxic agent to the tumor. Understanding the pharmacokinetics (PK) and pharmacodynamics (PD) of ADCs is crucial in their design to optimize dose and regimen, to maximize efficacy and to minimize toxicity in patients. Significant progress has been made in recent years in this area, however, many fundamental questions still remain. This review discusses factors to consider while assessing the disposition of ADCs, and the unique challenges associated with these therapeutics. Current tools that are available and strategies to enable appropriate assessment are also discussed. © 2015 Genentech Inc. Biopharmaceutics & Drug Disposition Published by John Wiley & Sons Ltd. PMID:25904406

  7. 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

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

    ERIC Educational Resources Information Center

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

    1997-01-01

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

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

    ERIC Educational Resources Information Center

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

    1995-01-01

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

  10. 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...

  11. [The use of saliva for exposure assessments on designer drugs among adolescents].

    PubMed

    Napierała, Marta; Tezyk, Artur; Piznal, Małgorzata; Bogusiewicz, Joanna; Florek, Ewa

    2015-01-01

    Drug use is one of the fundamental problems of the contemporary world. Due to the debilitating effects on physical and mental health and the possibility of impaired social functions, it is extremely important to assess exposure to psychoactive substances among high-risk groups. Taking into account characteristics of adolescence, one of them includes young people. To assess the exposure of young people to drugs, survey research is the most commonly use. To establish reliability of the information indicated by the students, toxicological studies could be a good manner. High-performance liquid chromatography coupled with mass spectrometry (LC-MS) is currently one of the most common techniques use for the detection and determination of psychoactive substances in biological material. In practice, an important issue in toxicological studies is the selection of a suitable biological material. Taking into account economic considerations and the method of sampling, the saliva is an increasingly used alternative material. The aim of this study was to assess the exposure of junior high school students on psychoactive substances--designer drugs, through the analysis of surveys and qualitative analysis of saliva taken from teenagers. It has been shown that surveys are a relatively quick and easy form of assessing the exposure of young people to psychoactive substances, but require verification through toxicological analysis of biological material for the presence of psychoactive substances for their reliability. Poznan secondary school students experimented with designer drugs at a similar level as respondents of nationwide survey from 2013. PMID:26946561

  12. 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…

  13. 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…

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

    PubMed

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

    2014-09-01

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

  15. On assessing model fit for distribution-free longitudinal models under missing data.

    PubMed

    Wu, P; Tu, X M; Kowalski, J

    2014-01-15

    The generalized estimating equation (GEE), a distribution-free, or semi-parametric, approach for modeling longitudinal data, is used in a wide range of behavioral, psychotherapy, pharmaceutical drug safety, and healthcare-related research studies. Most popular methods for assessing model fit are based on the likelihood function for parametric models, rendering them inappropriate for distribution-free GEE. One rare exception is a score statistic initially proposed by Tsiatis for logistic regression (1980) and later extended by Barnhart and Willamson to GEE (1998). Because GEE only provides valid inference under the missing completely at random assumption and missing values arising in most longitudinal studies do not follow such a restricted mechanism, this GEE-based score test has very limited applications in practice. We propose extensions of this goodness-of-fit test to address missing data under the missing at random assumption, a more realistic model that applies to most studies in practice. We examine the performance of the proposed tests using simulated data and demonstrate the utilities of such tests with data from a real study on geriatric depression and associated medical comorbidities. PMID:23897653

  16. 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...

  17. 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

  18. 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

  19. 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.

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

    PubMed

    Vicknasingam, B; Navaratnam, V

    2008-02-01

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

  1. Assessment of Rainfall-induced Landslide Potential and Spatial Distribution

    NASA Astrophysics Data System (ADS)

    Chen, Yie-Ruey; Tsai, Kuang-Jung; Chen, Jing-Wen; Chiang, Jie-Lun; Hsieh, Shun-Chieh; Chue, Yung-Sheng

    2016-04-01

    Recently, due to the global climate change, most of the time the rainfall in Taiwan is of short duration but with high intensity. Due to Taiwan's steep terrain, rainfall-induced landslides often occur and lead to human causalities and properties loss. Taiwan's government has invested huge reconstruction funds to the affected areas. However, after rehabilitation they still face the risk of secondary sediment disasters. Therefore, this study assesses rainfall-induced (secondary) landslide potential and spatial distribution in watershed of Southern Taiwan under extreme climate change. The study areas in this research are Baolai and Jianshan villages in the watershed of the Laonongxi River Basin in the Southern Taiwan. This study focused on the 3 years after Typhoon Morakot (2009 to 2011). During this period, the study area experienced six heavy rainfall events including five typhoons and one heavy rainfall. The genetic adaptive neural network, texture analysis and GIS were implemented in the analysis techniques for the interpretation of satellite images and to obtain surface information and hazard log data and to analyze land use change. A multivariate hazards evaluation method was applied to quantitatively analyze the weights of various natural environmental and slope development hazard factors. Furthermore, this study established a slope landslide potential assessment model and depicted a slope landslide potential diagram by using the GIS platform. The interaction between (secondary) landslide mechanism, scale, and location was analyzed using association analysis of landslide historical data and regional environmental characteristics. The results of image classification before and after six heavy rainfall events show that the values of coefficient of agreement are at medium-high level. By multivariate hazards evaluation method, geology and the effective accumulative rainfall (EAR) are the most important factors. Slope, distance from fault, aspect, land disturbance

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

    PubMed

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

    2016-01-01

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

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

    PubMed

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

    2013-01-01

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

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

    PubMed

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

    2016-04-01

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

  5. Biomarker-based drug safety assessment in the age of systems pharmacology: from foundational to regulatory science.

    PubMed

    Zhang, Chen; Hong, Huixiao; Mendrick, Donna L; Tang, Yun; Cheng, Feixiong

    2015-01-01

    Improved biomarker-based assessment of drug safety is needed in drug discovery and development as well as regulatory evaluation. However, identifying drug safety-related biomarkers such as genes, proteins, miRNA and single-nucleotide polymorphisms remains a big challenge. The advances of 'omics' and computational technologies such as genomics, transcriptomics, metabolomics, proteomics, systems biology, network biology and systems pharmacology enable us to explore drug actions at the organ and organismal levels. Computational and experimental systems pharmacology approaches could be utilized to facilitate biomarker-based drug safety assessment for drug discovery and development and to inform better regulatory decisions. In this article, we review the current status and advances of systems pharmacology approaches for the development of predictive models to identify biomarkers for drug safety assessment.

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

    PubMed

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

    2016-01-13

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

  7. Target specific delivery of anticancer drug in silk fibroin based 3D distribution model of bone-breast cancer cells.

    PubMed

    Subia, Bano; Dey, Tuli; Sharma, Shaily; Kundu, Subhas C

    2015-02-01

    To avoid the indiscriminating action of anticancer drugs, the cancer cell specific targeting of drug molecule becomes a preferred choice for the treatment. The successful screening of the drug molecules in 2D culture system requires further validation. The failure of target specific drug in animal model raises the issue of creating a platform in between the in vitro (2D) and in vivo animal testing. The metastatic breast cancer cells migrate and settle at different sites such as bone tissue. This work evaluates the in vitro 3D model of the breast cancer and bone cells to understand the cellular interactions in the presence of a targeted anticancer drug delivery system. The silk fibroin based cytocompatible 3D scaffold is used as in vitro 3D distribution model. Human breast adenocarcinoma and osteoblast like cells are cocultured to evaluate the efficiency of doxorubicin loaded folic acid conjugated silk fibroin nanoparticle as drug delivery system. Decreasing population of the cancer cells, which lower the levels of vascular endothelial growth factors, glucose consumption, and lactate production are observed in the drug treated coculture constructs. The drug treated constructs do not show any major impact on bone mineralization. The diminished expression of osteogenic markers such as osteocalcein and alkaline phosphatase are recorded. The result indicates that this type of silk based 3D in vitro coculture model may be utilized as a bridge between the traditional 2D and animal model system to evaluate the new drug molecule (s) or to reassay the known drug molecules or to develop target specific drug in cancer research. PMID:25557227

  8. Target specific delivery of anticancer drug in silk fibroin based 3D distribution model of bone-breast cancer cells.

    PubMed

    Subia, Bano; Dey, Tuli; Sharma, Shaily; Kundu, Subhas C

    2015-02-01

    To avoid the indiscriminating action of anticancer drugs, the cancer cell specific targeting of drug molecule becomes a preferred choice for the treatment. The successful screening of the drug molecules in 2D culture system requires further validation. The failure of target specific drug in animal model raises the issue of creating a platform in between the in vitro (2D) and in vivo animal testing. The metastatic breast cancer cells migrate and settle at different sites such as bone tissue. This work evaluates the in vitro 3D model of the breast cancer and bone cells to understand the cellular interactions in the presence of a targeted anticancer drug delivery system. The silk fibroin based cytocompatible 3D scaffold is used as in vitro 3D distribution model. Human breast adenocarcinoma and osteoblast like cells are cocultured to evaluate the efficiency of doxorubicin loaded folic acid conjugated silk fibroin nanoparticle as drug delivery system. Decreasing population of the cancer cells, which lower the levels of vascular endothelial growth factors, glucose consumption, and lactate production are observed in the drug treated coculture constructs. The drug treated constructs do not show any major impact on bone mineralization. The diminished expression of osteogenic markers such as osteocalcein and alkaline phosphatase are recorded. The result indicates that this type of silk based 3D in vitro coculture model may be utilized as a bridge between the traditional 2D and animal model system to evaluate the new drug molecule (s) or to reassay the known drug molecules or to develop target specific drug in cancer research.

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

    PubMed Central

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

    2010-01-01

    In this paper, we illustrate how advanced computational modelling and simulation can be used to investigate drug-induced effects on cardiac electrophysiology and on specific biomarkers of pro-arrhythmic risk. To do so, we first perform a thorough literature review of proposed arrhythmic risk biomarkers from the ionic to the electrocardiogram levels. The review highlights the variety of proposed biomarkers, the complexity of the mechanisms of drug-induced pro-arrhythmia and the existence of significant animal species differences in drug-induced effects on cardiac electrophysiology. Predicting drug-induced pro-arrhythmic risk solely using experiments is challenging both preclinically and clinically, as attested by the rise in the cost of releasing new compounds to the market. Computational modelling and simulation has significantly contributed to the understanding of cardiac electrophysiology and arrhythmias over the last 40 years. In the second part of this paper, we illustrate how state-of-the-art open source computational modelling and simulation tools can be used to simulate multi-scale effects of drug-induced ion channel block in ventricular electrophysiology at the cellular, tissue and whole ventricular levels for different animal species. We believe that the use of computational modelling and simulation in combination with experimental techniques could be a powerful tool for the assessment of drug safety pharmacology. PMID:20478918

  10. Improving the assessment of heart toxicity for all new drugs through translational regulatory science.

    PubMed

    Johannesen, L; Vicente, J; Gray, R A; Galeotti, L; Loring, Z; Garnett, C E; Florian, J; Ugander, M; Stockbridge, N; Strauss, D G

    2014-05-01

    Fourteen drugs have been removed from the market worldwide because they cause torsade de pointes. Most drugs that cause torsade can be identified by assessing whether they block the human ether à gogo related gene (hERG) potassium channel and prolong the QT interval on the electrocardiogram. In response, regulatory agencies require new drugs to undergo "thorough QT" studies. However, some drugs block hERG potassium channels and prolong QT with minimal torsade risk because they also block calcium and/or sodium channels. Through analysis of clinical and preclinical data from 34 studies submitted to the US Food and Drug Administration and by computer simulations, we demonstrate that by dividing the QT interval into its components of depolarization (QRS), early repolarization (J-Tpeak), and late repolarization (Tpeak-Tend), along with atrioventricular conduction delay (PR), it may be possible to determine which hERG potassium channel blockers also have calcium and/or sodium channel blocking activity. This translational regulatory science approach may enable innovative drugs that otherwise would have been labeled unsafe to come to market.

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

    PubMed Central

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

    2016-01-01

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

  12. 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.

  13. 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.

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

    PubMed

    Huster, W J; Enas, G G

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

  15. 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...

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

    Code of Federal Regulations, 2010 CFR

    2010-01-01

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

  17. 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...

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

    Code of Federal Regulations, 2012 CFR

    2012-01-01

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

  19. 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...

  20. Vulvovaginal candidiasis: species distribution, fluconazole resistance and drug efflux pump gene overexpression.

    PubMed

    Zhang, Jie-Yu; Liu, Jin-Hui; Liu, Fa-Di; Xia, Yan-Hua; Wang, Jing; Liu, Xi; Zhang, Zhi-Qin; Zhu, Na; Yan-Yan; Ying, Ying; Huang, Xiao-Tian

    2014-10-01

    The increasing incidence of vulvovaginal candidiasis (VVC) and the emergence of fluconazole resistance are an indisputable fact. However, little information is available regarding the correlation between fluconazole resistance in vaginal Candida albicans and the expression of drug efflux pump genes. In this study, we investigated the species distribution, fluconazole susceptibility profiles and the mechanisms of fluconazole resistance in Candida strains. In total, 785 clinical Candida isolates were collected from patients with VVC. C. albicans was the most frequently isolated species(n = 529) followed by C. glabrata (n = 164) and C. krusei (n = 57). Of all Candida isolates, 4.7% were resistant to fluconazole. We randomly selected 18 fluconazole resistant isolates of C. albicans to evaluate the expression of CDR1, CDR2, MDR1 and FLU1 genes. Compared with fluconazole-susceptible C. albicans isolates, CDR1 gene expression displayed 3.16-fold relative increase, which was statistically significant. CDR2, MDR1 and FLU1 overexpression was observed in several fluconazole-resistant C. albicans isolates, but statistical significance was not achieved. These results demonstrate a high frequency of non-albicans species (32.6%); however, C. albicans is the most common Candida species implicated in vaginitis, and this strain displays considerable fluconazole resistance. Meanwhile, our study further indicates that fluconazole resistance in C. albicans may correlate with CDR1 gene overexpression.

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

    PubMed

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

    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.

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

    PubMed Central

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

    2015-01-01

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

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

    PubMed

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

    2016-06-01

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

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

    PubMed

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

    2010-10-01

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

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

    PubMed

    Külahci, Fatih; Sen, Zekai

    2009-02-01

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

  6. ASSESSMENT OF PRACTICE AT RETAIL PHARMACIES IN PAKISTAN: EXTENT OF COMPLIANCE WITH THE PREVAILING DRUG LAW OF PAKISTAN.

    PubMed

    Ullah, Hanif; Zada, Wahid; Khan, Muhammad Sona; Iqbal, Muhammad; Chohan, Osaam; Raza, Naeem; Khawaja, Naeem Raza; Abid, Syed Mobasher Ali; Murtazai, Ghulam

    2016-01-01

    The main objective of this study was to assess the practice at retail pharmacies in Pakistan and to compare the same in rural and urban areas. The maintenance of pharmacy and drug inspectors' visit was also assessed. This cross sectional study was conducted in Abbottabad, Pakistan during October-November, 2012. A sample of 215 drug sellers or drug stores was selected by employing convenient sampling method. With a response rate of 91.6%, 197 drug sellers participated in this study. All the drug sellers were male. Overall, 35% (n = 197) of the drug sellers did not have any professional qualification. A majority of the drug sellers were involved in various malpractices like selling of medicines without prescription (80.7%), prescribing practice (60.9%), prescription intervention (62.4%) and selling of controlled substances (66%) without a license for selling it. These malpractices were significantly higher in rural area than that in urban area. PMID:27476300

  7. ASSESSMENT OF PRACTICE AT RETAIL PHARMACIES IN PAKISTAN: EXTENT OF COMPLIANCE WITH THE PREVAILING DRUG LAW OF PAKISTAN.

    PubMed

    Ullah, Hanif; Zada, Wahid; Khan, Muhammad Sona; Iqbal, Muhammad; Chohan, Osaam; Raza, Naeem; Khawaja, Naeem Raza; Abid, Syed Mobasher Ali; Murtazai, Ghulam

    2016-01-01

    The main objective of this study was to assess the practice at retail pharmacies in Pakistan and to compare the same in rural and urban areas. The maintenance of pharmacy and drug inspectors' visit was also assessed. This cross sectional study was conducted in Abbottabad, Pakistan during October-November, 2012. A sample of 215 drug sellers or drug stores was selected by employing convenient sampling method. With a response rate of 91.6%, 197 drug sellers participated in this study. All the drug sellers were male. Overall, 35% (n = 197) of the drug sellers did not have any professional qualification. A majority of the drug sellers were involved in various malpractices like selling of medicines without prescription (80.7%), prescribing practice (60.9%), prescription intervention (62.4%) and selling of controlled substances (66%) without a license for selling it. These malpractices were significantly higher in rural area than that in urban area.

  8. Adverse Outcome Pathways as Tools to Assess Drug-Induced Toxicity.

    PubMed

    Vinken, Mathieu

    2016-01-01

    Adverse outcome pathways (AOPs) are novel tools in toxicology and human risk assessment with broad potential. AOPs are designed to provide a clear-cut mechanistic representation of toxicological effects that span over different layers of biological organization. AOPs share a common structure consisting of a molecular initiating event, a series of key events connected by key event relationships, and an adverse outcome. Development and evaluation of AOPs ideally complies with guidelines issued by the Organization for Economic Cooperation and Development. AOP frameworks have yet been proposed for major types of drug-induced injury, especially in the liver, including steatosis, fibrosis, and cholestasis. These newly postulated AOPs can serve a number of purposes pertinent to safety assessment of drugs, in particular the establishment of quantitative structure-activity relationships, the development of novel in vitro toxicity screening tests, and the elaboration of prioritization strategies. PMID:27311472

  9. 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

  10. 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

  11. 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

  12. A Platform for Rapid, Quantitative Assessment of Multiple Drug Combinations Simultaneously in Solid Tumors In Vivo

    PubMed Central

    Grenley, Marc O.; Casalini, Joseph R.; Tretyak, Ilona; Ditzler, Sally H.; Thirstrup, Derek J.; Frazier, Jason P.; Pierce, Daniel W.; Carleton, Michael; Klinghoffer, Richard A.

