Sample records for assessing drug distribution

  1. 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.

  2. Drug–Drug Interaction Prediction Assessment

    Microsoft Academic Search

    Jihao Zhou; Zhaohui Qin; Quinney K. Sara; Seongho Kim; Zhiping Wang; Stephen D. Hall; Lang Li

    2009-01-01

    Model-based drug–drug interaction (DDI) is an important in-silico tool to assess the in vivo consequences of in vitro DDI. Before its general application to new drug compounds, the DDI model is always established from known interaction data. For the first time, tests for difference and equivalent tests are implemented to compare reported and model-base simulated DDI (log AUCR) in the

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

    PubMed Central

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

    2010-01-01

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

  4. Distribution feeder reliability assessment

    Microsoft Academic Search

    A. A. Chowdhury

    2005-01-01

    Historical distribution feeder reliability assessment generally summarizes discrete interruption events occurring at specific locations over specific time periods; whereas, predictive assessment estimates the long-run behavior of systems by combining component failure rates and repair (restoration) times that describe the central tendency of an entire distribution of possible values with feeder configurations. The outage time due to component failures can substantially

  5. 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

  6. Target assessment for antiparasitic drug discovery.

    PubMed

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

    2007-12-01

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

  7. Audit mechanism for hospital drug distribution.

    PubMed

    Broekemeier, R L; Brewer, P E; Johnson, M K

    1980-01-01

    The development and application of a pharmacy department audit of its unit dose drug distribution system is described. Criteria used in the program were based on broad drug distribution criteria developed by the Minnesota Society of Hospital Pharmacists' PSRO Liaison Committee, with subcriteria developed by the staff of the hospital pharmacy department. Month-long audits are based on one of three criteria. A committee consisting of two staff pharmacists, one administrative pharmacist and one technician audits a predetermined number of randomly selected medication orders, medication profiles, filled medication orders or medication drawers. Deficiency patterns are identified, and appropriate corrective action is taken. Audits require approximately eight hours of pharmacist time and three hours of technician time per month per criterion. Audit of the drug distribution system makes pharmacy staff more aware of the quality of service it provides. PMID:7189096

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

    PubMed Central

    Foster, S. D.

    1991-01-01

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

  9. 77 FR 44177 - Antimicrobial Animal Drug Sales and Distribution Reporting

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-07-27

    ...DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration 21 CFR Part 514 [Docket No. FDA-2012-N-0447] Antimicrobial Animal Drug Sales and Distribution Reporting AGENCY: Food and Drug Administration, HHS. ACTION: Advance...

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

    SciTech Connect

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

    2010-03-01

    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.

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

    Microsoft Academic Search

    Patrick Poulin; Sean Ekins; Frank-Peter Theil

    2011-01-01

    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

  12. Drug policy in China: pharmaceutical distribution in rural areas.

    PubMed

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

    1999-03-01

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

  13. Optimizing Distribution of Pandemic Influenza Antiviral Drugs

    PubMed Central

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

    2015-01-01

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

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

    PubMed Central

    Nikoli?, Božana S.; Ili?, 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. Effects of cellular pharmacology on drug distribution in tissues.

    PubMed Central

    Rippley, R K; Stokes, C L

    1995-01-01

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

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

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... Removal of the exemption of drugs distributed under the Federal Food, Drug and Cosmetic... Removal of the exemption of drugs distributed under the Federal Food, Drug and Cosmetic...particular drug product is manufactured and distributed in a manner that prevents...

  17. 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

    ... Removal of the exemption of drugs distributed under the Federal Food, Drug and Cosmetic... Removal of the exemption of drugs distributed under the Federal Food, Drug and Cosmetic...particular drug product is manufactured and distributed in a manner that prevents...

  18. 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

    ... Removal of the exemption of drugs distributed under the Federal Food, Drug and Cosmetic... Removal of the exemption of drugs distributed under the Federal Food, Drug and Cosmetic...particular drug product is manufactured and distributed in a manner that prevents...

  19. 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...Requirements for wholesale distribution of prescription drugs...50 Section 203.50 Food and Drugs FOOD AND DRUG ADMINISTRATION...MARKETING Wholesale Distribution § 203.50...