    2016-01-01

    While advances in high-throughput screening have resulted in increased ability to identify synergistic anti-cancer drug combinations, validation of drug synergy in the in vivo setting and prioritization of combinations for clinical development remain low-throughput and resource intensive. Furthermore, there is currently no viable method for prospectively assessing drug synergy directly in human patients in order to potentially tailor therapies. To address these issues we have employed the previously described CIVO platform and developed a quantitative approach for investigating multiple combination hypotheses simultaneously in single living tumors. This platform provides a rapid, quantitative and cost effective approach to compare and prioritize drug combinations based on evidence of synergistic tumor cell killing in the live tumor context. Using a gemcitabine resistant model of pancreatic cancer, we efficiently investigated nine rationally selected Abraxane-based combinations employing only 19 xenografted mice. Among the drugs tested, the BCL2/BCLxL inhibitor ABT-263 was identified as the one agent that synergized with Abraxane® to enhance acute induction of localized apoptosis in this model of human pancreatic cancer. Importantly, results obtained with CIVO accurately predicted the outcome of systemic dosing studies in the same model where superior tumor regression induced by the Abraxane/ABT-263 combination was observed compared to that induced by either single agent. This supports expanded use of CIVO as an in vivo platform for expedited in vivo drug combination validation and sets the stage for performing toxicity-sparing drug combination studies directly in cancer patients with solid malignancies. PMID:27359113

  13. Assessment of Potential Herb-Drug Interactions among Nigerian Adults with Type-2 Diabetes.

    PubMed

    Ezuruike, Udoamaka; Prieto, Jose M

    2016-01-01

    It is becoming increasingly evident that patients with diabetes do not rely only on prescription drugs for their disease management. The use of herbal medicines is one of the self-management practices adopted by these patients, often without the knowledge of their healthcare practitioners. This study assessed the potential for pharmacokinetic herb-drug interactions (HDIs) amongst Nigerian adult diabetic patients. This was done through a literature analysis of the pharmacokinetic profile of their herbal medicines and prescription drugs, based on information obtained from 112 patients with type-2 diabetes attending two secondary health care facilities in Nigeria. Fifty percent of the informants used herbal medicines alongside their prescription drugs. Worryingly, 60% of the patients taking herbal medicines did not know their identity, thus increasing the risk of unidentified HDIs. By comparing the pharmacokinetic profile of eight identified herbs taken by the patients for the management of diabetes against those of the prescription drugs, several scenarios of potential HDIs were identified and their clinical relevance is discussed. The lack of clinical predictors points toward cultural factors as the influence for herb use, making it more difficult to identify these patients and in turn monitor potential HDIs. In identifying these possible interactions, we have highlighted the need for healthcare professionals to promote a proactive monitoring of patients' use of herbal medicines. PMID:27559312

  14. Assessment of Potential Herb-Drug Interactions among Nigerian Adults with Type-2 Diabetes

    PubMed Central

    Ezuruike, Udoamaka; Prieto, Jose M.

    2016-01-01

    It is becoming increasingly evident that patients with diabetes do not rely only on prescription drugs for their disease management. The use of herbal medicines is one of the self-management practices adopted by these patients, often without the knowledge of their healthcare practitioners. This study assessed the potential for pharmacokinetic herb-drug interactions (HDIs) amongst Nigerian adult diabetic patients. This was done through a literature analysis of the pharmacokinetic profile of their herbal medicines and prescription drugs, based on information obtained from 112 patients with type-2 diabetes attending two secondary health care facilities in Nigeria. Fifty percent of the informants used herbal medicines alongside their prescription drugs. Worryingly, 60% of the patients taking herbal medicines did not know their identity, thus increasing the risk of unidentified HDIs. By comparing the pharmacokinetic profile of eight identified herbs taken by the patients for the management of diabetes against those of the prescription drugs, several scenarios of potential HDIs were identified and their clinical relevance is discussed. The lack of clinical predictors points toward cultural factors as the influence for herb use, making it more difficult to identify these patients and in turn monitor potential HDIs. In identifying these possible interactions, we have highlighted the need for healthcare professionals to promote a proactive monitoring of patients' use of herbal medicines. PMID:27559312

  15. Using Group Projects to Assess the Learning of Sampling Distributions

    ERIC Educational Resources Information Center

    Neidigh, Robert O.; Dunkelberger, Jake

    2012-01-01

    In an introductory business statistics course, student groups used sample data to compare a set of sample means to the theoretical sampling distribution. Each group was given a production measurement with a population mean and standard deviation. The groups were also provided an excel spreadsheet with 40 sample measurements per week for 52 weeks…

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

    PubMed Central

    Leurent, C

    2015-01-01

    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

  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 Central

    2010-01-01

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

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

    NASA Astrophysics Data System (ADS)

    Yilmaz, Şeyda; Bayrak, Erdem; Bayrak, Yusuf

    2016-04-01

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

  19. 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.

  20. 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.

  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 mPa·s), chlorpheniramine maleate (CPM) as a model and fumed silicon dioxide (Aerosil(®) 200) was prepared via direct compression. The distribution of atoms and HPMC imaging were characterized using scanning electron microscope (SEM)/ energy-dispersive X-ray spectroscopy (EDX), and near-infrared (NIR) analysis, respectively as a function of time. A texture analyzer was also used to characterize the thickness and maintenance of gel layer of HPMC matrix tablet. The HPMC matrix tablets showed Higuchi release kinetics with no lag time against the square root of time. High viscosity grades of HPMC gave retarded release rate because of the greater swelling and gel thickness as characterized by texture analyzer. According to the NIR imaging, low-viscosity-grade HPMC (6 mPa·s) quickly leached out onto the surface of the tablet, while the high-viscosity-grade HPMC (4000 mPa·s) formed much thicker gel layer around the tablet and maintained longer via slow erosion, resulting in retarded drug release. The atomic distribution of the drug (chlorine, carbon, oxygen), HPMC (carbon, oxygen) and silicon dioxide (silica, oxygen) and NIR imaging of HPMC corresponded with the dissolution behaviors of drug as a function of time. The use of imaging and texture analyses could be applicable to explain the release- modulating mechanism of hydrophilic HPMC matrix tablets. PMID:23855499

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

    PubMed

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

    2013-12-01

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

  3. 7 CFR 1230.72 - Distribution of assessments.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... AGREEMENTS AND ORDERS; MISCELLANEOUS COMMODITIES), DEPARTMENT OF AGRICULTURE PORK PROMOTION, RESEARCH, AND CONSUMER INFORMATION Pork Promotion, Research, and Consumer Information Order Expenses and Assessments...) A State association which was conducting a pork promotion program in the period from July 1, 1984...

  4. 7 CFR 1230.72 - Distribution of assessments.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... AGREEMENTS AND ORDERS; MISCELLANEOUS COMMODITIES), DEPARTMENT OF AGRICULTURE PORK PROMOTION, RESEARCH, AND CONSUMER INFORMATION Pork Promotion, Research, and Consumer Information Order Expenses and Assessments...) A State association which was conducting a pork promotion program in the period from July 1, 1984...

  5. 7 CFR 1230.72 - Distribution of assessments.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... AGREEMENTS AND ORDERS; MISCELLANEOUS COMMODITIES), DEPARTMENT OF AGRICULTURE PORK PROMOTION, RESEARCH, AND CONSUMER INFORMATION Pork Promotion, Research, and Consumer Information Order Expenses and Assessments...) A State association which was conducting a pork promotion program in the period from July 1, 1984...

  6. 7 CFR 1230.72 - Distribution of assessments.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... AGREEMENTS AND ORDERS; MISCELLANEOUS COMMODITIES), DEPARTMENT OF AGRICULTURE PORK PROMOTION, RESEARCH, AND CONSUMER INFORMATION Pork Promotion, Research, and Consumer Information Order Expenses and Assessments...) A State association which was conducting a pork promotion program in the period from July 1, 1984...

  7. 7 CFR 1230.72 - Distribution of assessments.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... AGREEMENTS AND ORDERS; MISCELLANEOUS COMMODITIES), DEPARTMENT OF AGRICULTURE PORK PROMOTION, RESEARCH, AND CONSUMER INFORMATION Pork Promotion, Research, and Consumer Information Order Expenses and Assessments...) A State association which was conducting a pork promotion program in the period from July 1, 1984...

  8. 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...

  9. 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.

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

    NASA Astrophysics Data System (ADS)

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

    1982-11-01

    The installation of distributed solar-power systems presents electric utilities with a host of questions. Some of the technical and economic impacts of these systems are discussed. Among the technical interconnect issues are isolated operation, power quality, line safety, and metering options. Economic issues include user purchase criteria, structures and installation costs, marketing and product distribution costs, and interconnect costs. An interactive computer program that allows easy calculation of allowable system prices and allowable generation-equipment prices was developed as part of this project. It is concluded that the technical problems raised by distributed solar systems are surmountable, but their resolution may be costly. The stringent purchase criteria likely to be imposed by many potential system users and the economies of large-scale systems make small systems (less than 10 to 20 kW) less attractive than larger systems. Utilities that consider life-cycle costs in making investment decisions and third-party investors who have tax and financial advantages are likely to place the highest value on solar-power systems.

  11. Analysis of Diffusion-Controlled Dissolution from Polydisperse Collections of Drug Particles with an Assessed Mathematical Model.

    PubMed

    Wang, Yanxing; Abrahamsson, Bertil; Lindfors, Lennart; Brasseur, James G

    2015-09-01

    We introduce a "hierarchical" modeling strategy designed to be systematically extensible to increase the detail of dissolution predictions from polydisperse collections of drug particles and to be placed on firm mathematical and physical foundations with diffusion-dominated dissolution at its core to predict dissolution and the evolution of particle size distribution. We assess the model with experimental data and demonstrate higher accuracy by treating the polydisperse nature of dissolution. A level in the hierarchy is applied to study elements of diffusion-driven dissolution, in particular the role of particle-size distribution width with varying dose level and the influences of "confinement" on the process of dissolution. Confinement influences surface molecular flux, directly by the increase in bulk concentration and indirectly by the relative volume of particles to container. We find that the dissolution process can be broadly categorized within three "regimes" defined by the ratio of total concentration Ctot to solubility CS . Sink conditions apply in the first regime, when C tot /CS<∼0.1. When C tot /CS>∼5 (regime 3) dissolution is dominated by confinement and normalized saturation time follows a simple power law relationship. Regime 2 is characterized by a "saturation singularity" where dissolution is sensitive to both initial particle size distribution and confinement. PMID:25989144

  12. Analysis of Diffusion-Controlled Dissolution from Polydisperse Collections of Drug Particles with an Assessed Mathematical Model.

    PubMed

    Wang, Yanxing; Abrahamsson, Bertil; Lindfors, Lennart; Brasseur, James G

    2015-09-01

    We introduce a "hierarchical" modeling strategy designed to be systematically extensible to increase the detail of dissolution predictions from polydisperse collections of drug particles and to be placed on firm mathematical and physical foundations with diffusion-dominated dissolution at its core to predict dissolution and the evolution of particle size distribution. We assess the model with experimental data and demonstrate higher accuracy by treating the polydisperse nature of dissolution. A level in the hierarchy is applied to study elements of diffusion-driven dissolution, in particular the role of particle-size distribution width with varying dose level and the influences of "confinement" on the process of dissolution. Confinement influences surface molecular flux, directly by the increase in bulk concentration and indirectly by the relative volume of particles to container. We find that the dissolution process can be broadly categorized within three "regimes" defined by the ratio of total concentration Ctot to solubility CS . Sink conditions apply in the first regime, when C tot /CS<∼0.1. When C tot /CS>∼5 (regime 3) dissolution is dominated by confinement and normalized saturation time follows a simple power law relationship. Regime 2 is characterized by a "saturation singularity" where dissolution is sensitive to both initial particle size distribution and confinement.

  13. 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.

  14. A pharmacy too far? Equity and spatial distribution of outcomes in the delivery of subsidized artemisinin-based combination therapies through private drug shops

    PubMed Central

    2010-01-01

    Background Millions of individuals with malaria-like fevers purchase drugs from private retailers, but artemisinin-based combination therapies (ACTs), the only effective treatment in regions with high levels of resistance to older drugs, are rarely obtained through these outlets due to their relatively high cost. To encourage scale up of ACTs, the Affordable Medicines Facility – malaria is being launched to subsidize their price. The Government of Tanzania and the Clinton Foundation piloted this subsidized distribution model in two Tanzanian districts to examine concerns about whether the intervention will successfully reach poor, rural communities. Methods Stocking of ACTs and other antimalarial drugs in all retail shops was observed at baseline and in four subsequent surveys over 15 months. Exit interviews were conducted with antimalarial drug customers during each survey period. All shops and facilities were georeferenced, and variables related to population density and proximity to distribution hubs, roads, and other facilities were calculated. To understand the equity of impact, shops stocking ACTs and consumers buying them were compared to those that did not, according to geographic and socioeconomic variables. Patterning in ACT stocking and sales was evaluated against that of other common antimalarials to identify factors that may have impacted access. Qualitative data were used to assess motivations underlying stocking, distribution, and buying disparities. Results Results indicated that although total ACT purchases rose from negligible levels to nearly half of total antimalarial sales over the course of the pilot, considerable geographic variation in stocking and sales persisted and was related to a variety of socio-spatial factors; ACTs were stocked more often in shops located closer to district towns (p<0.01) and major roads (p<0.01) and frequented by individuals of higher socioeconomic status (p<0.01). However, other antimalarial drugs displayed

  15. 78 FR 59308 - Antimicrobial Animal Drug Sales and Distribution Annual Summary Report Data Tables

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-09-26

    ... From the Federal Register Online via the Government Publishing Office DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration 21 CFR Part 514 Antimicrobial Animal Drug Sales and... security and confidential business information. In the Federal Register of July 27, 2012 (77 FR 44177),...

  16. 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... CONTAINING BYPRODUCT MATERIAL Exempt Concentrations and Items § 32.21 Radioactive drug: Manufacture... application to, a human being; (5) The carbon-14 urea is in the form of a capsule, identified as...

  17. 10 CFR 32.21 - Radioactive drug: Manufacture, preparation, or transfer for commercial distribution of capsules...

    Code of Federal Regulations, 2011 CFR

    2011-01-01

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

  18. 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... CONTAINING BYPRODUCT MATERIAL Exempt Concentrations and Items § 32.21 Radioactive drug: Manufacture... application to, a human being; (5) The carbon-14 urea is in the form of a capsule, identified as...

  19. 10 CFR 32.21 - Radioactive drug: Manufacture, preparation, or transfer for commercial distribution of capsules...

    Code of Federal Regulations, 2013 CFR

    2013-01-01

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

  20. 77 FR 59156 - Antimicrobial Animal Drug Sales and Distribution Reporting; Extension of Comment Period

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-09-26

    ...The Food and Drug Administration (FDA) is extending the comment period for the advance notice of proposed rulemaking that appeared in the Federal Register of July 27, 2012. In the advance notice of proposed rulemaking, FDA requested comments regarding potential changes to its regulations relating to records and reports for approved antimicrobial new animal drugs. The Agency is taking this......

  1. 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

  2. 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.

  3. 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

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

    PubMed Central

    2011-01-01

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

  5. 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.

  6. 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

  7. The role of validated analytical methods in JECFA drug assessments and evaluation for recommending MRLs.

    PubMed

    Boison, Joe O

    2016-05-01

    The Joint Food and Agriculture Organization and World Health Organization (FAO/WHO) Expert Committee on Food Additives (JECFA) is one of three Codex committees tasked with applying risk analysis and relying on independent scientific advice provided by expert bodies organized by FAO/WHO when developing standards. While not officially part of the Codex Alimentarius Commission structure, JECFA provides independent scientific advice to the Commission and its specialist committees such as the Codex Committee on Residues of Veterinary Drugs in Foods (CCRVDF) in setting maximum residue limits (MRLs) for veterinary drugs. Codex methods of analysis (Types I, II, III, and IV) are defined in the Codex Procedural Manual as are criteria to be used for selecting methods of analysis. However, if a method is to be used under a single laboratory condition to support regulatory work, it must be validated according to an internationally recognized protocol and the use of the method must be embedded in a quality assurance system in compliance with ISO/IEC 17025:2005. This paper examines the attributes of the methods used to generate residue depletion data for drug registration and/or licensing and for supporting regulatory enforcement initiatives that experts consider to be useful and appropriate in their assessment of methods of analysis. Copyright © 2016 Her Majesty the Queen in Right of Canada. Drug Testing and Analysis © 2016 John Wiley & Sons, Ltd. PMID:27443214

  8. Assessments of pharmacokinetic drug interactions and tolerability of albendazole, praziquantel and ivermectin combinations.

    PubMed

    Na-Bangchang, K; Kietinun, S; Pawa, K K; Hanpitakpong, W; Na-Bangchang, C; Lazdins, J

    2006-04-01

    The pharmacokinetic interactions and tolerability of albendazole, praziquantel and ivermectin combinations were assessed in 23 healthy Thai volunteers (12 males and 11 females). The study was an open, randomised, three-way crossover design in which each subject attended the study on three separate occasions (Phases I, II and III), of 4 d or 8 d each, with at least 1 or 2 weeks (but not longer than 2 months) between each phase. All subjects received the three study drug regimens as follows: regimen I, oral praziquantel (40 mg/kg body weight); regimen II, oral ivermectin (200 microg/kg body weight) given concurrently with an oral dose of albendazole (400 mg); and regimen III, oral ivermectin given concurrently with albendazole and praziquantel. All treatment regimens showed acceptable tolerability profiles. The incidence of overall drug-related adverse events was significantly higher following regimens I (12/23) and III (7/23) compared with that following regimen II (0/23). Six statistically significant changes in the pharmacokinetic parameters of albendazole sulphoxide (Cmax, AUC0-infinity, Vz/F, CL/F), praziquantel (Vz/F) and ivermectin (AUC0-infinity) were observed when the three drugs were given concurrently. However, based on US Food and Drug Administration criteria, these changes were not considered of clinical relevance. PMID:16271272

  9. Real-time assessment of alcohol drinking and drug use in opioid-dependent polydrug users.

    PubMed

    Preston, Kenzie L; Jobes, Michelle L; Phillips, Karran A; Epstein, David H

    2016-10-01

    We investigated relationships between drinking, other drug use, and drug craving, using ecological momentary assessment (EMA), in a sample of polydrug users who were not heavy drinkers. In a prospective longitudinal cohort study, 114 heroin and cocaine users on methadone-maintenance treatment carried handheld electronic diaries during waking hours and were screened for drug and alcohol use for up to 25 weeks. Individuals who fulfilled the Diagnostic and Statistical Manual of Mental Disorders criteria for alcohol abuse or dependence were excluded. Participants responded to 2-5 random prompts per day to report on their moods, cravings, and activities and initiated entries when they used or acutely craved heroin or cocaine. Drinking alcohol was assessed in both types of entries. Breath alcohol was measured three times weekly. Participants reported drinking alcohol in 1.6% of random-prompt entries, 3.7% of event-contingent entries when craving cocaine and/or heroin, and 11.6% of event-contingent entries when using cocaine and/or heroin. Alcohol drinking was also associated with higher craving ratings and prestudy alcohol use. More drinking was detected by ambulatory self-report than by in-clinic breath testing. Even though we had screened out heavy drinkers from our sample of polydrug users, drinking was associated with heroin and cocaine craving and actual use. PMID:27579810

  10. Urinary metabolites to assess in vivo ontogeny of hepatic drug metabolism in early neonatal life.

    PubMed

    Allegaert, K; Verbesselt, R; Rayyan, M; Debeer, A; de Hoon, J

    2007-05-01

    In addition to size-dependent allometric metabolic activity, most isoenzymes display age-dependent isoenzyme-specific ontogeny. We therefore need probe drugs to describe isoenzyme-specific ontogeny to develop more sophisticated, physiologically based models. We illustrate the feasibility and the relevance of in vivo assessment of hepatic metabolism, based on observations on urinary elimination of paracetamol and tramadol metabolites in neonates. On the basis of the observations on tramadol disposition, we were able to document that O-demethylation phenotypic activity developed sooner when compared with N-demethylation. During repeated administration of intravenous paracetamol, it was documented that, in addition to postmenstrual and postnatal age (PNA), repeated administration also contributed to the urinary excretion of glucuronidated paracetamol. In both probe drugs evaluated, age only in part explained the interindividual variability observed. Urine metabolites to assess in vivo metabolism of drugs routinely administered in neonates likely increase both the feasibility and clinical relevance of studies on in vivo isoenzyme-specific ontogeny in neonates. PMID:17609736

  11. Assessment of quantitative imaging of contaminant distributions in porous media

    NASA Astrophysics Data System (ADS)

    Catania, F.; Massabò, M.; Valle, M.; Bracco, G.; Paladino, O.

    2008-01-01

    In this article an experimental setup designed to assist in the characterization of complex solute transport problems in porous media is described. Glass beads representing the medium are confined in a 2-D transparent Perspex box and a water flow transports a fluorescent dye. Under suitable illumination, the dye emits visible light which is collected by a CCD camera. The image acquired by this non-invasive optical technique is processed to estimate the 2-dimensional distribution of tracer concentrations by using an appropriate calibration curve that links fluorescent intensity and solute concentration. Details about the dye choice and discussion about photobleaching are reported. An analysis of the experimental error on the concentration profile is also presented. A few recent results of a study on contaminant plume within a homogenous porous matrix constituted by glass beads having mean diameter of 1 mm or 2 mm shows the performance of constructed model.

  12. 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…

  13. 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…

  14. 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

  15. Natural flavonoids silymarin and quercetin improve the brain distribution of co-administered P-gp substrate drugs.

    PubMed

    Ravikumar Reddy, D; Khurana, Amit; Bale, Swarna; Ravirala, Ramu; Samba Siva Reddy, V; Mohankumar, M; Godugu, Chandraiah

    2016-01-01

    P-glycoprotein (P-gp), a well known efflux transporter in the blood brain barrier inhibits the uptake of substrate drugs into brain. The main aim of this study is to evaluate the effect of natural product based P-gp inhibitors on brain penetration of various CNS drugs which are P-gp substrates. In this study, we have evaluated the inhibitory effects of natural bioflavonoids (quercetin and silymarin) on P-gp by using digoxin and quinidine as model P-gp model substrate drugs. In vitro inhibitory effects were evaluated in Caco-2 cell lines using digoxin as a model drug and in vivo P-gp inhibiting effect was evaluated in mice model using quinidine as model drug. The accumulation and bidirectional transport of digoxin in Caco-2 cells was determined in presence and absence of quercetin and silymarin. Elacridar was used as standard P-gp inhibitor and used to compare the inhibitory effects of test compounds. The apical to basolateral transport of digoxin was increased where as basolateral to apical transport of digoxin was decreased in concentration dependent manner in the presence of elacridar, quercetin and silymarin. After intravenous administration of P-gp inhibitors, brain levels of quinidine were estimated using LC-MS method. Increased brain uptake was observed with quercetin (2.5-fold) and silymarin (3.5-fold). Though the brain penetration potential of P-gp substrates was lower than that observed in elacridar, both quercetin and silymarin improved plasma quinidine levels. Caco-2 permeability studies and brain uptake indicate that both quercetin and silymarin can inhibit P-gp mediated efflux of drug into brain. Our results suggest that both silymarin and quercetin could potentially increase the brain distribution of co-administered drugs that are P-gp substrates.

  16. Natural flavonoids silymarin and quercetin improve the brain distribution of co-administered P-gp substrate drugs.

    PubMed

    Ravikumar Reddy, D; Khurana, Amit; Bale, Swarna; Ravirala, Ramu; Samba Siva Reddy, V; Mohankumar, M; Godugu, Chandraiah

    2016-01-01

    P-glycoprotein (P-gp), a well known efflux transporter in the blood brain barrier inhibits the uptake of substrate drugs into brain. The main aim of this study is to evaluate the effect of natural product based P-gp inhibitors on brain penetration of various CNS drugs which are P-gp substrates. In this study, we have evaluated the inhibitory effects of natural bioflavonoids (quercetin and silymarin) on P-gp by using digoxin and quinidine as model P-gp model substrate drugs. In vitro inhibitory effects were evaluated in Caco-2 cell lines using digoxin as a model drug and in vivo P-gp inhibiting effect was evaluated in mice model using quinidine as model drug. The accumulation and bidirectional transport of digoxin in Caco-2 cells was determined in presence and absence of quercetin and silymarin. Elacridar was used as standard P-gp inhibitor and used to compare the inhibitory effects of test compounds. The apical to basolateral transport of digoxin was increased where as basolateral to apical transport of digoxin was decreased in concentration dependent manner in the presence of elacridar, quercetin and silymarin. After intravenous administration of P-gp inhibitors, brain levels of quinidine were estimated using LC-MS method. Increased brain uptake was observed with quercetin (2.5-fold) and silymarin (3.5-fold). Though the brain penetration potential of P-gp substrates was lower than that observed in elacridar, both quercetin and silymarin improved plasma quinidine levels. Caco-2 permeability studies and brain uptake indicate that both quercetin and silymarin can inhibit P-gp mediated efflux of drug into brain. Our results suggest that both silymarin and quercetin could potentially increase the brain distribution of co-administered drugs that are P-gp substrates. PMID:27652191

  17. 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

  18. 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...

  19. Monitoring, removal and risk assessment of cytostatic drugs in hospital wastewater.

    PubMed

    Lenz, K; Mahnik, S N; Weissenbacher, N; Mader, R M; Krenn, P; Hann, S; Koellensperger, G; Uhl, M; Knasmüller, S; Ferk, F; Bursch, W; Fuerhacker, M

    2007-01-01

    Cytostatic agents are applied in cancer therapy and subsequently excreted into hospital wastewater. As these substances are known to be carcinogenic, mutagenic and toxic for reproduction, they should be removed from wastewater at their source of origin. In this study the fate and effects of the cancerostatic platinum compounds (CPC) cisplatin, carboplatin, oxaliplatin, 5-fluorouracil (5-FU) and the anthracyclines doxorubicin, daunorubicin and epirubicin were investigated in hospital wastewater. Wastewater from the in-patient treatment ward of a hospital in Vienna was collected and monitored for the occurrence of the selected drugs. A calculation model was established to spot the correlation between administered dosage and measured concentrations. To investigate the fate of the selected substances during wastewater treatment, the oncologic wastewater was treated in a pilot membrane bioreactor system (MBR) and in downstream advanced wastewater treatment processes (adsorption to activated carbon and UV-treatment). Genotoxic effects of the oncologic wastewater were assessed before and after wastewater treatment followed by a risk assessment. Monitoring concentrations of the selected cytostatics in the oncologic wastewater were in line with calculated concentrations. Due to different mechanisms (adsorption, biodegradation) in the MBR-system 5 - FU and the anthracyclines were removed < LOD, whereas CPC were removed by 60%. In parallel, genotoxic effects could be reduced significantly by the MBR-system. The risk for humans, the aquatic and terrestrial environment by hospital wastewater containing cytostatic drugs was classified as small in a preliminary risk assessment.

  20. 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.

  1. A challenge for diagnosing acute liver injury with concomitant/sequential exposure to multiple drugs: can causality assessment scales be utilized to identify the offending drug?

    PubMed

    Lim, Roxanne; Choudry, Hassan; Conner, Kim; Karnsakul, Wikrom

    2014-01-01

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

  2. A criterion for assessing homogeneity distribution in hyperspectral images. Part 1: homogeneity index bases and blending processes.

    PubMed

    Rosas, Juan G; Blanco, Marcelo

    2012-11-01

    The Process Analytical Technologies (PAT) initiative of the US Food and Drug Administration (US FDA) has established a framework for the development of imaging techniques to determine the real-time distribution of mixture components during the production of solid dosage forms. This study, which is the first in a series of two parts, uses existing mixing indices and a new criterion called the "percentage of homogeneity" (H%) to assess image homogeneity. Image analysis techniques use feature extraction procedures to extract information from images subjected to treatments including colour segmentation and binarization. The surface distribution of components was determined by macropixel analysis, which splits an image into non-overlapping blocks of a preset size and calculates several statistical parameters for the resulting divisional structure. Such parameters were used to compute mixing indices. In this work, we explored the potential of image processing in combination with mixing indices and H% for assessing blending end-point and component distribution on images. As a simplified test, an arrangement of binary and ternary systems of coloured particles was mixed collecting at-line multispectral (MSI) and non-invasive RGB pictures at preset intervals. PMID:22818029

  3. A criterion for assessing homogeneity distribution in hyperspectral images. Part 1: homogeneity index bases and blending processes.

    PubMed

    Rosas, Juan G; Blanco, Marcelo

    2012-11-01

    The Process Analytical Technologies (PAT) initiative of the US Food and Drug Administration (US FDA) has established a framework for the development of imaging techniques to determine the real-time distribution of mixture components during the production of solid dosage forms. This study, which is the first in a series of two parts, uses existing mixing indices and a new criterion called the "percentage of homogeneity" (H%) to assess image homogeneity. Image analysis techniques use feature extraction procedures to extract information from images subjected to treatments including colour segmentation and binarization. The surface distribution of components was determined by macropixel analysis, which splits an image into non-overlapping blocks of a preset size and calculates several statistical parameters for the resulting divisional structure. Such parameters were used to compute mixing indices. In this work, we explored the potential of image processing in combination with mixing indices and H% for assessing blending end-point and component distribution on images. As a simplified test, an arrangement of binary and ternary systems of coloured particles was mixed collecting at-line multispectral (MSI) and non-invasive RGB pictures at preset intervals.

  4. Assessment of drug metabolism enzyme and transporter pharmacogenetics in drug discovery and early development: perspectives of the I-PWG.

    PubMed

    Brian, William; Tremaine, Larry M; Arefayene, Million; de Kanter, Ruben; Evers, Raymond; Guo, Yingying; Kalabus, James; Lin, Wen; Loi, Cho-Ming; Xiao, Guangqing

    2016-04-01

    Genetic variants of drug metabolism enzymes and transporters can result in high pharmacokinetic and pharmacodynamic variability, unwanted characteristics of efficacious and safe drugs. Ideally, the contributions of these enzymes and transporters to drug disposition can be predicted from in vitro experiments and in silico modeling in discovery or early development, and then be utilized during clinical development. Recently, regulatory agencies have provided guidance on the preclinical investigation of pharmacogenetics, for application to clinical drug development. This white paper summarizes the results of an industry survey conducted by the Industry Pharmacogenomics Working Group on current practice and challenges with using in vitro systems and in silico models to understand pharmacogenetic causes of variability in drug disposition.

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

    USGS Publications Warehouse

    Olea, R.A.

    2011-01-01

    The triangular distribution is a popular choice when it comes to modeling bounded continuous random variables. Its wide acceptance derives mostly from its simple analytic properties and the ease with which modelers can specify its three parameters through the extremes and the mode. On the negative side, hardly any real process follows a triangular distribution, which from the outset puts at a disadvantage any model employing triangular distributions. At a time when numerical techniques such as the Monte Carlo method are displacing analytic approaches in stochastic resource assessments, easy specification remains the most attractive characteristic of the triangular distribution. The beta distribution is another continuous distribution defined within a finite interval offering wider flexibility in style of variation, thus allowing consideration of models in which the random variables closely follow the observed or expected styles of variation. Despite its more complex definition, generation of values following a beta distribution is as straightforward as generating values following a triangular distribution, leaving the selection of parameters as the main impediment to practically considering beta distributions. This contribution intends to promote the acceptance of the beta distribution by explaining its properties and offering several suggestions to facilitate the specification of its two shape parameters. In general, given the same distributional parameters, use of the beta distributions in stochastic modeling may yield significantly different results, yet better estimates, than the triangular distribution. ?? 2011 International Association for Mathematical Geology (outside the USA).

  6. Effects of Interim Assessments across the Achievement Distribution: Evidence From an Experiment

    ERIC Educational Resources Information Center

    Konstantopoulos, Spyros; Li, Wei; Miller, Shazia R.; van der Ploeg, Arie

    2016-01-01

    We use data from a large-scale experiment conducted in Indiana in 2009-2010 to examine the impact of two interim assessment programs (mCLASS and Acuity) across the mathematics and reading achievement distributions. Specifically, we focus on whether the use of interim assessments has a particularly strong effect on improving outcomes for low…

  7. Biological effect on drug distribution and vascular healing via paclitaxel‐coated balloon technology in drug eluting stent restenosis swine model

    PubMed Central

    Li, Yan; Tellez, Armando; Rousselle, Serge D.; Dillon, Krista N.; Garza, Javier A.; Barry, Chris

    2015-01-01

    Objectives To evaluate the biological effect of a paclitaxel‐coated balloon (PCB) technology on vascular drug distribution and healing in drug eluting stent restenosis (DES‐ISR) swine model. Background The mechanism of action and healing response via PCB technology in DES‐ISR is not completely understood. Methods A total of 27 bare metal stents were implanted in coronary arteries and 30 days later the in‐stent restenosis was treated with PCB. Treated segments were harvested at 1 hr, 14 days and 30 days post treatment for the pharmacokinetic analysis. In addition, 24 DES were implanted in coronary arteries for 30 days, then all DES‐ISRs were treated with either PCB (n = 12) or uncoated balloon (n = 12). At day 60, vessels were harvested for histology following angiography and optical coherence tomography (OCT). Results The paclitaxel level in neointimal tissue was about 18 times higher (P = 0.0004) at 1 hr C max, and retained about five times higher (P = 0.008) at day 60 than that in vessel wall. A homogenous distribution of paclitaxel in ISR was demonstrated by using fluorescently labeled paclitaxel. Notably, in DES‐ISR, both termination OCT and quantitative coronary angioplasty showed a significant neointimal reduction and less late lumen loss (P = 0.05 and P = 0.03, respectively) post PCB versus post uncoated balloon. The PES‐ISR + PCB group displayed higher levels of peri‐strut inflammation and fibrin scores compared to the ‐limus DES‐ISR + PCB group. Conclusions In ISR, paclitaxel is primarily deposited in neointimal tissue and effectively retained over time following PCB use. Despite the presence of metallic struts, a uniform distribution was characterized. PCB demonstrated an equivalent biological effect in DES‐ISR without significantly increasing inflammation. © 2015 Wiley Periodicals, Inc. PMID:26613810

  8. [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

  9. The Use of Transporter Probe Drug Cocktails for the Assessment of Transporter-Based Drug-Drug Interactions in a Clinical Setting-Proposal of a Four Component Transporter Cocktail.

    PubMed

    Ebner, Thomas; Ishiguro, Naoki; Taub, Mitchell E

    2015-09-01

    Probe drug cocktails are used clinically to assess the potential for drug-drug interactions (DDIs), and in particular, DDIs resulting from coadministration of substrates and inhibitors of cytochrome P450 enzymes. However, a probe drug cocktail has not been identified to assess DDIs involving inhibition of drug transporters. We propose a cocktail consisting of the following substrates to explore the potential for DDIs caused by inhibition of key transporters: digoxin (P-glycoprotein, P-gp), rosuvastatin (breast cancer resistance protein, BCRP; organic anion transporting polypeptides, OATP), metformin (organic cation transporter, OCT; multidrug and toxin extrusion transporters, MATE), and furosemide (organic anion transporter, OAT). Furosemide was evaluated in vitro, and is a substrate of OAT1 and OAT3, with Km values of 38.9 and 21.5 μM, respectively. Furosemide was also identified as a substrate of BCRP, OATP1B1, and OATP1B3. Furosemide inhibited BCRP (50% inhibition of drug transport: 170 μM), but did not inhibit OATP1B1, OATP1B3, OCT2, MATE1, and MATE2-K at concentrations below 300 μM, and P-gp at concentrations below 2000 μM. Conservative approaches for the estimation of the likelihood of in vivo DDIs indicate a remote chance of in vivo transporter inhibition by these probe drugs when administered at low single oral doses. This four component probe drug cocktail is therefore proposed for clinical evaluation. PMID:25981193

  10. The Use of Transporter Probe Drug Cocktails for the Assessment of Transporter-Based Drug-Drug Interactions in a Clinical Setting-Proposal of a Four Component Transporter Cocktail.

    PubMed

    Ebner, Thomas; Ishiguro, Naoki; Taub, Mitchell E

    2015-09-01

    Probe drug cocktails are used clinically to assess the potential for drug-drug interactions (DDIs), and in particular, DDIs resulting from coadministration of substrates and inhibitors of cytochrome P450 enzymes. However, a probe drug cocktail has not been identified to assess DDIs involving inhibition of drug transporters. We propose a cocktail consisting of the following substrates to explore the potential for DDIs caused by inhibition of key transporters: digoxin (P-glycoprotein, P-gp), rosuvastatin (breast cancer resistance protein, BCRP; organic anion transporting polypeptides, OATP), metformin (organic cation transporter, OCT; multidrug and toxin extrusion transporters, MATE), and furosemide (organic anion transporter, OAT). Furosemide was evaluated in vitro, and is a substrate of OAT1 and OAT3, with Km values of 38.9 and 21.5 μM, respectively. Furosemide was also identified as a substrate of BCRP, OATP1B1, and OATP1B3. Furosemide inhibited BCRP (50% inhibition of drug transport: 170 μM), but did not inhibit OATP1B1, OATP1B3, OCT2, MATE1, and MATE2-K at concentrations below 300 μM, and P-gp at concentrations below 2000 μM. Conservative approaches for the estimation of the likelihood of in vivo DDIs indicate a remote chance of in vivo transporter inhibition by these probe drugs when administered at low single oral doses. This four component probe drug cocktail is therefore proposed for clinical evaluation.

  11. 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

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

    PubMed Central

    Phillips, Matthew D.

    2016-01-01

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

  13. 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 1.0 mg/kg/inj of histamine was effective in moving responding to the alternate lever, whereas saline, 0.1, or 0.3 mg/kg/inj of histamine were not. Histamine injections produced reliable selection of the alternate lever when they were presented on the same lever for three consecutive sessions, but not when they were switched between levers on each session. In addition, histamine produced greater selection of the alternate lever when it was presented with shorter intertrial interval durations. These findings indicate that, with appropriate parameters, the aversive effects of histamine and perhaps other drugs can be established rapidly using a concurrent choice procedure. PMID:20885811

  14. [Assessment of benefits of drug therapies: memantine for Alzheimer's disease as an example].

    PubMed

    Rüther, E; Hellweg, R; Janetzky, W

    2012-12-01

    After the approval of a drug, which represents a first assessment, independent institutions and medical professional associations provide further evaluations. Here, the question is to be asked whether common or diverging evaluation methods exist that can have an impact on the result. In principle, two methods are used: meta-analyses and responder analyses. Meta-analyses and the resulting effect sizes have to be interpreted according to the field of application (for example, the type and severity degree of a disease) with medical expertise. Omitting this can lead to incorrect evaluations and to a discrepancy of evaluation results. In the case of memantine, the merely biometric evaluation of meta-analyses performed by the IQWiG led to a denial of the benefit, while the same data, considering clinical routine, led professional associations to recommend memantine for moderate to severe Alzheimer´s disease. In contrast to meta-analyses, responder analyses directly show the benefit of a therapy option in the presence of significant group differences, as the selected responder criteria are based on the indication. The corresponding results of the responder analyses on memantine were also acknowledged by the IQWiG and led to a positive evaluation of memantine. This discrepancy of evaluation results illustrates the fact that statistical procedures are necessary when evaluating drug and non-drug therapy options but, that the interpretation of the results with medical expertise is essential.