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

    PubMed Central

    Bate, Roger; Hess, Kimberly

    2010-01-01

    Background Internet-sourced drugs are often considered suspect. The World Health Organization reports that drugs from websites that conceal their physical address are counterfeit in over 50 percent of cases; the U.S. Food and Drug Administration (FDA) works with the National Association of Boards of Pharmacy (NABP) to regularly update a list of websites likely to sell drugs that are illegal or of questionable quality. Methods and Findings This study examines drug purchasing over the Internet, by comparing the sales of five popular drugs from a selection of websites stratified by NABP or other ratings. The drugs were assessed for price, conditions of purchase, and basic quality. Prices and conditions of purchase varied widely. Some websites advertised single pills while others only permitted the purchase of large quantities. Not all websites delivered the exact drugs ordered, some delivered no drugs at all; many websites shipped from multiple international locations, and from locations that were different from those advertised on the websites. All drug samples were tested against approved U.S. brand formulations using Raman spectrometry. Many (17) websites substituted drugs, often in different formulations from the brands requested. These drugs, some of which were probably generics or perhaps non-bioequivalent copy versions, could not be assessed accurately. Of those drugs that could be assessed, none failed from “approved”, “legally compliant” or “not recommended” websites (0 out of 86), whereas 8.6% (3 out of 35) failed from “highly not recommended” and unidentifiable websites. Conclusions Of those drugs that could be assessed, all except Viagra® passed spectrometry testing. Of those that failed, few could be identified either by a country of manufacture listed on the packaging, or by the physical location of the website pharmacy. If confirmed by future studies on other drug samples, then U.S. consumers should be able to reduce their risk by relying on credentialing agencies recommended lists and by using common sense when examining packaging and pills. PMID:20730049

  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. 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

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

  3. 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

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

  4. 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

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

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

    Code of Federal Regulations, 2014 CFR

    2014-04-01

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

  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

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

  7. 21 CFR 1310.10 - Removal of the exemption of drugs distributed under the Food, Drug and Cosmetic Act.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

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

  8. 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,...

  9. [Drugs and assessment of gastrointestinal motility].

    PubMed

    Brignoli, R; Meier, R; Miazza, B

    1993-01-01

    Any determination of gastrointestinal motility is based on two assumptions: (1) That the patient is examined in "physiological" conditions and (2) that the values measured truly reflect the parameter the investigator wishes to examine. A large array of very different drugs shares the ability to modify the digestive motility (i.e. gastrokinetics) or to alter the content of the digestive tube in such a way that it affects the outcome of some measurements (i.e. acid suppression leads to false results in ph-metry dependent methods). Therefore, it seems advisable to ask the patient whether he is taking any drug--including non prescription medications--and check if this substance or type of substances could affect the outcome of the motility measurement envisioned. In this paper, the authors present a list of the principal drugs known to affect different motility-measurement methods. The real or apparent stimulating or inhibitory effects of drugs on four main segments of the digestive tube (esophagus, stomach, small intestines and colon) are indicated in an alphabetically ordered table. In a short review, the drugs are broadly classified according to their mechanism and site of action. Besides a number of drugs used in practice because of their action on the enteric nervous system, there is a large spectrum of compounds affecting motility, whose main therapeutic application lies outside the digestive tract, such as: psychotropic drugs, antiparkinsonian drugs, bronchodilators, antitussives, antihistamines, antimigraine drugs, antihypertensive agents, etc. This second category is more likely to escape unnoticed as a potential source of false results in the measurement of digestive motility. PMID:8211050

  10. [Current problems in assessing drug prices].

    PubMed

    Lucioni, C

    1989-01-01

    Two reasons provide historical justification for controlling drug prices: safeguarding the consumer and safeguarding public demand. Due to the increased presence of the "third payer" in public health systems this second reason has become more important. Nevertheless, over the last decade, a third purpose has attached to public control of prices: promotion of drug manufacturers economic development. The justification offered for this is that development of pharmaceutical companies contributes to the economic growth of the host country by creating employment, exports and research activity. The situations in Germany, Great Britain and United States are often cited in support of this thesis. As a model for price policy in Italy, however, it has not been successful. The rapid growth of prices in fact has not created greater employment and the foreign exchange deficit has risen rapidly. In other words the growing cost of drugs to the National Health Service has not produced hoped-for economic benefits. It would therefore be opportune to modify the mechanisms of price control by seeking a better balance in the interests involved (safeguarding public demand versus manufacturers economic growth). Methodologies available point to the evaluation of the therapeutic utility of a drug as a useful tool for this purpose. By this method the price of a new drug may only be higher than that of a drug already on the market if its therapeutic utility (which does not coincide only with clinical effectiveness) is greater. Appropriate evaluation techniques of benefits deriving from a new drug (cost-effectiveness and cost-utility) do exist and can be taken into consideration in a new method of calculating drug price. PMID:2634234

  11. 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

  12. 77 FR 59156 - Antimicrobial Animal Drug Sales and Distribution Reporting; Extension of Comment Period

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-09-26

    ...HEALTH AND HUMAN SERVICES Food and Drug Administration 21...Antimicrobial Animal Drug Sales and Distribution Reporting; Extension of Comment Period AGENCY: Food and Drug Administration...SUMMARY: The Food and Drug...