  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 1.0 mg/kg/inj of histamine was effective in moving responding to the alternate lever, whereas saline, 0.1, or 0.3 mg/kg/inj of histamine were not. Histamine injections produced reliable selection of the alternate lever when they were presented on the same lever for three consecutive sessions, but not when they were switched between levers on each session. In addition, histamine produced greater selection of the alternate lever when it was presented with shorter intertrial interval durations. These findings indicate that, with appropriate parameters, the aversive effects of histamine and perhaps other drugs can be established rapidly using a concurrent choice procedure.

  16. Assessment of substance abuse liability in rodents: self-administration, drug discrimination, and locomotor sensitization.

    PubMed

    Paterson, Neil E

    2012-09-01

    Assessing abuse liability is a crucial step in the development of a novel chemical entity (NCE) with central nervous system (CNS) activity or with chemical or pharmacological properties in common with known abused substances. Rodent assessment of abuse liability is highly attractive due to its relatively low cost and high predictive validity. Described in this unit are three rodent assays commonly used to provide data on the potential for abuse liability based on the acute effects of NCEs: specifically, self-administration, drug discrimination, and locomotor sensitization. As these assays provide insight into the potential abuse liability of NCEs as well as in vivo pharmacological mechanism(s) of action, they should form a key part of the development process for novel therapeutics aimed at treating CNS disorders.

  17. Psychometric properties of an instrument to assess Medicare beneficiaries' prescription drug plan experiences.

    PubMed

    Martino, Steven C; Elliott, Marc N; Cleary, Paul D; Kanouse, David E; Brown, Julie A; Spritzer, Karen L; Heller, Amy; Hays, Ron D

    2009-01-01

    Using data from 335,249 Medicare beneficiaries who responded to the 2007 Medicare Consumer Assessment of Healthcare Providers and Systems (CAHPS) survey, along with data from 22 cognitive interviews, we investigated the reliability and validity of an instrument designed to assess beneficiaries' experiences with their prescription drug plans. Composite measures derived from the instrument had acceptable internal consistency and sufficient plan-level reliability to inform consumer choice, quality improvement, and payor oversight. These measures were positively associated with members' overall rating of the plan and their willingness to recommend the plan. Moreover, each was independently useful in predicting beneficiaries' global ratings of their plan. This instrument can be an important tool for helping beneficiaries to choose a plan that best meets their needs. PMID:19544934

  18. 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

  19. 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.

  20. 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.

  1. 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

  2. Use of the whole-embryo culture system in drug safety assessment?

    PubMed

    Bechter, R; Schön, H

    1988-01-01

    The embryotoxicity and, in particular, the teratogenic potential of three new drug combinations were investigated. The interactions of the single components (all already on the market) in the different drug mixtures were determined by testing the single components in addition to the drug combinations. In order to evaluate the usefulness of these results for safety assessment, the no-effect concentrations (NEC) of the single compounds or the mixed drug preparations, with respect to embryonic growth and differentiation and the presence of anomalies, were compared with human plasma/serum levels during therapeutic use. In addition, in vivo animal data of the single components were used to put into perspective the NEC values after direct in vitro exposure of embryos. Embryotoxicity, measured as a retardation of growth and of differentiation, as well as an increased percentage of cultured embryos with morphological abnormalities, was present at concentrations of 100 mug/ml for the preparation KT 1/300 (ketotifen/theophylline). These effects could be attributed to the component theophylline, as ketotifen was free of an embryotoxic/teratogenic potential in vitro. In the case of the compound mix VKB/BQ, a combination of pindolol, clopamide and endralazine, the in vitro effects of the mixture on embryonic development could also be attributed to one of the compounds (pindolol) in the mixture. In the case of HYCT 4520, the effects of the components hydergine (co-dergocrine mesylate), clopamide and triamterene on embryonic growth, differentiation and anomalies were additive in the drug mixture. None of the compounds was reported to be associated with human teratogenicity. The NEC of the components in the whole-embryo culture system, tested either as a mixture or as individual compounds, were higher than the human peak plasma levels measured during therapeutic use of the compounds. In addition, the single components were reported to be non-teratogenic in in vivo teratogenicity

  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 0–12). The median CHS was 2845 (interquartile range 1865–3977). Adjusting for age and sex, every 1000-unit CHS increase was associated with greater mortality (odds ratio [OR] 1.47, 95% confidence interval [CI] 1.07–2.01, p = 0.02), and persistent hepatitis C infection (OR 1.29, 95% CI 1.02–1.67, p = 0.04). The likelihood of substance-induced psychosis increased 1.39-fold (95% CI 1.13–1.67, p = 0.001). The amount spent on drugs increased 1.51-fold (1.40–1.62, p < 0.001) and the odds of having committed a crime increased 1.74-fold (1.46–2.10, p < 0.001). Multimorbid illness increased 1.43-fold (95% CI 1.26–1.63, 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. 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.

  6. Prediction and assessment of ecogenotoxicity of antineoplastic drugs in binary mixtures.

    PubMed

    Kundi, Michael; Parrella, Alfredo; Lavorgna, Margherita; Criscuolo, Emma; Russo, Chiara; Isidori, Marina

    2016-08-01

    The combined genotoxic effects of four anticancer drugs (5-fluorouracil [5-FU], cisplatin [CDDP], etoposide [ET], and imatinib mesylate [IM]) were studied testing their binary mixtures in two crustaceans that are part of the freshwater food chain, namely Daphnia magna and Ceriodaphnia dubia. Genotoxicity was assessed using the in vivo comet assay. Assessment was based on two distinct effect sizes determined from dose-response experiments. Doses for single and combined exposures expected to result in these effect sizes were computed based on Bliss independence as reference model. Statistical comparison by analysis of variance of single and combined toxicities allowed accepting or rejecting the independency hypothesis. The results obtained for D. magna showed independent action for all mixtures except for IM+5-FU that showed an antagonistic interaction. In C. dubia, most mixtures had antagonist interactions except IM+5-FU and IM+CDDP that showed Bliss independence. Despite the antagonistic interactions, our results demonstrated that combinations of anticancer drugs could be of environmental concern because effects occur at very low concentrations that are in the range of concentrations encountered in aquatic systems.

  7. Anti-malarial drug quality in Lagos and Accra - a comparison of various quality assessments

    PubMed Central

    2010-01-01

    Background Two major cities in West Africa, Accra, the capital of Ghana, and Lagos, the largest city of Nigeria, have significant problems with substandard pharmaceuticals. Both have actively combated the problem in recent years, particularly by screening products on the market using the Global Pharma Health Fund e.V. Minilab® protocol. Random sampling of medicines from the two cities at least twice over the past 30 months allows a tentative assessment of whether improvements in drug quality have occurred. Since intelligence provided by investigators indicates that some counterfeit producers may be adapting products to pass Minilab tests, the results are compared with those from a Raman spectrometer and discrepancies are discussed. Methods Between mid-2007 and early-2010, samples of anti-malarial drugs were bought covertly from pharmacies in Lagos on three different occasions (October 2007, December 2008, February 2010), and from pharmacies in Accra on two different occasions (October 2007, February 2010). All samples were tested using the Minilab® protocol, which includes disintegration and active ingredient assays as well as visual inspection, and most samples were also tested by Raman spectrometry. Results In Lagos, the failure rate in the 2010 sampling fell to 29% of the 2007 finding using the Minilab® protocol, 53% using Raman spectrometry, and 46% using visual inspection. In Accra, the failure rate in the 2010 sampling fell to 54% of the 2007 finding using the Minilab® protocol, 72% using Raman spectrometry, and 90% using visual inspection. Conclusions The evidence presented shows that drug quality is probably improving in both cities, especially Lagos, since major reductions of failure rates over time occur with all means of assessment. Many more samples failed when examined by Raman spectrometry than by Minilab® protocol. The discrepancy is most likely caused by the two techniques measuring different aspects of the medication and hence the discrepancy

  8. Assessing Drug Efficacy in a Miniaturized Pancreatic Cancer In Vitro 3D Cell Culture Model.

    PubMed

    Shelper, Todd B; Lovitt, Carrie J; Avery, Vicky M

    2016-09-01

    Pancreatic cancer continues to have one of the poorest prognoses among all cancers. The drug discovery efforts for this disease have largely failed, with no significant improvement in survival outcomes for advanced pancreatic cancer patients over the past 20 years. Traditional in vitro cell culture techniques have been used extensively in both basic and early drug discovery; however, these systems offer poor models to assess emerging therapeutics. More predictive cell-based models, which better capture the cellular heterogeneity and complexities of solid pancreatic tumors, are urgently needed not only to improve drug discovery success but also to provide insight into the tumor biology. Pancreatic tumors are characterized by a unique micro-environment that is surrounded by a dense stroma. A complex network of interactions between extracellular matrix (ECM) components and the effects of cell-to-cell contacts may enhance survival pathways within in vivo tumors. This biological and physical complexity is lost in traditional cell monolayer models. To explore the predictive potential of a more complex cellular system, a three-dimensional (3D) micro-tumor assay was evaluated. Efficacy of six current chemotherapeutics was determined against a panel of primary and metastatic pancreatic tumor cell lines in a miniaturized ECM-based 3D cell culture system. Suitability for potential use in high-throughput screening applications was assessed, including ascertaining the effects that miniaturization and automation had on assay robustness. Cellular health was determined by utilizing an indirect population-based metabolic activity assay and a direct imaging-based cell viability assay. PMID:27552143

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

    PubMed

    Tisdale, James E

    2016-05-01

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

  10. 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.

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

    PubMed

    Berezhkovskiy, Leonid M

    2013-02-01

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

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

    PubMed

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

    2016-05-01

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

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

    PubMed Central

    2014-01-01

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

  14. Evolution of health technology assessment: best practices of the pan-Canadian Oncology Drug Review

    PubMed Central

    Rocchi, Angela; Chabot, Isabelle; Glennie, Judith

    2015-01-01

    Background In 2007, Canada chose to develop a separate and distinct path for oncology drug health technology assessment (HTA). In 2013, the decision was made to transfer the pan-Canadian Oncology Drug Review (pCODR) to the Canadian Agency for Drugs and Technologies in Health (CADTH), to align the pCODR and CADTH Common Drug Review processes while building on the best practices of both. The objective of this research was to conduct an examination of the best practices established by the pCODR. Methods A qualitative research approach was taken to assess the policies, processes, and practices of the pCODR, based on internationally accepted best practice “principles” in HTA, with a particular focus on stakeholder engagement. Publicly available information regarding the approach of the pCODR was used to gauge the agency’s performance against these principles. In addition, stakeholder observations and real-world experiences were gathered through key informant interviews to be inclusive of perspectives from patient advocacy groups, provincial and/or cancer agency decision-makers, community and academic oncologists, industry, expert committee members, and health economists. Results This analysis indicated that, through the pCODR, oncology stakeholders have had a voice in and have come to trust the quality and relevance of oncology HTA as a vital tool to ensure the best decisions for Canadians with cancer and their health care system. It could be expected that adoption of the principles and processes of the pCODR would bring a similar level of engagement and trust to other HTA organizations in Canada and elsewhere. Conclusion The results of this research led to recommendations for improvement and potential extrapolation of these best practices to other HTA organizations worldwide, along with suggestions for continued evolution of the pCODR in conjunction with its integration into the CADTH. It is clear that the transition of the pCODR to CADTH provides an opportunity

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

    PubMed

    Järbe, Torbjörn U C; Gifford, Roger S

    2014-02-27

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

  16. “Herbal incense”: Designer drug blends as cannabimimetics and their assessment by drug discrimination and other in vivo bioassays

    PubMed Central

    Järbe, Torbjörn U.C.; Gifford, Roger S.

    2014-01-01

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

  17. Wide-field lifetime-based FRET imaging for the assessment of early functional distribution of transferrin-based delivery in breast tumor-bearing small animals

    NASA Astrophysics Data System (ADS)

    Sinsuebphon, Nattawut; Rudkouskaya, Alena; Barroso, Margarida; Intes, Xavier

    2016-02-01

    Targeted drug delivery is a critical aspect of successful cancer therapy. Assessment of dynamic distribution of the drug provides relative concentration and bioavailability at the target tissue. The most common approach of the assessment is intensity-based imaging, which only provides information about anatomical distribution. Observation of biomolecular interactions can be performed using Förster resonance energy transfer (FRET). Thus, FRET-based imaging can assess functional distribution and provide potential therapeutic outcomes. In this study, we used wide-field lifetime-based FRET imaging for the study of early functional distribution of transferrin delivery in breast cancer tumor models in small animals. Transferrin is a carrier for cancer drug delivery. Its interaction with its receptor is within a few nanometers, which is suitable for FRET. Alexa Fluor® 700 and Alexa Fluor® 750 were conjugated to holo-transferrin which were then administered via tail vein injection to the mice implanted with T47D breast cancer xenografts. Images were continuously acquired for 60 minutes post-injection. The results showed that transferrin was primarily distributed to the liver, the urinary bladder, and the tumor. The cellular uptake of transferrin, which was indicated by the level of FRET, was high in the liver but very low in the urinary bladder. The results also suggested that the fluorescence intensity and FRET signals were independent. The liver showed increasing intensity and increasing FRET during the observation period, while the urinary bladder showed increasing intensity but minimal FRET. Tumors gave varied results corresponding to their FRET progression. These results were relevant to the biomolecular events that occurred in the animals.

  18. Assessing cancer drugs for reimbursement: methodology, relationship between effect size and medical need.

    PubMed

    de Sahb-Berkovitch, Rima; Woronoff-Lemsi, Marie-Christine; Molimard, Mathieu

    2010-01-01

    Reimbursement is assessed by the Transparency Commission from the Health Authority (HAS) using a medical benefit (SMR) score that gives access to reimbursement, an "improvement of medical service rendered" (ASMR) that determines the added therapeutic value, and the target population. Assessing cancer drugs for reimbursement raises the same issues as other therapeutic classes, with some key differences. Overall survival (OS) is considered by the Transparency Commission as the endpoint for assessing clinical benefit, and yet it is not an applicable primary endpoint in all types of cancer. Later lines of treatment, particularly during the development process, may make it difficult to interpret OS as the primary endpoint. Therefore, progression-free survival (PFS) for metastatic situations and disease-free survival (DFS) in adjuvant situations are wholly relevant endpoints for decisions on the reimbursement of a new cancer drug. Effect size is assessed using actuarial survival curves of the product versus the comparator, and it is difficult to summarise them into one single parameter. Results are generally interpreted based on median survival, which is fragmented because it only measures one point of the curve. The hazard ratio measures the effect of treatment throughout the duration of survival and is therefore more comprehensive in quantifying clinical benefit. Determining an effect size threshold for granting reimbursement is difficult given the diversity of cancer settings and the level of medical need, which influences assessment of the clinical relevance of the observed difference. Rapid progress in comparators (700 molecules in development) and the identification of predictive factors of efficacy (biomarkers, histology, etc.) during development may lead to different ASMR scores per population, or to the restriction of the target population to a subgroup of the marketing authorisation (MA) population in which the expected effect size is greater. To address these

  19. Assessing cancer drugs for reimbursement: methodology, relationship between effect size and medical need.

    PubMed

    de Sahb-Berkovitch, Rima; Woronoff-Lemsi, Marie-Christine; Molimard, Mathieu

    2010-01-01

    Reimbursement is assessed by the Transparency Commission from the Health Authority (HAS) using a medical benefit (SMR) score that gives access to reimbursement, an "improvement of medical service rendered" (ASMR) that determines the added therapeutic value, and the target population. Assessing cancer drugs for reimbursement raises the same issues as other therapeutic classes, with some key differences. Overall survival (OS) is considered by the Transparency Commission as the endpoint for assessing clinical benefit, and yet it is not an applicable primary endpoint in all types of cancer. Later lines of treatment, particularly during the development process, may make it difficult to interpret OS as the primary endpoint. Therefore, progression-free survival (PFS) for metastatic situations and disease-free survival (DFS) in adjuvant situations are wholly relevant endpoints for decisions on the reimbursement of a new cancer drug. Effect size is assessed using actuarial survival curves of the product versus the comparator, and it is difficult to summarise them into one single parameter. Results are generally interpreted based on median survival, which is fragmented because it only measures one point of the curve. The hazard ratio measures the effect of treatment throughout the duration of survival and is therefore more comprehensive in quantifying clinical benefit. Determining an effect size threshold for granting reimbursement is difficult given the diversity of cancer settings and the level of medical need, which influences assessment of the clinical relevance of the observed difference. Rapid progress in comparators (700 molecules in development) and the identification of predictive factors of efficacy (biomarkers, histology, etc.) during development may lead to different ASMR scores per population, or to the restriction of the target population to a subgroup of the marketing authorisation (MA) population in which the expected effect size is greater. To address these

  20. Complacent and conflicting scientific expertise in British and American drug regulation: clinical risk assessment of triazolam.

    PubMed

    Abraham, J; Sheppard, J

    1999-12-01

    This paper presents a case study in the production and interpretation of regulatory science, focusing on the conflicting British and American clinical risk assessments of triazolam (Halcion) - the most controversial sleeping pill in the world. The regulation of triazolam is shown to be more permissive in the USA than in the UK. Six principal socio-political factors are put forward to explain this; differential regulatory trust; regulators' socio-technical data selections; medico-scientific disciplinary influences; organizational and professional interests; conflicts of interest of expert advisers; and the growth of the neo-liberal regulatory state. The risk assessments of both the British and American regulatory agencies are shown to be complacent relative to technical standards which the agencies themselves later accepted. It is suggested that, when the interests of pharmaceutical manufacturers and patients diverge, regulatory assessments are crucially affected by whether regulators are predisposed to award the benefit of the scientific doubts to the manufacturers or patients, and by the balance of such predispositions both within and between regulatory institutions of scientific expertise. The triazolam case indicates that the amount of trust placed in the pharmaceutical industry by the British American regulatory systems may hamper detection of flaws in manufacturers' medical data in a timely manner and, as a consequence, compromise patients' interests. Some policy implications for drug regulation are sketched. PMID:11624110

  1. Complacent and conflicting scientific expertise in British and American drug regulation: clinical risk assessment of triazolam.

    PubMed

    Abraham, J; Sheppard, J

    1999-12-01

    This paper presents a case study in the production and interpretation of regulatory science, focusing on the conflicting British and American clinical risk assessments of triazolam (Halcion) - the most controversial sleeping pill in the world. The regulation of triazolam is shown to be more permissive in the USA than in the UK. Six principal socio-political factors are put forward to explain this; differential regulatory trust; regulators' socio-technical data selections; medico-scientific disciplinary influences; organizational and professional interests; conflicts of interest of expert advisers; and the growth of the neo-liberal regulatory state. The risk assessments of both the British and American regulatory agencies are shown to be complacent relative to technical standards which the agencies themselves later accepted. It is suggested that, when the interests of pharmaceutical manufacturers and patients diverge, regulatory assessments are crucially affected by whether regulators are predisposed to award the benefit of the scientific doubts to the manufacturers or patients, and by the balance of such predispositions both within and between regulatory institutions of scientific expertise. The triazolam case indicates that the amount of trust placed in the pharmaceutical industry by the British American regulatory systems may hamper detection of flaws in manufacturers' medical data in a timely manner and, as a consequence, compromise patients' interests. Some policy implications for drug regulation are sketched.