  13. Designer drugs 2015: assessment and management.

    PubMed

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

    2015-01-01

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

  14. Assessing illicit drug use among adults with schizophrenia.

    PubMed

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

    2012-12-30

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

  15. Managed care pharmacy, socioeconomic assessments and drug adoption decisions

    Microsoft Academic Search

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

    1997-01-01

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

  16. 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...Guidance for Industry on Compliance...Reporting Drug Sample Distribution Information...Availability AGENCY: Food and Drug Administration...SUMMARY: The Food and Drug Administration...guidance for industry entitled...Reporting Drug Sample Distribution Information...

  17. Role of transport proteins in drug absorption, distribution and excretion.

    PubMed

    Ayrton, A; Morgan, P

    2001-01-01

    1. The molecular and functional characterization of transport proteins is emerging rapidly and significant numbers of drugs have been shown to be substrates or inhibitors. The purpose of this review is to highlight the in vivo preclinical and clinical evidence that supports a role for transport proteins in attenuating the absorption, distribution and excretion (ADE) of drugs. 2. For absorption, a clear role has emerged for P-glycoprotein in limiting permeability across the gastrointestinal tract. As a result, a wide variety of drugs suffer from incomplete, variable and non-linear absorption. Similarly, at the blood-brain barrier a range of drugs has limited brain penetration due to P-glycoprotein-mediated efflux, which can limit therapeutic effectiveness of CNS agents. In the liver, transport proteins are present on the sinusoidal membrane that can be the rate-limiting step in hepatic clearance for some drugs. Mechanistic studies clearly suggest a key role and broad substrate specificity for the OATP family of sinusoidal transporters. Mainly ATP-dependent transport proteins such as P-glycoprotein and MRP2 govern active biliary excretion. 3. Drug-drug interactions have been demonstrated involving inhibition or induction of transport proteins. Clinically significant interactions in the gastrointestinal tract and kidney have been observed with inhibitors such as ketoconazole, erythromycin, verapamil, quinidine, probenecid and cimetidine. Clinically significant inhibition at the blood-brain barrier is more difficult to demonstrate, relying on pharmacodynamic and toxicodynamic changes, but an example is quinidine increasing loperamide-induced central effects in humans. 4. This review highlights the emerging role of transport proteins in ADE of drugs and suggests these need to be considered, in drug discovery and development, with respect to variability in drug disposition and response. PMID:11569523

  18. Use of radioactive compounds and autoradiography to determine drug tissue distribution.

    PubMed

    Solon, Eric G

    2012-03-19

    Radioactivity has been used in drug discovery and development for several decades because it offers researchers a highly sensitive way to quantitatively assess the absorption, distribution, metabolism, and/or excretion (ADME) of chemical entities by incorporating a radioactive isotope into the structure of the drug molecule. Regulatory agencies around the world require drug makers to characterize the ADME properties of prospective new drugs as one way to help ensure that patients are not exposed to dangerous drug and/or drug metabolite levels before they can be approved for human use. Radiolabeled compounds have consistently proved to be the most efficient tool for determining that information, even though attempts have been made to use nonradioactive techniques. The techniques of quantitative whole-body autoradiography (QWBA) and microautoradiography (MARG), which rely on the use of radiolabeled drugs, are two techniques that are routinely used to examine tissue distribution of drugs in discovery and development. These techniques provide drug researchers with quantitative tissue concentration data and a visual location of those concentrations in intact organs, tissues, and cells of laboratory animals. It is important for readers to realize that these techniques visualize total radioactivity, which can include the parent molecule along with its metabolites, and/or degradation products or impurities. This requires investigators to treat the quantitative data with caution unless the identity of the radioactivity is determined using some type of other bioanalytical techniques, such as mass spectroscopy and/or radio-HPLC, which can be easily performed on the tissue obtained from the animals used for QWBA and/or MARG. Nevertheless, these data are used in drug discovery and development to answer questions related to tissue penetration, fetal/placental transfer, tissue retention, routes of elimination, drug-drug interactions, enzyme induction/inhibition, formulation comparisons, in vivo compound solubility, differential metabolite distribution, interspecies comparisons, and to predict human exposure to parent drugs, metabolites, and radiation during clinical studies. This review will consider the strategic use of WBA, QWBA, and MARG in the pharmaceutical industry. Case studies and anecdotal information will also be presented; however, readers should realize that these are general examples and that some details have been omitted for brevity and/or because the data is proprietary and could not be presented at this time. Nevertheless, the images and discussions are provided to demonstrate how the techniques can and have been used to examine in situ tissue distribution of therapeutic compounds. PMID:22280496