  2. Challenge tests to assess airway hyperresponsiveness and efficacy of drugs used in the treatment of asthma.

    PubMed

    Anderson, S D

    1996-01-01

    Bronchial provocation tests are useful to diagnose and assess severity of asthma and to follow response to treatment. The tests used include those stimuli that act "directly" on receptors causing contraction of airway smooth muscle, e.g., pharmacological agents, and those stimuli that act "indirectly" by causing release of endogenous mediators that cause the airways to narrow. These "indirect" stimuli include physical ones such as airway drying from hyperpnea and changes in airway osmolarity from inhaling aerosols of water and hyperosmolar saline. Indirect stimuli cause the airways to narrow in response to endogenously released substances from inflammatory cells or nerves and responses are thought to reflect the presence and severity of inflammation of asthma. Challenge with hyperosmolar saline is now being used as an indirect test because it also identifies persons with exercise-induced asthma and is appropriate to assess suitability for diving with SCUBA. Hyperosmolar challenge is also useful to assess the effect of both the acute and chronic treatment with antiinflammatory drugs. This, combined with the potential to collect inflammatory cells in sputum induced by the same stimulus should result in this challenge being more widely used, not only in the hospital laboratory but also in epidemiology and occupational asthma.

  3. Dendrimer, liposomes, carbon nanotubes and PLGA nanoparticles: one platform assessment of drug delivery potential.

    PubMed

    Mody, Nishi; Tekade, Rakesh Kumar; Mehra, Neelesh Kumar; Chopdey, Prashant; Jain, Narendra Kumar

    2014-04-01

    Liposomes (LIP), nanoparticles (NP), dendrimers (DEN), and carbon nanotubes (CNTs), represent eminent classes of drug delivery devices. A study was carried out herewith by employing docetaxel (DTX) as model drug to assess their comparative drug delivery potentials. Under optimized conditions, highest entrapment of DTX was observed in CNT-based formulation (DTX-CNTs, 74.70 ± 4.9%) followed by nanoparticles (DTX-NP, 62.34 ± 1.5%), liposome (49.2 ± 1.51%), and dendrimers (28.26 ± 1.74%). All the formulations were found to be of nanometric size. In vitro release studies were carried out in PBS (pH 7.0 and 4.0), wherein all the formulations showed biphasic release pattern. Cytotoxicity assay in human cervical cancer SiHa cells inferred lowest IC50 value of 1,235.09 ± 41.93 nM with DTX-CNTs, followed by DTX-DEN, DTX-LIP, DTX-NP with IC50 values of 1,571.22 ± 151.27, 1,653.98 ± 72.89, 1,922.75 ± 75.15 nM, respectively. Plain DTX showed higher hemolytic toxicity of 22.48 ± 0.94%, however loading of DTX inside nanocarriers drastically reduced its hemolytic toxicity (DTX-DEN, 17.22 ± 0.48%; DTX-LIP, 4.13 ± 0.19%; DTX-NP, 6.43 ± 0.44%; DTX-CNTs, 14.87 ± 1.69%). PMID:24431104

  4. Assessment of Dengue virus helicase and methyltransferase as targets for fragment-based drug discovery.

    PubMed

    Coutard, Bruno; Decroly, Etienne; Li, Changqing; Sharff, Andrew; Lescar, Julien; Bricogne, Gérard; Barral, Karine

    2014-06-01

    Seasonal and pandemic flaviviruses continue to be leading global health concerns. With the view to help drug discovery against Dengue virus (DENV), a fragment-based experimental approach was applied to identify small molecule ligands targeting two main components of the flavivirus replication complex: the NS3 helicase (Hel) and the NS5 mRNA methyltransferase (MTase) domains. A library of 500 drug-like fragments was first screened by thermal-shift assay (TSA) leading to the identification of 36 and 32 fragment hits binding Hel and MTase from DENV, respectively. In a second stage, we set up a fragment-based X-ray crystallographic screening (FBS-X) in order to provide both validated fragment hits and structural binding information. No fragment hit was confirmed for DENV Hel. In contrast, a total of seven fragments were identified as DENV MTase binders and structures of MTase-fragment hit complexes were solved at resolution at least 2.0Å or better. All fragment hits identified contain either a five- or six-membered aromatic ring or both, and three novel binding sites were located on the MTase. To further characterize the fragment hits identified by TSA and FBS-X, we performed enzymatic assays to assess their inhibition effect on the N7- and 2'-O-MTase enzymatic activities: five of these fragment hits inhibit at least one of the two activities with IC50 ranging from 180μM to 9mM. This work validates the FBS-X strategy for identifying new anti-flaviviral hits targeting MTase, while Hel might not be an amenable target for fragment-based drug discovery (FBDD). This approach proved to be a fast and efficient screening method for FBDD target validation and discovery of starting hits for the development of higher affinity molecules that bind to novel allosteric sites. PMID:24704437

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

    PubMed Central

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

    2014-01-01

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

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

    PubMed

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

    2012-05-01

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

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

    PubMed Central

    Guo, Su

    2009-01-01

    Background Zebrafish is becoming an increasingly attractive model organism for understanding biology and developing therapeutics, because as a vertebrate, it shares considerable similarity with mammals in both genetic compositions and tissue/organ structures, and yet remains accessible to high throughput phenotype-based genetic and small molecule compound screening. Objective/method The focus of this review is on the nervous system, which is arguably the most complex organ and known to be afflicted by more than six hundred disorders in humans. I discuss the past, present, and future of using zebrafish to assess the impact of small molecule drugs on neural development and function, in light of understanding and treating neurodevelopmental disorders such as autism, neurodegenerative disorders including Alzheimer’s, Parkinson’s, and Hungtington’s disease, and neural system dysfunctions such as anxiety/depression and addiction. Conclusion These studies hold promise to reveal fundamental mechanisms governing nervous system development and function, and to facilitate small molecule drug discovery for the many types of neurological disorders. PMID:19774094

  8. Theoretical Assessment of Fluorinated Phospholipids in the Design of Liposomal Drug-Delivery Systems.

    PubMed

    Madsen, Jesper J; Fristrup, Peter; Peters, Günther H

    2016-09-15

    Fluorinated phospholipid analogues are investigated as potential substrates for phospholipase A2 (PLA2) using classical molecular dynamics simulations and quantum mechanics/density functional theory calculations. The fluorinated phospholipid analogues are α-fluoro (HF-ProAEL) and α,α-difluoro (F2-ProAEL) conjugates of (R)-1-O-hexadecyl-2-palmitoyl-sn-glycero-3-phoshocholineglycerol (ProAEL). Our results provide a theoretical assessment of the potential usefulness of these fluorinated lipids in the rational design of liposomal drug-delivery systems. The α-fluorine-substituted phospholipid analogues are found to be substrates for secretory PLA2, with sufficient accessibility of water to the active site to allow for enzymatic hydrolysis. Because of the inherently less stable nature of HF-ProAEL and F2-ProAEL when compared to that of ProAEL, the hydrolytic reaction is predicted to occur at a progressively faster rate; the more electronegative substituent at the α-position effectively lowers the energy barrier for hydrolysis. We conclude that the partially fluorinated phospholipid analogues facilitate rational design of liposomal vesicles of phospholipid mixtures with desirable physicochemical properties and that are still subjects for important and pharmaceutically proven drug-delivery mechanisms. PMID:27557037

  9. Assessment of MEKC suitability for residue drug monitoring on pharmaceutical manufacturing equipment.

    PubMed

    Boca, Madalina Brindusa; Pretorius, Etheresia; Kgaje, Christopher; Apostolides, Zeno

    2008-03-13

    The suitability of micellar electrokinetic chromatography for the simultaneous trace determination of several compounds (sulfamethoxazole, trimethoprim, sulfanilic acid, sulfanilamide, 3,4,5-trimethoxybenzoic acid and nonoxynol-9) was assessed. The mixture was separated within 14min at an applied voltage of 22kV by using 30mM phosphate electrolyte, containing 10mM SDS, adjusted to pH 7.8. Under optimized separation conditions acceptable levels of linearity, precision and accuracy were obtained for all compounds. The method could be used as part of a cleaning validation study when assaying trace levels of co-trimoxazole drug, some of its decomposition products and detergent in the swab samples collected from pharmaceutical manufacturing equipment, after cleaning. PMID:18178359

  10. 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.

  11. 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

  12. Mining hidden knowledge for drug safety assessment: topic modeling of LiverTox as a case study

    PubMed Central

    2014-01-01

    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

  13. A new method to assess Pavlovian conditioning of psychostimulant drug effects.

    PubMed

    Damianopoulos, E N; Carey, R J

    1994-07-01

    Experimental studies of psychoactive drugs by pavlovian drug-conditioning methods, which originally began with investigations of drug-induced responses mediated by the autonomic nervous system, have now been expanded to include drug-induced response effects expressed as modulations of spontaneous motoric behaviors. In the latter application, however, equivalent behavioral response outcomes in post-treatment tests for conditioning can occur following a psychostimulant drug treatment either through drug interference effects on habituation processes, drug-induced stress effects and/or by pavlovian conditioning of the drug-induced motoric activation effect. Current methodologies for the study of pavlovian conditioned drug effects and/or drug sensitization cannot distinguish among these possibilities. This methodological inadequacy was addressed by a modification of the conventional paired-unpaired treatment protocol. In the new protocol, the animal is sequentially placed into two test compartments with the drug treatment administered in conjunction with placement into the second test compartment. This design permits a differentiation of a pavlovian conditioned drug responses from non-conditioned drug effects through continuous measurement of the non-drug behavioral baseline in both the drug and non-drug control treatment groups combined with multiple response measurements and post-treatment tests for conditioning at variable post-conditioning intervals. The present study details the use of the new modified pavlovian protocol with repeated cocaine (10 mg/kg) treatment. A cocaine conditioned response at 1, 7, and 21 days post-conditioning was identified and distinguished from habituation and stress effects.

  14. Studies on the drug resistance profile of Enterococcus faecium distributed from poultry retailers to hospitals.

    PubMed

    Limayem, Alya; Donofrio, Robert Scott; Zhang, Chao; Haller, Edward; Johnson, Michael G

    2015-01-01

    The multidrug resistant Enterococcus faecium (MEF) strains originating from farm animals are proliferating at a substantial pace to impact downstream food chains and could reach hospitals. This study was conducted to elucidate the drug susceptibility profile of MEF strains collected from poultry products in Ann Arbor, MI area and clinical settings from Michigan State Lab and Moffitt Cancer Center (MCC) in Florida. Presumptive positive Enterococcus isolates at species level were identified by Matrix Assisted Laser Desorption/Ionization Time-of-Flight (MALDI-TOF) analysis. The antibiotic susceptibility profile for both poultry and clinical strains was determined by the Thermo Scientific's Sensititre conform to the National Committee for Clinical Laboratory Standards (NCCLS) and validated via quantitative real-time PCR (qPCR) methods. Out of 50 poultry samples (Turkey: n = 30; Chicken: n = 20), 36 samples were positive for Enterococcus species from which 20.83% were identified as E. faecium. All the E. faecium isolates were multidrug resistant and displayed resistance to the last alternative drug, quinupristin/dalfopristin (QD) used to treat vancomycin resistant E. faecium (VRE) in hospitals. Results indicate the presence of MEF strains in food animals and clinical settings that are also resistant to QD.

  15. 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.

  16. 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

  17. Assessing tephra total grain-size distribution: Insights from field data analysis

    NASA Astrophysics Data System (ADS)

    Costa, A.; Pioli, L.; Bonadonna, C.

    2016-06-01

    The Total Grain-Size Distribution (TGSD) of tephra deposits is crucial for hazard assessment and provides fundamental insights into eruption dynamics. It controls both the mass distribution within the eruptive plume and the sedimentation processes and can provide essential information on the fragmentation mechanisms. TGSD is typically calculated by integrating deposit grain-size at different locations. The result of such integration is affected not only by the number, but also by the spatial distribution and distance from the vent of the sampling sites. In order to evaluate the reliability of TGSDs, we assessed representative sampling distances for pyroclasts of different sizes through dedicated numerical simulations of tephra dispersal. Results reveal that, depending on wind conditions, a representative grain-size distribution of tephra deposits down to ∼100 μm can be obtained by integrating samples collected at distances from less than one tenth up to a few tens of the column height. The statistical properties of TGSDs representative of a range of eruption styles were calculated by fitting the data with a few general distributions given by the sum of two log-normal distributions (bi-Gaussian in Φ-units), the sum of two Weibull distributions, and a generalized log-logistic distribution for the cumulative number distributions. The main parameters of the bi-lognormal fitting correlate with height of the eruptive columns and magma viscosity, allowing general relationships to be used for estimating TGSD generated in a variety of eruptive styles and for different magma compositions. Fitting results of the cumulative number distribution show two different power law trends for coarse and fine fractions of tephra particles, respectively. Our results shed light on the complex processes that control the size of particles being injected into the atmosphere during volcanic explosive eruptions and represent the first attempt to assess TGSD on the basis of pivotal physical

  18. 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

  19. A qualitative study to assess community barriers to malaria mass drug administration trials in the Gambia

    PubMed Central

    2014-01-01

    Background Mass drug administration (MDA) is a strategy widely used in the control of human parasitic diseases but has been rarely attempted with malaria, the most common and dangerous parasitic disease in humans. MDA is an intervention strategy that involves simultaneously dispensing treatment to an entire population in a given geographic area. With some areas in sub-Saharan Africa documenting a decline in malaria transmission, the feasibility of MDA to further reduce malaria transmission is being considered. Understanding community perceptions of such an activity is vitally important for the design of the study and gaining the support of participants in order to maximize compliance and adherence. Methods A qualitative study to assess factors likely to influence community acceptance of MDA in the seasonal and low malaria transmission setting of The Gambia was conducted. Using in-depth interviews, the perceptions, knowledge and attitudes of medical personnel and community members who have undergone MDA trials in The Gambia were investigated. Results Several major themes emerged, namely: 1) the importance of timing of rounds of MDA doses for maximum participation; 2) the need to educate the target population with accurate information on the procedures, drug regimen, and possible side effects to enhance adherence; 3) the need for continuous sensitization meetings to maintain and increase uptake of MDA; and, 4) the importance for defining roles in the delivery and assessment of MDA, including existing healthcare structures. Discussion To increase the likelihood of participation in MDA trials in this setting, activities should be undertaken just before and during the rainy season when community members are less mobile. Importantly, fears regarding blood sampling and side effects of the drug regimen need to be addressed prior to the start of the trial and repeated throughout the study period. Accurate and frequent communication is essential, and village leaders should

  20. 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…

  1. 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

  2. Comparative QSAR- and fragments distribution analysis of drugs, druglikes, metabolic substances, and antimicrobial compounds.

    PubMed

    Karakoc, Emre; Sahinalp, S Cenk; Cherkasov, Artem

    2006-01-01

    A number of binary QSAR models have been developed using methods of artificial neural networks, k-nearest neighbors, linear discriminative analysis, and multiple linear regression and have been compared for their ability to recognize five types of chemical compounds that include conventional drugs, inactive druglikes, antimicrobial substituents, and bacterial and human metabolites. Thus, 20 binary classifiers have been created using a variety of 'inductive' and traditional 2D QSAR descriptors which allowed up to 99% accurate separation of the studied groups of activities. The comparison of the performance by four computational approaches demonstrated that the neural nets result in generally more accurate predictions, followed closely by k-nearest neighbors methods. It has also been demonstrated that complementation of 'inductive' descriptors with conventional QSAR parameters does not generally improve the quality of resulting solutions, conforming high predictive ability of 'inductive' variables. The conducted comparative QSAR analysis based on a novel linear optimization approach has helped to identify the extent of overlapping between the studied groups of compounds, such as cross-recognition of bacterial metabolites and antimicrobial compounds reflecting their immanent resemblance and similar origin. Human metabolites have been characterized as a very distinctive class of substances, separated from all other groups in the descriptors space and exhibiting different QSAR behavior. The analysis of unique structural fragments and substituents revealed inhomogeneous scale-free organization of human metabolites illustrating the fact that certain molecular scaffolds (such as sugars and nucleotides) may be strongly favored by natural evolution. The established scale-free organization of human metabolites has been contemplated as a factor of their unique positioning in the descriptors space and their distinctive QSAR properties. It is anticipated that the study may bring

  3. Facilitating political decisions using species distribution models to assess restoration measures in heavily modified estuaries.

    PubMed

    Heuner, Maike; Weber, Arnd; Schröder, Uwe; Kleinschmit, Birgit; Schröder, Boris

    2016-09-15

    The European Water Framework Directive requires a good ecological potential for heavily modified water bodies. This standard has not been reached for most large estuaries by 2015. Management plans for estuaries fall short in linking implementations between restoration measures and underlying spatial analyses. The distribution of emergent macrophytes - as an indicator of habitat quality - is here used to assess the ecological potential. Emergent macrophytes are capable of settling on gentle tidal flats where hydrodynamic stress is comparatively low. Analyzing their habitats based on spatial data, we set up species distribution models with 'elevation relative to mean high water', 'mean bank slope', and 'length of bottom friction' from shallow water up to the vegetation belt as key predictors representing hydrodynamic stress. Effects of restoration scenarios on habitats were assessed applying these models. Our findings endorse species distribution models as crucial spatial planning tools for implementing restoration measures in modified estuaries.

  4. Facilitating political decisions using species distribution models to assess restoration measures in heavily modified estuaries.

    PubMed

    Heuner, Maike; Weber, Arnd; Schröder, Uwe; Kleinschmit, Birgit; Schröder, Boris

    2016-09-15

    The European Water Framework Directive requires a good ecological potential for heavily modified water bodies. This standard has not been reached for most large estuaries by 2015. Management plans for estuaries fall short in linking implementations between restoration measures and underlying spatial analyses. The distribution of emergent macrophytes - as an indicator of habitat quality - is here used to assess the ecological potential. Emergent macrophytes are capable of settling on gentle tidal flats where hydrodynamic stress is comparatively low. Analyzing their habitats based on spatial data, we set up species distribution models with 'elevation relative to mean high water', 'mean bank slope', and 'length of bottom friction' from shallow water up to the vegetation belt as key predictors representing hydrodynamic stress. Effects of restoration scenarios on habitats were assessed applying these models. Our findings endorse species distribution models as crucial spatial planning tools for implementing restoration measures in modified estuaries. PMID:27339739

  5. 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.