  19. Nasal distribution of radioactive drug administered using two dosage forms.

    PubMed

    Vidgren, P; Vidgren, M; Paronen, P; Vainio, P; Nuutinen, J

    1991-01-01

    The deposition patterns of 99mtechnetium labelled disodium cromoglycate particles administered either from a metered dose aerosol with a conventional nasal adaptor or from a dry powder nasal inhaler were studied using gamma camera. Disodium cromoglycate particles were firstly labelled with 99mTc using the spray drying technique. Both the metered dose aerosol and the dry powder dosage form were formulated using these radioactive drug particles. Seven healthy volunteers inhaled either three aerosol doses or one dry powder dose unit into one nostril. The drug dose reaching nasal cavity after administration from these two dosage forms was about the same. The deposition patterns as well as the changes in distribution due to the mucociliary transport were monitored by a gamma camera equipped with a low energy all purpose collimator. Initially drug doses deposited in a wider area of the nasal cavity when disodium cromoglycate particles were administered as a dry powder dosage form. In addition, retention index (%) which illustrates the movements of drug particles by mucociliary transport from the initial area of application seemed to be slightly higher for a metered dose aerosol than for a dry powder dosage form. At the end of the 30 minutes measuring period the area of the mucosal layer covered by radioactive drug particles was clearly wider for the dry powder dosage form than for the metered dose aerosol. Thus it is well possible to administer drug particles effectively into the nasal cavity as a dry powder dosage form. PMID:1820917

  20. A reliability assessment methodology for distribution systems with distributed generation 

    E-print Network

    Duttagupta, Suchismita Sujaya

    2006-08-16

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

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

    PubMed

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

    2015-03-01

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

  2. 78 FR 59308 - Antimicrobial Animal Drug Sales and Distribution Annual Summary Report Data Tables

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-09-26

    ...OF HEALTH AND HUMAN SERVICES Food and Drug Administration 21 CFR Part 514 [Docket...FDA-2012-N-0447] Antimicrobial Animal Drug Sales and Distribution Annual Summary Report Data Tables AGENCY: Food and Drug Administration, HHS. ACTION:...

  3. 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 (?-hydroxybutyric acid, propofol, ketamine and phencyclidine) and cognitive enhancers (methylphenidate and modafinil), and some important plant-derived hallucinogens (lysergide, salvinorin A, psilocybin and psilocin), as well as of nicotine in humans are summarized in this article. The isoenzymes (e.g., cytochrome P450, glucuronyltransferases, esterases and reductases) involved in the metabolism of drugs and some pharmacokinetic data are discussed. The relevance of such data is discussed for predicting possible interactions with other xenobiotics, understanding pharmacokinetic behavior and pharmacogenomic variations, assessing toxic risks, developing suitable toxicological analysis procedures, and finally for interpretating drug testing results. PMID:21332315

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

    PubMed

    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(ss)) in humans under in vivo conditions. This correlation method demonstrated inaccurate predictions of V(ss) for particular basic drugs that did not follow the original correlation principle. Therefore, the novelty of this study is to provide clarity on the actual hypotheses to identify i) the impact of pharmacological mode of action on the generic correlation of RBCu-Kpu, ii) additional mechanisms of tissue distribution for the outlier drugs, iii) molecular features and properties that differentiate compounds as outliers in the original correlation analysis in order to facilitate its applicability domain alongside the properties already used so far, and finally iv) to present a novel and refined correlation method that is superior to what has been previously published for the prediction of human V(ss) of basic drugs. Applying a refined correlation method after identifying outliers would facilitate the prediction of more accurate distribution parameters as key inputs used in physiologically based pharmacokinetic (PBPK) and phospholipidosis models. PMID:21034759

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

    SciTech Connect

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

    2011-01-15

    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.

  6. Monitoring the Intragastric Distribution of a Colloidal Drug Carrier Model by Magnetic Resonance Imaging

    Microsoft Academic Search

    Henryk Faas; Werner Schwizer; Christine Feinle; Hans Lengsfeld; Chris de Smidt; Peter Boesiger; Michael Fried; Thomas Rades

    2001-01-01

    Purpose. Monitoring the distribution of drugs or drug delivery systems in the human gastrointestinal tract is an important prerequisite for the design of orally administered drugs. We investigated the intragastric distribution of a colloidal drug delivery system (liposomes containing the contrast agent Gd-DOTA) by magnetic resonance imaging.

  7. Assessment of Distributed Object Rod Fatoohi

    E-print Network

    Fatoohi, Rod

    Assessment of Distributed Object Middleware Rod Fatoohi San Jose State U. & NASA Ames Research Center ESTO/ESDIS Technology Transfer Workshop June 5, 2000, Greenbelt, Maryland #12;Contributers ! Tom '98 (15 mos): Joint project GSFC/ARC/SJSU - ECS Distributed Object Middleware & Alternative Technology

  8. 7 CFR 1230.74 - Prohibited use of distributed assessments.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ...2011-01-01 false Prohibited use of distributed assessments. 1230.74 Section...Assessments § 1230.74 Prohibited use of distributed assessments. (a) No funds...certified public accountant of all funds distributed to such organizations pursuant to...

  9. 7 CFR 1230.74 - Prohibited use of distributed assessments.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ...2013-01-01 false Prohibited use of distributed assessments. 1230.74 Section...Assessments § 1230.74 Prohibited use of distributed assessments. (a) No funds...certified public accountant of all funds distributed to such organizations pursuant to...