  6. Development and validation of an instrument to assess treatment adherence for each individual drug taken by a patient

    PubMed Central

    Sidorkiewicz, Stéphanie; Tran, Viet-Thi; Cousyn, Cécile; Perrodeau, Elodie; Ravaud, Philippe

    2016-01-01

    Objective To develop and validate an instrument to assess adherence to each individual drug taken by patients undergoing long-term treatment. Design Multicentre prospective observational validation study. Setting Six general practitioners' clinics and 6 university hospitals in Paris, France. Participants Patients 18 years and older receiving at least one long-term treatment. Methods The instrument was developed from a literature search and interviews with experts. Clarity and wording were assessed during pilot testing with 51 patients. The tool was validated in a sample of consecutive patients. We assessed agreement between adherence measured with our tool and drug diaries and compared measurements from our instrument with (1) the Lu instrument; (2) the Adherence Estimator (AE); (3) patient's adherence assessed by physicians; (4) the Morisky Medication Adherence Scale-4 items (MMAS-4); and (5) the Treatment Burden Questionnaire (TBQ). Reliability was assessed by a test–retest method. Results A total of 243 patients taking 961 drugs were recruited in 2014. We found good agreement between adherence measured by our tool and drug diaries (intraclass correlation coefficient (ICC) 0.69, 95% CI 0.34 to 0.91) and a linear relationship between measurement with our tool and (1) the Lu instrument (p<0.01); (2) 2 items of the AE (perceived need for medication (p<0.01) and concerns about medication (p<0.01)); (3) patients' adherence assessed by their physicians (p<0.01); (4) the MMAS-4 (p<0.01) and (5) the TBQ (p<0.01). Reliability of the retest was good (ICC 0.67, 95% CI 0.42 to 0.85). Conclusions We developed an instrument with acceptable validity and reliability to assess adherence for each drug taken by patients, usable in hospital and primary care settings. PMID:27165645

  7. 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 product´s safety, efficacy and quality. Good practices for storage, transport, distribution and quality control procedures must follow. In contrast to other high-burden countries, Brazil produces tuberculosis drugs through a strong network of public sector drug manufacturers regulated by a World Health Organization-certified national sanitary authority. The installed capacity for production surpasses the 71,000 needed treatments in the country. However, in order to be prepared to act as a global supplier, important bottlenecks are to be overcome. This article presents an in-depth analysis of the current status of production of tuberculosis drugs in Brazil and the bottlenecks and opportunities for the country to sustain national demand and play a role as a potential global supplier. Raw material and drug production, quality control, international certification and pre-qualification, political commitment and regulatory aspects are discussed, as well recommendations for tackling these bottlenecks. This discussion becomes more important as new drugs and regimens to

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

    PubMed Central

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

    2014-01-01

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

  9. The Possibility of Using the ICR Mouse as an Animal Model to Assess Antimonkeypox Drug Efficacy.

    PubMed

    Sergeev, Al A; Kabanov, A S; Bulychev, L E; Sergeev, Ar A; Pyankov, O V; Bodnev, S A; Galahova, D O; Zamedyanskaya, A S; Titova, K A; Glotov, A G; Taranov, O S; Omigov, V V; Shishkina, L N; Agafonov, A P; Sergeev, A N

    2016-10-01

    As a result of the conducted experimental studies on intranasal challenge of ICR mice, rabbits and miniature pigs (even in the maximum variant) with the doses of 4.0-5.5 lg PFU of monkeypox virus (MPXV), some clinical signs such as purulent conjunctivitis, blepharitis and ruffled fur were found only in mice. The 50% infective dose (C ID50 ) of MPXV for these animals estimated by the presence of external clinical signs was 4.8 lg PFU, and L ID50 estimated by the virus presence in the lungs of mice 7 days post-infection taking into account its 10% application in the animal respiratory tract was 1.4 lg PFU. When studying the dynamics of MPXV propagation in mice challenged intranasally with 25 L ID50 of MPXV, the maximum pathogen accumulation was revealed in nasal cavity, lungs and brain: 5.7 ± 0.1, 5.5 ± 0.1 and 5.3 ± 0.3 lg PFU/ml, respectively. The pathomorphological examination of these animals revealed the presence and replication of the pathogen in the traditional primary target cells for MPXV (mononuclear phagocyte system cells and respiratory tract epitheliocytes) as well as in some other types of cells (endothelial cells, reticular cells, connective tissue cells). Our use of these animals to assess the antiviral efficacy of some drugs demonstrated the agreement of the results (a significant positive effect of NIOCH-14 and ST-246) with those described in scientific literature, which opens up the prospects of using ICR mice as animal models for monkeypox to develop preventive antismallpox drugs.

  10. 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

  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.

  12. 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

  13. 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

    assess efficacy of novel therapeutic drugs with cognition enhancing potential. PMID:25181033

  14. The Possibility of Using the ICR Mouse as an Animal Model to Assess Antimonkeypox Drug Efficacy.

    PubMed

    Sergeev, Al A; Kabanov, A S; Bulychev, L E; Sergeev, Ar A; Pyankov, O V; Bodnev, S A; Galahova, D O; Zamedyanskaya, A S; Titova, K A; Glotov, A G; Taranov, O S; Omigov, V V; Shishkina, L N; Agafonov, A P; Sergeev, A N

    2016-10-01

    As a result of the conducted experimental studies on intranasal challenge of ICR mice, rabbits and miniature pigs (even in the maximum variant) with the doses of 4.0-5.5 lg PFU of monkeypox virus (MPXV), some clinical signs such as purulent conjunctivitis, blepharitis and ruffled fur were found only in mice. The 50% infective dose (C ID50 ) of MPXV for these animals estimated by the presence of external clinical signs was 4.8 lg PFU, and L ID50 estimated by the virus presence in the lungs of mice 7 days post-infection taking into account its 10% application in the animal respiratory tract was 1.4 lg PFU. When studying the dynamics of MPXV propagation in mice challenged intranasally with 25 L ID50 of MPXV, the maximum pathogen accumulation was revealed in nasal cavity, lungs and brain: 5.7 ± 0.1, 5.5 ± 0.1 and 5.3 ± 0.3 lg PFU/ml, respectively. The pathomorphological examination of these animals revealed the presence and replication of the pathogen in the traditional primary target cells for MPXV (mononuclear phagocyte system cells and respiratory tract epitheliocytes) as well as in some other types of cells (endothelial cells, reticular cells, connective tissue cells). Our use of these animals to assess the antiviral efficacy of some drugs demonstrated the agreement of the results (a significant positive effect of NIOCH-14 and ST-246) with those described in scientific literature, which opens up the prospects of using ICR mice as animal models for monkeypox to develop preventive antismallpox drugs. PMID:25597343

  15. 75 FR 4400 - Draft Guidance for Industry on Assessment of Abuse Potential of Drugs; Availability

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-01-27

    ... central nervous system, drugs that are chemically or pharmacologically similar to other drugs with known... Abuse (NIDA), as described in a Memorandum of Understanding (MOU) of March 8, 1985 (50 FR 9518). When...

  16. 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

  17. 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.

  18. Toward an increased understanding of the barriers to colonic drug absorption in humans: implications for early controlled release candidate assessment.

    PubMed

    Tannergren, Christer; Bergendal, Anna; Lennernäs, Hans; Abrahamsson, Bertil

    2009-01-01

    The purpose of this study was to increase the understanding of in vivo colonic drug absorption in humans by summarizing and evaluating all regional in vivo human absorption data with focus on the interpretation of the colonic absorption data in relation to intestinal permeability and solubility. In addition, the usefulness of the Biopharmaceutics Classification System (BCS) in early assessment of the in vivo colonic absorption potential of controlled release drug candidates was investigated. Clinical regional absorption data (Cmax, Tmax, and AUC) of 42 drugs were collected from journal articles, abstracts, and internal reports, and the relative bioavailability in the colon (Frel(colon)) was obtained directly or calculated. Bioavailability, fraction dose absorbed, and information if the compounds were substrates for P-glycoprotein (P-gp) or cytochrome P450 3A (CYP3A) were also obtained. The BCS I drugs were well absorbed in the colon (Frel(colon) > 70%), although some drugs had lower values due to bacterial degradation in the colon. The low permeability drugs (BCS III/IV) had a lower degree of absorption in the colon (Frel(colon) < 50%). There was a clear correlation between in vitro Caco-2 permeability and Frel(colon), and atenolol and metoprolol may function as permeability markers for low and high colonic absorption, respectively. No obvious effect of P-gp on the colonic absorption of the drugs in this study was detected. There was insufficient data available to fully assess the impact of low solubility and slow dissolution rate. The estimated in vivo fractions dissolved of the only two compounds administered to the colon as both a solution and as solid particles were 55% and 92%, respectively. In conclusion, permeability and solubility are important barriers to colonic absorption in humans, and in vitro testing of these properties is recommended in early assessment of colonic absorption potential.

  19. 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

  20. 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.

  1. 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…

  2. Selecting the Right Tool: A Compendium of Alcohol and Other Drug Assessment and Evaluation Instruments for Use in Higher Education.

    ERIC Educational Resources Information Center

    Presley, Cheryl; Austin, S. Bryn; Jacobs, Judith

    The purpose of this compendium is to assist administrators, staff, evaluators, and alcohol and other drug (AOD) prevention specialists in identifying and selecting feasible, informative, and appropriate evaluation instruments to assess AOD use and monitor program effectiveness on campus. The use of qualitative methods in the evaluation of…

  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. An epidemiological assessment of drug dependence in Malaysia--a trend analysis.

    PubMed

    Navaratnam, V; Foong, K

    1989-06-01

    Information from the national drug abuse monitoring system was analysed to determine the trends in extent and pattern of drug dependence in Malaysia over the period 1970 to 1986. The annual incidence and prevalence rates of reported drug dependents increased by many folds when compared to the early seventies. Generally, the profile of drug dependents identified has remained relatively stable throughout the years. A stable pattern of drug abuse was also noted over this period. Factors influencing the trend patterns are discussed, as well as the implications of these findings for policy purposes. PMID:2626130

  5. Determination of the statistical distributions of model parameters for probabilistic risk assessment

    SciTech Connect

    Fields, D.E.; Glandon, S.R.

    1981-01-01

    Successful probabilistic risk assessment depends heavily on knowledge of the distribution of model parameters we have developed. The TERPED computer code is a versatile methodology for determining with what confidence a parameter set may be considered to have a normal or lognormal frequency distribution. Several measures of central tendency are computed. Other options include computation of the chi-square statistic, the Kolmogorov-Smirnov non-parametric statistic, and Pearson's correlation coefficient. Cumulative probability plots are produced either in high resolution (pen-and-ink or film) or in printerplot form.

  6. [Spatial distribution and landscape ecological impact degree assessment of quarry in Zhuhai City].

    PubMed

    Wu, Zhifeng; Wang, Jizeng; Zhuo, Muning; Wan, Hongfu

    2004-02-01

    Artificial erosion is one of the typical artificial landscape degradation. Based on the support of GIS and RS and combined with field investigation data, the spatial distribution characteristics and landscape ecological impact degree of quarry were analyzed. There were 235 quarries in Zhuhai city, which concentrated on Sanzao town and Jingan town. According to buffer analysis, the quarries distribution had a obviously logarithm relationship with its distances from roads. 152 quarries with the area of more than 5000 m2 were assessed by landscape ecological impact degree (LEI) index. The results indicated that 9 quarries belonged to great influence level and 19 quarries belonged to strong influence on ecological environment.

  7. Preclinical assessment of CNS drug action using eye movements in mice

    PubMed Central

    Cahill, Hugh; Rattner, Amir; Nathans, Jeremy

    2011-01-01

    The drug development process for CNS indications is hampered by a paucity of preclinical tests that accurately predict drug efficacy in humans. Here, we show that a wide variety of CNS-active drugs induce characteristic alterations in visual stimulus–induced and/or spontaneous eye movements in mice. Active compounds included sedatives and antipsychotic, antidepressant, and antiseizure drugs as well as drugs of abuse, such as cocaine, morphine, and phencyclidine. The use of quantitative eye-movement analysis was demonstrated by comparing it with the commonly used rotarod test of motor coordination and by using eye movements to monitor pharmacokinetics, blood-brain barrier penetration, drug-receptor interactions, heavy metal toxicity, pharmacologic treatment in a model of schizophrenia, and degenerative CNS disease. We conclude that eye-movement analysis could complement existing animal tests to improve preclinical drug development. PMID:21821912

  8. 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.

  9. Development, validation and utility of an in vitro technique for assessment of potential clinical drug-drug interactions involving P-glycoprotein.

    PubMed

    Keogh, John P; Kunta, Jeevan R

    2006-04-01

    Regulatory interest is increasing for drug transporters generally and P-glycoprotein (Pgp) in particular, primarily in the area of drug-drug interactions. To aid in both identifying and discharging the potential liabilities associated with drug-transporter interactions, the pharmaceutical industry has a growing requirement for routine and robust non-clinical assays. An assay was designed, optimised and validated to determine the in vitro inhibitory potency of new chemical entities (NCEs) towards human Pgp-mediated transport. [3H]-Digoxin was established as a suitable probe substrate by investigating its characteristics in the in vitro system (MDCKII-MDR1 cells grown in 24-multiwell inserts). The inhibitory potencies (apparent IC50) of known Pgp inhibitors astemizole, GF120918, ketoconazole, itraconazole, quinidine, verapamil and quinine were determined over at least a 1000-fold concentration range. Validation was carried out using manual and automatic techniques. [3H]-Digoxin was found to be stable and have good mass balance in the system. In contrast to [A-->B] transport, [3H]-digoxin [B-->A] transport rates were readily measured with good reproducibility. There was no evidence of saturation of transport up to 10 microM digoxin and 30 nM digoxin was selected for routine assay use, reflecting clinical therapeutic concentrations. IC50 values ranged over approximately 100-fold with excellent reproducibility. Results from manual and automated versions were in close agreement. This method is suitable for routine use to assess the in vitro inhibitory potency of NCEs on Pgp-mediated digoxin transport. Comparison of IC50 values against clinical interaction profiles for the probe inhibitors indicated the in vitro assay is predictive of clinical digoxin-drug interactions mediated via Pgp.

  10. 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

  11. 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

  12. Drug and herb induced liver injury: Council for International Organizations of Medical Sciences scale for causality assessment.

    PubMed

    Teschke, Rolf; Wolff, Albrecht; Frenzel, Christian; Schwarzenboeck, Alexander; Schulze, Johannes; Eickhoff, Axel

    2014-01-27

    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.

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

    NASA Astrophysics Data System (ADS)

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

    1997-05-01

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

  14. Establishment of a Predictive In Vitro Assay for Assessment of the Hepatotoxic Potential of Oligonucleotide Drugs

    PubMed Central

    Sewing, Sabine; Boess, Franziska; Moisan, Annie; Bertinetti-Lapatki, Cristina; Minz, Tanja; Hedtjaern, Maj; Tessier, Yann; Schuler, Franz; Singer, Thomas; Roth, Adrian B.

    2016-01-01

    Single stranded oligonucleotides (SSO) represent a novel therapeutic modality that opens new space to address previously undruggable targets. In spite of their proven efficacy, the development of promising SSO drug candidates has been limited by reported cases of SSO-associated hepatotoxicity. The mechanisms of SSO induced liver toxicity are poorly understood, and up to now no preclinical in vitro model has been established that allows prediction of the hepatotoxicity risk of a given SSO. Therefore, preclinical assessment of hepatic liability currently relies on rodent studies that require large cohorts of animals and lengthy protocols. Here, we describe the establishment and validation of an in vitro assay using primary hepatocytes that recapitulates the hepatotoxic profile of SSOs previously observed in rodents. In vitro cytotoxicity upon unassisted delivery was measured as an increase in extracellular lactate dehydrogenase (LDH) levels and concomitant reduction in intracellular glutathione and ATP levels after 3 days of treatment. Furthermore, toxic, but not safe, SSOs led to an increase in miR-122 in cell culture supernatants after 2 days of exposure, revealing the potential use of miR122 as a selective translational biomarker for detection of SSO-induced hepatotoxicity. Overall, we have developed and validated for the first time a robust in vitro screening assay for SSO liver safety profiling which allows rapid prioritization of candidate molecules early on in development. PMID:27442522

  15. [Patient response to and assessment of intracavernous drug injection and vacuum].

    PubMed

    Vives Suñé, A; Ribé Subirá, N; Manasia, P; Pomerol Monseny, J M

    2000-03-01

    One of the various therapeutic options currently used in erectile dysfunction (ED), vacuum is a procedure that should not be ruled out as it can benefit certain types of patient. To understand each patient's response and usage readiness, a vacuum test is routinely performed by the andrology service as part of the diagnostic study. The present study conducted on 200 patients with ED of different etiologies, included the vacuum test and the intracavernous injection of vasoactive drugs. The assessment included the response to each methodology; which of the two systems offered better response; and initial usage readiness to each system. Positive response was 93% in the vacuum test, and 40% in the intracavernous injection. Improved erection was reported by 73% with vacuum and only 13% with the intracavernous injection. With regard to usage readiness 60.5% favoured vacuum and only 14.5% the intracavernous injection. It was apparent that vacuum is a highly effective methodology with very high initial usage readiness, although ultimate use may be limited for different reasons.

  16. Establishment of a Predictive In Vitro Assay for Assessment of the Hepatotoxic Potential of Oligonucleotide Drugs.

    PubMed

    Sewing, Sabine; Boess, Franziska; Moisan, Annie; Bertinetti-Lapatki, Cristina; Minz, Tanja; Hedtjaern, Maj; Tessier, Yann; Schuler, Franz; Singer, Thomas; Roth, Adrian B

    2016-01-01

    Single stranded oligonucleotides (SSO) represent a novel therapeutic modality that opens new space to address previously undruggable targets. In spite of their proven efficacy, the development of promising SSO drug candidates has been limited by reported cases of SSO-associated hepatotoxicity. The mechanisms of SSO induced liver toxicity are poorly understood, and up to now no preclinical in vitro model has been established that allows prediction of the hepatotoxicity risk of a given SSO. Therefore, preclinical assessment of hepatic liability currently relies on rodent studies that require large cohorts of animals and lengthy protocols. Here, we describe the establishment and validation of an in vitro assay using primary hepatocytes that recapitulates the hepatotoxic profile of SSOs previously observed in rodents. In vitro cytotoxicity upon unassisted delivery was measured as an increase in extracellular lactate dehydrogenase (LDH) levels and concomitant reduction in intracellular glutathione and ATP levels after 3 days of treatment. Furthermore, toxic, but not safe, SSOs led to an increase in miR-122 in cell culture supernatants after 2 days of exposure, revealing the potential use of miR122 as a selective translational biomarker for detection of SSO-induced hepatotoxicity. Overall, we have developed and validated for the first time a robust in vitro screening assay for SSO liver safety profiling which allows rapid prioritization of candidate molecules early on in development. PMID:27442522

  17. Accuracy assessment and automation of free energy calculations for drug design.

    PubMed

    Christ, Clara D; Fox, Thomas

    2014-01-27

    As the free energy of binding of a ligand to its target is one of the crucial optimization parameters in drug design, its accurate prediction is highly desirable. In the present study we have assessed the average accuracy of free energy calculations for a total of 92 ligands binding to five different targets. To make this study and future larger scale applications possible we automated the setup procedure. Starting from user defined binding modes, the procedure decides which ligands to connect via a perturbation based on maximum common substructure criteria and produces all necessary parameter files for free energy calculations in AMBER 11. For the systems investigated, errors due to insufficient sampling were found to be substantial in some cases whereas differences in estimators (thermodynamic integration (TI) versus multistate Bennett acceptance ratio (MBAR)) were found to be negligible. Analytical uncertainty estimates calculated from a single free energy calculation were found to be much smaller than the sample standard deviation obtained from two independent free energy calculations. Agreement with experiment was found to be system dependent ranging from excellent to mediocre (RMSE = [0.9, 8.2, 4.7, 5.7, 8.7] kJ/mol). When restricting analyses to free energy calculations with sample standard deviations below 1 kJ/mol agreement with experiment improved (RMSE = [0.8, 6.9, 1.8, 3.9, 5.6] kJ/mol).