  10. 7 CFR 1230.74 - Prohibited use of distributed assessments.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ...2012-01-01 false Prohibited use of distributed assessments. 1230.74 Section...Assessments § 1230.74 Prohibited use of distributed assessments. (a) No funds...certified public accountant of all funds distributed to such organizations pursuant to...

  11. 7 CFR 1230.74 - Prohibited use of distributed assessments.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ...2010-01-01 false Prohibited use of distributed assessments. 1230.74 Section...Assessments § 1230.74 Prohibited use of distributed assessments. (a) No funds...certified public accountant of all funds distributed to such organizations pursuant to...

  12. 7 CFR 1230.74 - Prohibited use of distributed assessments.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ...2014-01-01 false Prohibited use of distributed assessments. 1230.74 Section...Assessments § 1230.74 Prohibited use of distributed assessments. (a) No funds...certified public accountant of all funds distributed to such organizations pursuant to...

  13. 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.

  14. Modelling intravascular delivery from drug-eluting stents with biodurable coating: investigation of anisotropic vascular drug diffusivity and arterial drug distribution.

    PubMed

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

    2014-01-01

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

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

    PubMed Central

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

    2012-01-01

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

  16. 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.

  17. Discriminative stimulus functions of CNS sedative drugs assessed by drug versus drug discrimination procedures in gerbils

    Microsoft Academic Search

    T. U. C. Järbe; M. D. B. Swedberg

    1998-01-01

    This study is concerned with dissecting out differences in the discriminative stimulus attributes between drugs from broader\\u000a pharmacological categories such as sedative\\/hypnotics where generalization tests often indicate shared stimulus effects. To\\u000a this end, the discriminative stimulus effects of three to five doses of either chlordiazepoxide (CDP), chlormethiazole (CMZ),\\u000a ethanol (ETOH), and pentobarbital (P-barb) were studied with gerbils in a two-choice,

  18. [Genotoxic risk assessment of nurses handling antineoplastic drugs].

    PubMed

    Boughattas, Aïcha Brahem; Bouraoui, Sana; Debbabi, Faten; El Ghazel, Hatem; Saad, Ali; Mrizak, Néjib

    2010-01-01

    The aim of this study is to assess the genotoxic effect of occupational exposure to antineoplastic drugs on oncology nurses in order to propose a strategy for adequate safety. The study included 20 oncology nurses from the Farhat Hached university hospital-Sousse (Tunisia) exposed to antineoplastic drugs compared to 20 controls. The two groups were paired according to sex, age, and smoking habits. The genotoxic risk assessment was carried out by the micronucleus test and chromosomal abnormalities. The search for the clinical effects of cytostatic drugs was based on a questionnaire. Determination of the level of the exposure to cytostatic was performed by calculation of the index of the exposure to these drugs. The median age of nurses was 36 years. A female prevalence (80%) was noted. The exposed period to cytostatic was 6.1 years. The middle index of cytostatic contact calculated for the whole of the nurses, was of 1.5. However this index becomes higher (>3) in nurses working at day care. A significant increase in frequencies rates for both micronucleus (9.40‰ vs 4.35‰) and chromosome abnormalities (1.85% vs 0.30%) were noted in exposed group more than controls. In conclusion, application of genotoxic tests may be useful to detect cytogenetic damage related to occupational exposure to a potentially cancerogenic environment. Results of the present biomonitoring study emphasize the need for developing safety programs. PMID:20870576

  19. Doxorubicin eluting beads - 1: effects of drug loading on bead characteristics and drug distribution.

    PubMed

    Lewis, Andrew L; Gonzalez, M Victoria; Leppard, Simon W; Brown, Joanna E; Stratford, Peter W; Phillips, Gary J; Lloyd, Andrew W

    2007-09-01

    DC Bead is a FDA cleared embolisation device for the treatment of hypervascular tumours and arteriovenous malformations. This product is currently evaluated in a number of centres in Europe as an embolic device for transarterial chemoembolisation (TACE). The beads consist of poly(vinyl alcohol) microspheres modified with sulfonic acid groups and are available at different size ranges varying from 100 to 900 microm in diameter. The beads were shown to actively sequester doxorubicin hydrochloride (dox) from solution in a time dependent upon the dose of the drug and size of the beads. Drug uptake was by an ion-exchange mechanism, and in the absence of other ions in solution, the beads could load a maximum of around 40 mg dox/mL hydrated beads, with >99% of drug being sequestered from the solution. A loading of 25 mg dox/mL beads was recommended as providing a practical therapeutic dose and optimum handling characteristics. There was a decrease in equilibrium water content of the beads with increasing dox loading, which resulted in a decrease in the average diameter of the beads and an increase in the compressive modulus. The deliverability properties, however, were not affected after drug loading. Using a variety of microscopic methods, the drug was shown to be distributed throughout the bead structure, but concentrated in the outer 20 microm surface layer, a feature related to the method of synthesis. This study characterises the properties of DC Bead loaded with dox with respect to important characteristics in embolisation and demonstrates the potential of this drug device combination for the treatment of hypervascular tumours such as hepatocellular carcinoma. PMID:17483878

  20. Improved Bioequivalence Assessment of Topical Dermatological Drug Products Using Dermatopharmacokinetics

    Microsoft Academic Search

    Berthe N’Dri-Stempfer; William C. Navidi; Richard H. Guy; Annette L. Bunge

    2009-01-01

    Purpose  A dermatopharmacokinetic (DPK) approach, in which drug levels in the stratum corneum (SC) are measured as a function of time\\u000a post-application and post-removal of the product using tape-strip sampling in vivo in humans, has been considered for the comparative assessment of topical bioavailability. Its application to-date has been\\u000a limited by contradictory results and concerns that variability in the method necessitates

  1. Photoacoustic drug delivery: the effect of laser parameters on the spatial distribution of delivered drug

    NASA Astrophysics Data System (ADS)

    Shangguan, HanQun; Casperson, Lee W.; Shearin, Alan; Gregory, Kenton W.; Prahl, Scott A.

    1995-05-01

    Photoacoustic drug delivery is a technique for delivering drugs to localized areas by timing laser-induced pressure transients to coincide with a bolus of drug. This study explores the effects of target material, laser energy, absorption coefficient, fiber size, repetition rate, and number of pulses on the spatial distribution of delivered drug. A microsecond flash-lamp pumped dye laser delivered 30-100 mJ pulses through optical fibers with diameters of 300-1000 micrometers . Vapor bubbles were created 1-5 mm above clear gelatin targets submerged in mineral oil containing a hydrophobic dye (D&C Red#17). The absorption coefficient of the oil-dye solution was varied from 50-300 cm-1. Spatially unconfined geometry was investigated. We have found that while the dye can be driven a few millimeters into the gels in both the axial and radial directions, the penetration was less than 500 micrometers when the gel surface remained macroscopically undamaged. Increasing the distance between the fiber tip and target, or decreasing the pulse energy reduced the extend of the delivery.

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

    PubMed

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

    2012-06-01

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

  3. Risk Assessment Principle for Engineered Nanotechnology in Food and Drug

    PubMed Central

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

    2012-01-01

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

  4. Modelling intravascular delivery from drug-eluting stents with biodurable coating: investigation of anisotropic vascular drug diffusivity and arterial drug distribution

    Microsoft Academic Search

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

    2012-01-01

    In-stent restenosis occurs in coronary arteries after implantation of drug-eluting stents with non-uniform restenosis thickness distribution in the artery cross section. Knowledge of the spatio-temporal drug uptake in the arterial wall is useful for investigating restenosis growth but may often be very expensive\\/difficult to acquire experimentally. In this study, local delivery of a hydrophobic drug from a drug-eluting stent implanted

  5. The use of mass balance principles to describe regional drug distribution and elimination

    Microsoft Academic Search

    Richard N. Upton; Laurence E. Mather; William B. Runciman; Craig Nancarrow; Ronda J. Carapetis

    1988-01-01

    Mass balance principles were used to derive a number of terms that are helpful in describing the rate and extent of regional drug uptake. Regional drug uptake was defined as the net movement of drug from the blood perfusing a region into the extravascular space of the region due to the distribution and\\/or elimination of the drug. By analogy with

  6. Bioluminescence for Assessing Drug Potency against Nonreplicating Mycobacterium tuberculosis.

    PubMed

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

    2015-07-01

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

  7. 7 CFR 1230.73 - Uses of distributed assessments.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 10 2011-01-01 2011-01-01 false Uses of distributed assessments. 1230.73 Section 1230.73 Agriculture...Order Expenses and Assessments § 1230.73 Uses of distributed assessments. (a) Each State association...

  8. 7 CFR 1230.73 - Uses of distributed assessments.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 10 2014-01-01 2014-01-01 false Uses of distributed assessments. 1230.73 Section 1230.73 Agriculture...Order Expenses and Assessments § 1230.73 Uses of distributed assessments. (a) Each State association...

  9. 7 CFR 1230.73 - Uses of distributed assessments.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... 10 2012-01-01 2012-01-01 false Uses of distributed assessments. 1230.73 Section 1230.73 Agriculture...Order Expenses and Assessments § 1230.73 Uses of distributed assessments. (a) Each State association...

  10. 7 CFR 1230.73 - Uses of distributed assessments.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 10 2010-01-01 2010-01-01 false Uses of distributed assessments. 1230.73 Section 1230.73 Agriculture...Order Expenses and Assessments § 1230.73 Uses of distributed assessments. (a) Each State association...