  18. 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.

  19. Establishment of a Predictive In Vitro Assay for Assessment of the Hepatotoxic Potential of Oligonucleotide Drugs.

    PubMed

    Sewing, Sabine; Boess, Franziska; Moisan, Annie; Bertinetti-Lapatki, Cristina; Minz, Tanja; Hedtjaern, Maj; Tessier, Yann; Schuler, Franz; Singer, Thomas; Roth, Adrian B

    2016-01-01

    Single stranded oligonucleotides (SSO) represent a novel therapeutic modality that opens new space to address previously undruggable targets. In spite of their proven efficacy, the development of promising SSO drug candidates has been limited by reported cases of SSO-associated hepatotoxicity. The mechanisms of SSO induced liver toxicity are poorly understood, and up to now no preclinical in vitro model has been established that allows prediction of the hepatotoxicity risk of a given SSO. Therefore, preclinical assessment of hepatic liability currently relies on rodent studies that require large cohorts of animals and lengthy protocols. Here, we describe the establishment and validation of an in vitro assay using primary hepatocytes that recapitulates the hepatotoxic profile of SSOs previously observed in rodents. In vitro cytotoxicity upon unassisted delivery was measured as an increase in extracellular lactate dehydrogenase (LDH) levels and concomitant reduction in intracellular glutathione and ATP levels after 3 days of treatment. Furthermore, toxic, but not safe, SSOs led to an increase in miR-122 in cell culture supernatants after 2 days of exposure, revealing the potential use of miR122 as a selective translational biomarker for detection of SSO-induced hepatotoxicity. Overall, we have developed and validated for the first time a robust in vitro screening assay for SSO liver safety profiling which allows rapid prioritization of candidate molecules early on in development.

  20. 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.

  1. 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).

  2. 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.

  3. Assessment of flood magnitude estimator uncertainty: Tolerance limits for the gamma and generalized gamma distributions

    SciTech Connect

    Ashkar, F.; Ouarda, T.B.M.J.

    1995-12-31

    The quantification of the uncertainty associated with hydrologic {open_quotes}design-event{close_quotes} estimations (e.g., flood quantile estimation by statistical flood frequency analysis) is an important problem in the assessment of the design risk associated with hydraulic structures. In and semi-arid regions the 2-parameter gamma (G2) distribution is a possible candidate for estimating flood-flow probabilities from annual flood series. The distribution has also many other hydrological applications. An approximate method is proposed for constructing approximate confidence intervals (CI`s) for quantiles of the G2 distribution. Simulation was used to test this approximate method, Similar simulation experiments were carried out for the 3-parameter generalized gamma (GG3) distribution, which has more shape flexibility than the G2. The methods of moments (MM) and of maximum likelihood (ML) were used to fit both the G2 and GG3 distributions. Useful results concerning both the G2 and GG3 distributions, based on these two estimation methods, were obtained.

  4. 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.

  5. 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

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

    NASA Astrophysics Data System (ADS)

    Aksoy, Ece; Panagos, Panos; Montanarella, Luca

    2013-04-01

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

  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.

  8. QQ-plots for assessing distributions of biomarker measurements and generating defensible summary statistics.

    PubMed

    Pleil, Joachim D

    2016-01-01

    One of the main uses of biomarker measurements is to compare different populations to each other and to assess risk in comparison to established parameters. This is most often done using summary statistics such as central tendency, variance components, confidence intervals, exceedance levels and percentiles. Such comparisons are only valid if the underlying assumptions of distribution are correct. This article discusses methodology for interpreting and evaluating data distributions using quartile-quartile plots (QQ-plots) and making decisions as to how to treat outliers, interpreting effects of mixed distributions, and identifying left-censored data. The QQ-plot graph is shown to be a simple and elegant tool for visual inspection of complex data and deciding if summary statistics should be performed after log-transformation. PMID:27491525

  9. 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.

  10. Measuring Topology of Low-Intensity DNA Methylation Sites for High Throughput Assessment of Epigenetic Drug-Induced Effects in Cancer Cells

    PubMed Central

    Gertych, Arkadiusz; Farkas, Daniel L.; Tajbakhsh, Jian

    2010-01-01

    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: LIM0.5 and LID0.5. 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. LIM0.5 and LID0.5 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

  11. Measuring topology of low-intensity DNA methylation sites for high-throughput assessment of epigenetic drug-induced effects in cancer cells

    SciTech Connect

    Gertych, Arkadiusz; 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

  12. 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.

  13. Quantitative microbial risk assessment of distributed drinking water using faecal indicator incidence and concentrations.

    PubMed

    van Lieverloo, J Hein M; Blokker, E J Mirjam; Medema, Gertjan

    2007-01-01

    Quantitative Microbial Risk Assessments (QMRA) have focused on drinking water system components upstream of distribution to customers, for nominal and event conditions. Yet some 15-33% of waterborne outbreaks are reported to be caused by contamination events in distribution systems. In the majority of these cases and probably in all non-outbreak contamination events, no pathogen concentration data was available. Faecal contamination events are usually detected or confirmed by the presence of E. coli or other faecal indicators, although the absence of this indicator is no guarantee of the absence of faecal pathogens. In this paper, the incidence and concentrations of various coliforms and sources of faecal contamination were used to estimate the possible concentrations of faecal pathogens and consequently the infection risks to consumers in event-affected areas. The results indicate that the infection risks may be very high, especially from Campylobacter and enteroviruses, but also that the uncertainties are very high. The high variability of pathogen to thermotolerant coliform ratios estimated in environmental samples severely limits the applicability of the approach described. Importantly, the highest ratios of enteroviruses to thermotolerant coliform were suggested from soil and shallow groundwaters, the most likely sources of faecal contamination that are detected in distribution systems. Epidemiological evaluations of non-outbreak faecal contamination of drinking water distribution systems and thorough tracking and characterisation of the contamination sources are necessary to assess the actual risks of these events.

  14. 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.

  15. Multiscale Modeling of Antibody-Drug Conjugates: Connecting Tissue and Cellular Distribution to Whole Animal Pharmacokinetics and Potential Implications for Efficacy.

    PubMed

    Cilliers, Cornelius; Guo, Hans; Liao, Jianshan; Christodolu, Nikolas; Thurber, Greg M

    2016-09-01

    Antibody-drug conjugates exhibit complex pharmacokinetics due to their combination of macromolecular and small molecule properties. These issues range from systemic concerns, such as deconjugation of the small molecule drug during the long antibody circulation time or rapid clearance from nonspecific interactions, to local tumor tissue heterogeneity, cell bystander effects, and endosomal escape. Mathematical models can be used to study the impact of these processes on overall distribution in an efficient manner, and several types of models have been used to analyze varying aspects of antibody distribution including physiologically based pharmacokinetic (PBPK) models and tissue-level simulations. However, these processes are quantitative in nature and cannot be handled qualitatively in isolation. For example, free antibody from deconjugation of the small molecule will impact the distribution of conjugated antibodies within the tumor. To incorporate these effects into a unified framework, we have coupled the systemic and organ-level distribution of a PBPK model with the tissue-level detail of a distributed parameter tumor model. We used this mathematical model to analyze new experimental results on the distribution of the clinical antibody-drug conjugate Kadcyla in HER2-positive mouse xenografts. This model is able to capture the impact of the drug-antibody ratio (DAR) on tumor penetration, the net result of drug deconjugation, and the effect of using unconjugated antibody to drive ADC penetration deeper into the tumor tissue. This modeling approach will provide quantitative and mechanistic support to experimental studies trying to parse the impact of multiple mechanisms of action for these complex drugs. PMID:27287046

  16. Evidence-based approach to assess passive diffusion and carrier-mediated drug transport.

    PubMed

    Di, Li; Artursson, Per; Avdeef, Alex; Ecker, Gerhard F; Faller, Bernard; Fischer, Holger; Houston, J Brian; Kansy, Manfred; Kerns, Edward H; Krämer, Stefanie D; Lennernäs, Hans; Sugano, Kiyohiko

    2012-08-01

    Evidence supporting the action of passive diffusion and carrier-mediated (CM) transport in drug bioavailability and disposition is discussed to refute the recently proposed theory that drug transport is CM-only and that new transporters will be discovered that possess transport characteristics ascribed to passive diffusion. Misconceptions and faulty speculations are addressed to provide reliable guidance on choosing appropriate tools for drug design and optimization.

  17. 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, André; 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

  18. 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

  19. 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.

  20. 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

  1. 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

  2. Assessment of Spatial Distribution of Growth in the Elongation Zone of Grass Leaf Blades 1

    PubMed Central

    Schnyder, Hans; Nelson, Curtis J.; Coutts, John H.

    1987-01-01

    Knowledge about the spatial distribution of growth is essential for understanding the leaf growth process. In grasses the elongation zone is located at the base of the leaf blade and is enclosed by sheaths of older leaves. Assessment of spatial growth distribution, therefore, necessitates use of a destructive method. We used a fine needle to make holes through bases of tillers at the location of the leaf elongation zone of tall fescue (Festuca arundinacea Schreb.), then measured the displacement of the holes after a 6 or 24 h interval. Needle holes caused a 22 to 41% decrease in daily leaf elongation so experiments were conducted to investigate if the spatial distribution of growth in the elongation zone was altered. Leaf elongation rate was reduced similarly when needle holes were made within or above the zone where cell elongation occurs. Distribution of elongation within the zone was the same when estimated by displacement of needle holes or ink marks placed on the epidermis of the elongation zone after surrounding tissue had been removed. Making holes at different locations within the elongation zone did not differentially affect the relative contribution of the damaged or undamaged parts to leaf elongation. These findings demonstrate that needle holes or ink marks in paired leaves can be used to estimate the relative distribution of growth in the elongation zone of undamaged tall fescue leaf blades. PMID:16665672

  3. Pharmacokinetic drug-drug interaction assessment of LCZ696 (an angiotensin receptor neprilysin inhibitor) with omeprazole, metformin or levonorgestrel-ethinyl estradiol in healthy subjects.

    PubMed

    Gan, Lu; Jiang, Xuemin; Mendonza, Anisha; Swan, Therese; Reynolds, Christine; Nguyen, Joanne; Pal, Parasar; Neelakantham, Srikanth; Dahlke, Marion; Langenickel, Thomas; Rajman, Iris; Akahori, Mizuki; Zhou, Wei; Rebello, Sam; Sunkara, Gangadhar

    2016-01-01

    LCZ696 is a novel angiotensin receptor neprilysin inhibitor in development for the treatment of cardiovascular diseases. Here, we assessed the potential for pharmacokinetic drug-drug interaction of LCZ696 (400 mg, single dose or once daily [q.d.]) when co-administered with omeprazole 40 mg q.d. (n = 28) or metformin 1000 mg q.d. (n = 27) or levonorgestrel-ethinyl estradiol 150/30 μg single dose (n = 24) in three separate open-label, single-sequence studies in healthy subjects. Pharmacokinetic parameters of LCZ696 analytes (sacubitril, LBQ657, and valsartan), metformin, and levonorgestrel-ethinyl estradiol were assessed. Omeprazole did not alter the AUCinf of sacubitril and pharmacokinetics of LBQ657; however, 7% decrease in the Cmax of sacubitril, and 11% and 13% decreases in AUCinf and Cmax of valsartan were observed. Co-administration of LCZ696 with metformin had no significant effect on the pharmacokinetics of LBQ657 and valsartan; however, AUCtau,ss and Cmax,ss of metformin were decreased by 23%. Co-administration of LCZ696 with levonorgestrel-ethinyl estradiol had no effect on the pharmacokinetics of ethinyl estradiol and LBQ657 or AUCinf of levonorgestrel. The Cmax of levonorgestrel decreased by 15%, and AUCtau,ss and Cmax,ss of valsartan decreased by 14% and 16%, respectively. Co-administration of LCZ696 with omeprazole, metformin, or levonorgestrel-ethinyl estradiol was not associated with any clinically relevant pharmacokinetic drug interactions. PMID:27119576

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

    NASA Astrophysics Data System (ADS)

    Maurer, Thomas; Brück, Yasemine; Hinz, Christoph; Gerke, Horst H.

    2015-04-01

    Structural heterogeneity, namely the spatial distribution of soils and sediments (represented by mineral particles), characterizes catchment hydrological behavior. In natural catchments, local geology and the specific geomorphic processes determine the characteristics and spatial distribution of structures. In constructed catchments, structural features are determined primarily by the construction processes and the geological origin of the parent material. Objectives are scenarios of 3D catchment structures in form of complete 3D description of soil hydraulic properties generated from the knowledge of the formation processes. The constructed hydrological catchment 'Hühnerwasser' (Lower Lusatia, Brandenburg, Germany) was used for the calibration and validation of model results due to its well-known conditions. For the modelling of structural features, a structure generator was used to model i) quasi-deterministic sediment distributions using input data from a geological model of the parent material excavation site; ii) sediment distributions that are conditioned to measurement data from soil sampling; and iii) stochastic component sediment distributions. All three approaches allow a randomization within definable limits. Furthermore, the spoil cone / spoil ridge orientation, internal layering, surface compaction and internal spoil cone compaction were modified. These generated structural models were incorporated in a gridded 3D volume model constructed with the GOCAD software. For selected scenarios, the impact of structure variation was assessed by hydrological modelling with HYDRUS 2D/3D software. For that purpose, 3D distributions of soil hydraulic properties were estimated based on generated sediment properties using adapted pedotransfer functions. Results from the hydrological model were compared them to measured discharges from the catchment. The impact of structural feature variation on flow behaviour was analysed by comparing different simulation scenarios

  5. Methodological approach to determine minor, considerable, and major treatment effects in the early benefit assessment of new drugs.

    PubMed

    Skipka, Guido; Wieseler, Beate; Kaiser, Thomas; Thomas, Stefanie; Bender, Ralf; Windeler, Jürgen; Lange, Stefan

    2016-01-01

    At the beginning of 2011, the early benefit assessment of new drugs was introduced in Germany with the Act on the Reform of the Market for Medicinal Products (AMNOG). The Federal Joint Committee (G-BA) generally commissions the Institute for Quality and Efficiency in Health Care (IQWiG) with this type of assessment, which examines whether a new drug shows an added benefit (a positive patient-relevant treatment effect) over the current standard therapy. IQWiG is required to assess the extent of added benefit on the basis of a dossier submitted by the pharmaceutical company responsible. In this context, IQWiG was faced with the task of developing a transparent and plausible approach for operationalizing how to determine the extent of added benefit. In the case of an added benefit, the law specifies three main extent categories (minor, considerable, major). To restrict value judgements to a minimum in the first stage of the assessment process, an explicit and abstract operationalization was needed. The present paper is limited to the situation of binary data (analysis of 2 × 2 tables), using the relative risk as an effect measure. For the treatment effect to be classified as a minor, considerable, or major added benefit, the methodological approach stipulates that the (two-sided) 95% confidence interval of the effect must exceed a specified distance to the zero effect. In summary, we assume that our approach provides a robust, transparent, and thus predictable foundation to determine minor, considerable, and major treatment effects on binary outcomes in the early benefit assessment of new drugs in Germany. After a decision on the added benefit of a new drug by G-BA, the classification of added benefit is used to inform pricing negotiations between the umbrella organization of statutory health insurance and the pharmaceutical companies. PMID:26134089

  6. Methodological approach to determine minor, considerable, and major treatment effects in the early benefit assessment of new drugs

    PubMed Central

    Wieseler, Beate; Kaiser, Thomas; Thomas, Stefanie; Bender, Ralf; Windeler, Jürgen; Lange, Stefan

    2016-01-01

    At the beginning of 2011, the early benefit assessment of new drugs was introduced in Germany with the Act on the Reform of the Market for Medicinal Products (AMNOG). The Federal Joint Committee (G‐BA) generally commissions the Institute for Quality and Efficiency in Health Care (IQWiG) with this type of assessment, which examines whether a new drug shows an added benefit (a positive patient‐relevant treatment effect) over the current standard therapy. IQWiG is required to assess the extent of added benefit on the basis of a dossier submitted by the pharmaceutical company responsible. In this context, IQWiG was faced with the task of developing a transparent and plausible approach for operationalizing how to determine the extent of added benefit. In the case of an added benefit, the law specifies three main extent categories (minor, considerable, major). To restrict value judgements to a minimum in the first stage of the assessment process, an explicit and abstract operationalization was needed. The present paper is limited to the situation of binary data (analysis of 2 × 2 tables), using the relative risk as an effect measure. For the treatment effect to be classified as a minor, considerable, or major added benefit, the methodological approach stipulates that the (two‐sided) 95% confidence interval of the effect must exceed a specified distance to the zero effect. In summary, we assume that our approach provides a robust, transparent, and thus predictable foundation to determine minor, considerable, and major treatment effects on binary outcomes in the early benefit assessment of new drugs in Germany. After a decision on the added benefit of a new drug by G‐BA, the classification of added benefit is used to inform pricing negotiations between the umbrella organization of statutory health insurance and the pharmaceutical companies. PMID:26134089

  7. A Collaborative Assessment Among 11 Pharmaceutical Companies of Misinformation in Commonly Used Online Drug Information Compendia

    PubMed Central

    Randhawa, Amarita S.; Babalola, Olakiitan; Henney, Zachary; Miller, Michele; Nelson, Tanya; Oza, Meerat; Patel, Chandni; Randhawa, Anupma S.; Riley, Joyce; Snyder, Scott; So, Sherri

    2016-01-01

    Background: Online drug information compendia (ODIC) are valuable tools that health care professionals (HCPs) and consumers use to educate themselves on pharmaceutical products. Research suggests that these resources, although informative and easily accessible, may contain misinformation, posing risk for product misuse and patient harm. Objective: Evaluate drug summaries within ODIC for accuracy and completeness and identify product-specific misinformation. Methods: Between August 2014 and January 2015, medical information (MI) specialists from 11 pharmaceutical/biotechnology companies systematically evaluated 270 drug summaries within 5 commonly used ODIC for misinformation. Using a standardized approach, errors were identified; classified as inaccurate, incomplete, or omitted; and categorized per sections of the Full Prescribing Information (FPI). On review of each drug summary, content-correction requests were proposed and supported by the respective product’s FPI. Results: Across the 270 drug summaries reviewed within the 5 compendia, the median of the total number of errors identified was 782, with the greatest number of errors occurring in the categories of Dosage and Administration, Patient Education, and Warnings and Precautions. The majority of errors were classified as incomplete, followed by inaccurate and omitted. Conclusion: This analysis demonstrates that ODIC may contain misinformation. HCPs and consumers should be aware of the potential for misinformation and consider more than 1 drug information resource, including the FPI and Medication Guide as well as pharmaceutical/biotechnology companies’ MI departments, to obtain unbiased, accurate, and complete product-specific drug information to help support the safe and effective use of prescription drug products. PMID:26917822

  8. In vitro assessment of pharmacogenetic susceptibility to toxic drug metabolites in humans.

    PubMed

    Spielberg, S P

    1984-05-15

    An experimental approach to the pharmacogenetics of human idiosyncratic drug reactions requires an assay for determining individual differences in susceptibility that does not expose patients to further drug-related risk. We have developed an in vitro drug toxicity assay designed to test the hypothesis that differences in susceptibility may be based on genetic abnormalities in the detoxification of electrophilic drug metabolites. Lymphocytes are challenged with metabolites generated by a murine hepatic microsomal system. By using cells from patients deficient in glutathione synthetase, we found that cells with decreased glutathione defenses are more sensitive to toxicity from metabolites of drugs such as acetaminophen, nitrofurantoin, and metronidazole. The assay was then applied to studying the pharmacogenetics of phenytoin hepatotoxicity. We found an inherited defect in the detoxification of phenytoin arene oxide metabolites in cells from patients and their relatives. The studies have led to an elucidation of a genetically heterogeneous group of detoxification defects for arene oxide metabolites of various aromatic drugs. Such experimental approaches may be useful in diagnosing idiosyncratic drug reactions, in establishing their pharmacogenetic basis, and perhaps in predicting toxicity potential of drugs for selected patients and families.