  11. 7 CFR 1230.73 - Uses of distributed assessments.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... 10 2013-01-01 2013-01-01 false Uses of distributed assessments. 1230.73 Section 1230.73 Agriculture...Order Expenses and Assessments § 1230.73 Uses of distributed assessments. (a) Each State association...

  12. Lab 4 GEO Assessing fish distribution

    E-print Network

    Wright, Dawn Jeannine

    Bound.mxd from the lab_4 folder that you previously copied to your student directory. C. The view opens showingLab 4 ­ GEO 465/565 Invisible Boundaries ____________________________ Assessing fish distribution the lab_4 folder from the Geo_565/data folder into the lab_4 folder in your student directory (or distance

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

    PubMed

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

    2013-05-01

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

  14. 21 CFR 212.90 - What actions must I take to control the distribution of PET drug products?

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ...ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) DRUGS: GENERAL CURRENT GOOD MANUFACTURING PRACTICE FOR POSITRON EMISSION TOMOGRAPHY DRUGS Distribution § 212.90 What actions must I take to control the distribution of PET drug...

  15. 21 CFR 212.90 - What actions must I take to control the distribution of PET drug products?

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ...ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) DRUGS: GENERAL CURRENT GOOD MANUFACTURING PRACTICE FOR POSITRON EMISSION TOMOGRAPHY DRUGS Distribution § 212.90 What actions must I take to control the distribution of PET drug...

  16. 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

    ...ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) DRUGS: GENERAL CURRENT GOOD MANUFACTURING PRACTICE FOR POSITRON EMISSION TOMOGRAPHY DRUGS Distribution § 212.90 What actions must I take to control the distribution of PET drug...

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

    PubMed Central

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

    2015-01-01

    Objective: The objective of the study was to assess the incidence and pattern of drug-drug interactions (DDIs) in hypertensive patients by using Micromedex and Medscape databases. Materials and Methods: A prospective observational study was carried out in a superspeciality hospital setting in South India for period of 9 months. Hypertensive patients who admitted into the hospital with the age more than 18 years, received more than 3 drugs per prescription and length of hospital stay for more than 24 hours were included in the study. An appropriate data was collected and assessed for DDIs with the help of Micromedex and Medscape databases. Results: A total of 227 patients were enrolled during the study period. Among the 227 patients, 48 of them developed 53 clinically significant DDIs. Out of 48 patients, most of them were in the age-group of 50–60 years [18 (37.49%)]. The percentage of DDIs were higher in males [30 (62.5%)] compared to females [18 (37.5%)]. The most common drugs responsible for DDIs in the present study were Insulin [18 (33.96%)] followed by Metoprolol [10 (18.86%)], Torsemide [8 (15.09%)], and Hydrochlorothiazide [8 (15.09%)]. The most commonly interacting pairs were Ciprofloxacin-Insulin [6 (11.32%)], followed by Metoprolol-Insulin [4 (7.54%)] and Atenolol-Insulin [4 (7.54%)]. The most common consequences of interacting pairs were reduced serum potassium levels and hyperglycemia. Conclusion: The overall incidence rate of DDIs was found to be 21.14% and the increasing number of co-morbidities (P ? 0.003) and polypharmacy (P ? 0.002) were the risk factor for the development of significant number of DDIs. PMID:25878964

  18. Validation of pharmacy records in drug exposure assessment

    Microsoft Academic Search

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

    1997-01-01

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

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

    PubMed Central

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

    2012-01-01

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

  20. Statistical assessment of Monte Carlo distributional tallies

    SciTech Connect

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

    2010-12-09

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

  1. A pilot study to assess an online training module to quickly identify drugs on resuscitation trays

    Microsoft Academic Search

    J.-F. Bussières; D. Lebel; S. Voytenko; C. Marquis; B. Bailey

    2011-01-01

    ObjectiveTo measure the median time required for healthcare professionals to identify drugs on resuscitation trays and to assess the usefulness of an online training module used to identify drugs on resuscitation trays.

  2. Comparison of Self-Reported Drug Use With Quantitative and Qualitative Urinalysis for Assessment of Drug Use in Treatment Studies

    Microsoft Academic Search

    Kenzie L. Preston; Kenneth Silverman; Charles R. Schuster; Edward J. Cone

    The effectiveness of substance abuse treatment programs can be monitored by self-reported drug use and objectively measured by qualitative and quantitative urinalysis. The advantages and disadvantages of each of these three methods of assessing drug use are reviewed. Data collected in a clinical trial of a behavioral treatment for cocaine abuse are used to evaluate the relationships among qualitative and

  3. 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…

  4. 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. PMID:23768432

  5. 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)

  6. The value of assessing cognitive function in drug development

    PubMed Central

    Wesnes, Keith A.

    2000-01-01

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

  7. 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

    ... false May SASPs pick up or store donated drug paraphernalia in their distribution...Property Requiring Special Handling Drug Paraphernalia § 102-41.230 May SASPs pick up or store donated drug paraphernalia in their...