  9. 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.

  10. 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…

  11. Assessing landscape structure and pattern fragmentation in semiarid ecosystems using patch-size distributions.

    PubMed

    Moreno-de Las Heras, Mariano; Saco, Patricia M; Willgoose, Garry R; Tongway, David J

    2011-10-01

    Spatial vegetation patterns are recognized as sources of valuable information that can be used to infer the state and functionality of semiarid ecosystems, particularly in the context of both climate and land use change. Recent studies have suggested that the patch-size distribution of vegetation in drylands can be described using power-law metrics, and that these scale-free distributions deviate from power-law linearity with characteristic scale lengths under the effects of increasing aridity or human disturbance, providing an early sign of desertification. These findings have been questioned by several modeling approaches, which have identified the presence of characteristic scale lengths on the patch-size distribution of semiarid periodic landscapes. We analyze the relationship between fragmentation of vegetation patterns and their patch-size distributions in semiarid landscapes showing different degree of periodicity (i.e., banding). Our assessment is based on the study of vegetation patterns derived from remote sensing in a series of semiarid Australian Mulga shrublands subjected to different disturbance levels. We use the patch-size probability density and cumulative probability distribution functions from both nondirectional and downslope analyses of the vegetation patterns. Our results indicate that the shape of the patch-size distribution of vegetation changes with the methodology of analysis applied and specific landscape traits, breaking the universal applicability of the power-law metrics. Characteristic scale lengths are detected in (quasi) periodic banded ecosystems when the methodology of analysis accounts for critical landscape anisotropies, using downslope transects in the direction of flow paths. In addition, a common signal of fragmentation is observed: the largest vegetation patches become increasingly less abundant under the effects of disturbance. This effect also explains deviations from power-law behavior in disturbed vegetation which

  12. The Added Value of Assessing Ligand-Receptor Binding Kinetics in Drug Discovery.

    PubMed

    Guo, Dong; Heitman, Laura H; IJzerman, Adriaan P

    2016-09-01

    In the past decade drug research community has started to appreciate the indispensable role of ligand-receptor binding kinetics (BK) in drug discovery. Next to the classical equilibrium-based drug evaluation process with affinity and potency values as outcomes, kinetic investigation of the ligand-receptor interaction can aid compound triage in the hit-to-lead campaign and provide additional information to understand the molecular mechanism of drug action. Translational models incorporating BK are emerging as well, which represent powerful tools for the prediction of in vivo effects. In this viewpoint we will summarize some recent findings and discuss and emphasize the added value of ligand-receptor binding kinetics in drug research. PMID:27660682

  13. Assessing the long-term impact of drug court participation on recidivism with generalized estimating equations.

    PubMed

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

    2007-11-01

    Drug courts are one of the most common strategies for dealing with the large proportion of criminal offenders who are drug-involved, yet methodological limitations limit the conclusions that can be drawn from many existing evaluations of their effectiveness. The current study examined the long-term impact of drug court participation compared to regular probation on the recidivism of 475 drug-involved offenders under supervision in Hillsborough County, Florida. Using a combination of self-reported data (collected through in-person interviews at baseline, i.e., the beginning of supervision) and administrative records, the study employed a repeated measures framework (examining five 6-month time periods from baseline to 30 months post-baseline) and generalized estimating equations to compare the likelihood of being arrested between drug court participants and a matched sample of comparison offenders. The results indicate that participation in drug court was associated with a significant decrease in the likelihood of being arrested in the 12-18 months post-baseline time period. Although the drug court effect was somewhat delayed (it was not significant prior to 12 months) and short-lived (it was not significant after 18 months), the fact that significant program effects were observed during a time period that coincides with the conclusion of drug court participation for graduates and a time period well beyond initial program exposure, suggests that drug court participants are more likely than comparable offenders not exposed to drug court to remain arrest free when no longer under community supervision.

  14. Bioprinted 3D Primary Liver Tissues Allow Assessment of Organ-Level Response to Clinical Drug Induced Toxicity In Vitro

    PubMed Central

    Funk, Juergen; Robbins, Justin B.; Crogan-Grundy, Candace; Presnell, Sharon C.; Singer, Thomas; Roth, Adrian B.

    2016-01-01

    Modeling clinically relevant tissue responses using cell models poses a significant challenge for drug development, in particular for drug induced liver injury (DILI). This is mainly because existing liver models lack longevity and tissue-level complexity which limits their utility in predictive toxicology. In this study, we established and characterized novel bioprinted human liver tissue mimetics comprised of patient-derived hepatocytes and non-parenchymal cells in a defined architecture. Scaffold-free assembly of different cell types in an in vivo-relevant architecture allowed for histologic analysis that revealed distinct intercellular hepatocyte junctions, CD31+ endothelial networks, and desmin positive, smooth muscle actin negative quiescent stellates. Unlike what was seen in 2D hepatocyte cultures, the tissues maintained levels of ATP, Albumin as well as expression and drug-induced enzyme activity of Cytochrome P450s over 4 weeks in culture. To assess the ability of the 3D liver cultures to model tissue-level DILI, dose responses of Trovafloxacin, a drug whose hepatotoxic potential could not be assessed by standard pre-clinical models, were compared to the structurally related non-toxic drug Levofloxacin. Trovafloxacin induced significant, dose-dependent toxicity at clinically relevant doses (≤ 4uM). Interestingly, Trovafloxacin toxicity was observed without lipopolysaccharide stimulation and in the absence of resident macrophages in contrast to earlier reports. Together, these results demonstrate that 3D bioprinted liver tissues can both effectively model DILI and distinguish between highly related compounds with differential profile. Thus, the combination of patient-derived primary cells with bioprinting technology here for the first time demonstrates superior performance in terms of mimicking human drug response in a known target organ at the tissue level. PMID:27387377

  15. Hospital distribution in a metropolitan city: assessment by a geographic information system grid modelling approach.

    PubMed

    Lee, Kwang-Soo; Moon, Kyeong-Jun

    2014-05-01

    Grid models were used to assess urban hospital distribution in Seoul, the capital of South Korea. A geographical information system (GIS) based analytical model was developed and applied to assess the situation in a metropolitan area with a population exceeding 10 million. Secondary data for this analysis were obtained from multiple sources: the Korean Statistical Information Service, the Korean Hospital Association and the Statistical Geographical Information System. A grid of cells measuring 1 × 1 km was superimposed on the city map and a set of variables related to population, economy, mobility and housing were identified and measured for each cell. Socio-demographic variables were included to reflect the characteristics of each area. Analytical models were then developed using GIS software with the number of hospitals as the dependent variable. Applying multiple linear regression and geographically weighted regression models, three factors (highway and major arterial road areas; number of subway entrances; and row house areas) were statistically significant in explaining the variance of hospital distribution for each cell. The overall results show that GIS is a useful tool for analysing and understanding location strategies. This approach appears a useful source of information for decision-makers concerned with the distribution of hospitals and other health care centres in a city.

  16. Towards a global water scarcity risk assessment framework: using scenarios and risk distributions

    NASA Astrophysics Data System (ADS)

    Veldkamp, Ted; Wada, Yoshihide; Aerts, Jeroen; Ward, Philip

    2016-04-01

    Over the past decades, changing hydro-climatic and socioeconomic conditions have led to increased water scarcity problems. A large number of studies have shown that these water scarcity conditions will worsen in the near future. Despite numerous calls for risk-based assessments of water scarcity, a framework that includes UNISDR's definition of risk does not yet exist at the global scale. This study provides a first step towards such a risk-based assessment, applying a Gamma distribution to estimate water scarcity conditions at the global scale under historic and future conditions, using multiple climate change projections and socioeconomic scenarios. Our study highlights that water scarcity risk increases given all future scenarios, up to >56.2% of the global population in 2080. Looking at the drivers of risk, we find that population growth outweigh the impacts of climate change at global and regional scales. Using a risk-based method to assess water scarcity in terms of Expected Annual Exposed Population, we show the results to be less sensitive than traditional water scarcity assessments to the use of fixed threshold to represent different levels of water scarcity. This becomes especially important when moving from global to local scales, whereby deviations increase up to 50% of estimated risk levels. Covering hazard, exposure, and vulnerability, risk-based methods are well-suited to assess water scarcity adaptation. Completing the presented risk framework therefore offers water managers a promising perspective to increase water security in a well-informed and adaptive manner.

  17. Assessment of absorption potential of poorly water-soluble drugs by using the dissolution/permeation system.

    PubMed

    Kataoka, Makoto; Yano, Koji; Hamatsu, Yoriko; Masaoka, Yoshie; Sakuma, Shinji; Yamashita, Shinji

    2013-11-01

    This study aims to assess the absorption potential of oral absorption of poorly water-soluble drugs by using the dissolution/permeation system (D/P system). The D/P system can be used to perform analysis of drug permeation under dissolution process and can predict the fraction of absorbed dose in humans. When celecoxib at 1/100 of a clinical dose was applied to the D/P system, percentage of dose dissolved and permeated significantly decreased with an increase in the applied amount, resulting in the oral absorption being predicted to be 22-55%. Whereas similar dissolution and permeation profiles of montelukast sodium were observed, estimated absorption (69-85%) was slightly affected. Zafirlukast absorption (33-36%) was not significantly affected by the dose, although zafirlukast did not show complete dissolution. The relationship between clinical dose and predicted oral absorption of drugs corresponded well to clinical observations. The limiting step of the oral absorption of celecoxib and montelukast sodium was solubility, while that of zafirlukast was dissolution rate. However, due to high permeability of montelukast, oral absorption was not affected by dose. Therefore, the D/P system is a useful tool to assess the absorption potential of poorly water-soluble drugs for oral use.

  18. Combining PET biodistribution and equilibrium dialysis assays to assess the free brain concentration and BBB transport of CNS drugs

    PubMed Central

    Gunn, Roger N; Summerfield, Scott G; Salinas, Cristian A; Read, Kevin D; Guo, Qi; Searle, Graham E; Parker, Christine A; Jeffrey, Phil; Laruelle, Marc

    2012-01-01

    The passage of drugs in and out of the brain is controlled by the blood–brain barrier (BBB), typically, using either passive diffusion across a concentration gradient or active transport via a protein carrier. In-vitro and preclinical measurements of BBB penetration do not always accurately predict the in-vivo situation in humans. Thus, the ability to assay the concentration of novel drug candidates in the human brain in vivo provides valuable information for derisking of candidate molecules early in drug development. Here, positron emission tomography (PET) measurements are combined with in-vitro equilibrium dialysis assays to enable assessment of transport and estimation of the free brain concentration in vivo. The PET and equilibrium dialysis data were obtained for 36 compounds in the pig. Predicted P-glycoprotein (P-gp) status of the compounds was consistent with the PET/equilibrium dialysis results. In particular, Loperamide, a well-known P-gp substrate, exhibited a significant concentration gradient consistent with active efflux and after inhibition of the P-gp process the gradient was removed. The ability to measure the free brain concentration and assess transport of novel compounds in the human brain with combined PET and equilibrium dialysis assays can be a useful tool in central nervous system (CNS) drug development. PMID:22274741

  19. Assessment of absorption potential of poorly water-soluble drugs by using the dissolution/permeation system.

    PubMed

    Kataoka, Makoto; Yano, Koji; Hamatsu, Yoriko; Masaoka, Yoshie; Sakuma, Shinji; Yamashita, Shinji

    2013-11-01

    This study aims to assess the absorption potential of oral absorption of poorly water-soluble drugs by using the dissolution/permeation system (D/P system). The D/P system can be used to perform analysis of drug permeation under dissolution process and can predict the fraction of absorbed dose in humans. When celecoxib at 1/100 of a clinical dose was applied to the D/P system, percentage of dose dissolved and permeated significantly decreased with an increase in the applied amount, resulting in the oral absorption being predicted to be 22-55%. Whereas similar dissolution and permeation profiles of montelukast sodium were observed, estimated absorption (69-85%) was slightly affected. Zafirlukast absorption (33-36%) was not significantly affected by the dose, although zafirlukast did not show complete dissolution. The relationship between clinical dose and predicted oral absorption of drugs corresponded well to clinical observations. The limiting step of the oral absorption of celecoxib and montelukast sodium was solubility, while that of zafirlukast was dissolution rate. However, due to high permeability of montelukast, oral absorption was not affected by dose. Therefore, the D/P system is a useful tool to assess the absorption potential of poorly water-soluble drugs for oral use. PMID:23811221

  20. Distribution and quantitative assessment of world crude oil reserves and resources

    USGS Publications Warehouse

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

    1983-01-01

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

  1. 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.

  2. 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

  3. 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.

  4. Determining Partition Coefficient (Log P), Distribution Coefficient (Log D) and Ionization Constant (pKa) in Early Drug Discovery.

    PubMed

    Bharate, Sonali S; Kumar, Vikas; Vishwakarma, Ram A

    2016-01-01

    An early prediction of physicochemical properties is highly desirable during drug discovery to find out a viable lead candidate. Although there are several methods available to determine partition coefficient (log P), distribution coefficient (log D) and ionization constant (pKa), none of them involves simple and fixed, miniaturized protocols for diverse set of compounds. Therefore, it is necessary to establish simple, uniform and medium-throughput protocols requiring small sample quantities for the determination of these physicochemical properties. Log P and log D were determined by shake flask method, wherein, the compound was partitioned between presaturated noctanol and water phase (water/PBS pH 7.4) and the concentration of compound in each phase was determined by HPLC. The pKa determination made use of UV spectrophotometric analysis in a 96-well microtiter plate containing a series of aqueous buffers ranging from pH 1.0 to 13.0. The medium-throughput miniaturized protocols described herein, for determination of log P, log D and pKa, are straightforward to set up and require very small quantities of sample (< 5 mg for all three properties). All established protocols were validated using diverse set of compounds.

  5. Determining Partition Coefficient (Log P), Distribution Coefficient (Log D) and Ionization Constant (pKa) in Early Drug Discovery.

    PubMed

    Bharate, Sonali S; Kumar, Vikas; Vishwakarma, Ram A

    2016-01-01

    An early prediction of physicochemical properties is highly desirable during drug discovery to find out a viable lead candidate. Although there are several methods available to determine partition coefficient (log P), distribution coefficient (log D) and ionization constant (pKa), none of them involves simple and fixed, miniaturized protocols for diverse set of compounds. Therefore, it is necessary to establish simple, uniform and medium-throughput protocols requiring small sample quantities for the determination of these physicochemical properties. Log P and log D were determined by shake flask method, wherein, the compound was partitioned between presaturated noctanol and water phase (water/PBS pH 7.4) and the concentration of compound in each phase was determined by HPLC. The pKa determination made use of UV spectrophotometric analysis in a 96-well microtiter plate containing a series of aqueous buffers ranging from pH 1.0 to 13.0. The medium-throughput miniaturized protocols described herein, for determination of log P, log D and pKa, are straightforward to set up and require very small quantities of sample (< 5 mg for all three properties). All established protocols were validated using diverse set of compounds. PMID:27137915

  6. In vitro and in vivo efficacy, toxicity, bio-distribution and resistance selection of a novel antibacterial drug candidate

    PubMed Central

    Brunetti, Jlenia; Falciani, Chiara; Roscia, Giulia; Pollini, Simona; Bindi, Stefano; Scali, Silvia; Arrieta, Unai Cossio; Gómez-Vallejo, Vanessa; Quercini, Leila; Ibba, Elisa; Prato, Marco; Rossolini, Gian Maria; Llop, Jordi; Bracci, Luisa; Pini, Alessandro

    2016-01-01

    A synthetic antimicrobial peptide was identified as a possible candidate for the development of a new antibacterial drug. The peptide, SET-M33L, showed a MIC90 below 1.5 μM and 3 μM for Pseudomonas aeruginosa and Klebsiella pneumoniae, respectively. In in vivo models of P. aeruginosa infections, the peptide and its pegylated form (SET-M33L-PEG) enabled a survival percentage of 60–80% in sepsis and lung infections when injected twice i.v. at 5 mg/Kg, and completely healed skin infections when administered topically. Plasma clearance showed different kinetics for SET-M33L and SET-M33L-PEG, the latter having greater persistence two hours after injection. Bio-distribution in organs did not show significant differences in uptake of the two peptides. Unlike colistin, SET-M33L did not select resistant mutants in bacterial cultures and also proved non genotoxic and to have much lower in vivo toxicity than antimicrobial peptides already used in clinical practice. The characterizations reported here are part of a preclinical development plan that should bring the molecule to clinical trial in the next few years. PMID:27169671

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

    PubMed Central

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

    2012-01-01

    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

  8. Initial distribution assessment of Aedes albopictus (Diptera: Culicidae) in the Barcelona, Spain, area.

    PubMed

    Roiz, D; Eritja, R; Molina, R; Melero-Alcibar, R; Lucientes, J

    2008-05-01

    The invasive species Aedes (Stegomyia) albopictus (Skuse 1894) (Diptera: Culicidae) has reached several European countries, including Albania, Belgium, Bosnia and Herzegovina, Croatia, France, Greece, Israel, Italy, Montenegro, Serbia, Slovenia, Switzerland, The Netherlands, and recently Spain (Med. Vet. Entomol. 20: 150-152, 2006). Here, we present the initial characterization of the distribution of Ae. albopictus in the municipality of Sant Cugat del Vallès, Barcelona, Spain, where it was found for the first time in the Iberian Peninsula. An ovitrap sampling campaign was developed from September to December 2004 to assess the spatial distribution and abundance of Ae. albopictus to evaluate the potential of an eradication attempt. The population of Ae. albopictus in the whole area was shown to be widespread within the municipality, and it included at least another one neighboring town, so authorities were advised to develop large-scale control measures. Some indirect evidence was collected on the introduction means and date. PMID:18533426