  8. 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

    ... false May SASPs pick up or store donated drug paraphernalia in their distribution...Property Requiring Special Handling Drug Paraphernalia § 102-41.230 May SASPs pick up or store donated drug paraphernalia in their...

  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

    ... false May SASPs pick up or store donated drug paraphernalia in their distribution...Property Requiring Special Handling Drug Paraphernalia § 102-41.230 May SASPs pick up or store donated drug paraphernalia in their...

  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

    ... false May SASPs pick up or store donated drug paraphernalia in their distribution...Property Requiring Special Handling Drug Paraphernalia § 102-41.230 May SASPs pick up or store donated drug paraphernalia in their...

  11. 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

    ... false May SASPs pick up or store donated drug paraphernalia in their distribution...Property Requiring Special Handling Drug Paraphernalia § 102-41.230 May SASPs pick up or store donated drug paraphernalia in their...

  12. [Assessment of the high cost drug program on an example of the interferon treatment of multiple sclerosis].

    PubMed

    Vlasov, Ia V; Dolgikh, G T; Dolgilh, T A; Kurapov, M A; Nilov, A I; Tarasova, S V; Churakov, M V; Khivintseva, E V

    2013-01-01

    Currently in Russia, there is a rather complicated situation with the distribution of expensive disease modifying drugs (DMD) purchased by the state for treatment of patients with multiple sclerosis. In this regard, it is necessary to carry out a serious organizational work in the direction of assessment of equivalence of biosimilars and original drugs concerning, first of all, efficacy and safety. Also, there is a problem of the replacement of one biosimilar by another in connection with organizational problems of shipping DMD to country regions. We present the results of the sociological research on the assessment of expensive drug provision by patients. The research has been carried out in 35 regions of the country. Based on these results, a strategy of the development of the program of provision with DMD should be developed all over the country. PMID:23528597

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

    PubMed Central

    Walker, D K

    2004-01-01

    The pharmaceutical industry continues to look for ways to reduce drug candidate attrition throughout the drug discovery and development process. A significant cause of attrition is due to safety issues arising either as a result of animal toxicity testing or in the clinical programme itself. A factor in the assessment of safety during early drug development is the pharmacokinetic profile of the compound. This allows safety data to be considered in the light of systemic drug exposure and therefore permits a quantitative assessment. This is particularly applicable when assessing the risk of a new chemical entity (NCE) in relation to safety parameters such as QT interval prolongation, where free plasma concentrations have been shown to be predictive of this property in relation to potency in preclinical testing. Prior to actual human exposure it is therefore important to be able to predict reliably the pharmacokinetic behaviour of an NCE in order to place such safety findings into a quantitative risk context. The emerging science of pharmacogenetics is likely to further our ability to assess the risk of NCEs to populations and individuals due to genetic variance. The drug metabolizing enzyme CYP2D6 has been recognized as providing the potential to result in widely differing systemic drug exposure in the patient population due to polymorphic expression. Further knowledge is likely to add to our understanding of population differences in exposure and response and aid in the identification of risk factors. One potential strategy for improving the effectiveness of the drug discovery process is to obtain clinical pharmacokinetic data more rapidly in order to assess more accurately the potential for both efficacy and safety of an NCE. Whilst procedures and technologies are available that allow this on the microdose scale, it is important that we recognize potential limitations of these approaches in order that they can be applied beneficially. PMID:15563358

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

    Microsoft Academic Search

    Hao-Ming Hsiao; Yi-Hsiang Chiu

    2012-01-01

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

  15. Assessment of ultrasonic vocalizations during drug self-administration in rats.

    PubMed

    Maier, Esther Y; Ma, Sean T; Ahrens, Allison; Schallert, Timothy J; Duvauchelle, Christine L

    2010-01-01

    Drug self-administration procedures are commonly used to study behavioral and neurochemical changes associated with human drug abuse, addiction and relapse. Various types of behavioral activity are commonly utilized as measures of drug motivation in animals. However, a crucial component of drug abuse relapse in abstinent cocaine users is "drug craving", which is difficult to model in animals, as it often occurs in the absence of overt behaviors. Yet, it is possible that a class of ultrasonic vocalizations (USVs) in rats may be a useful marker for affective responses to drug administration, drug anticipation and even drug craving. Rats vocalize in ultrasonic frequencies that serve as a communicatory function and express subjective emotional states. Several studies have shown that different call frequency ranges are associated with negative and positive emotional states. For instance, high frequency calls ("50-kHz") are associated with positive affect, whereas low frequency calls ("22-kHz") represent a negative emotional state. This article describes a procedure to assess rat USVs associated with daily cocaine self-administration. For this procedure, we utilized standard single-lever operant chambers housed within sound-attenuating boxes for cocaine self-administration sessions and utilized ultrasonic microphones, multi-channel recording hardware and specialized software programs to detect and analyze USVs. USVs measurements reflect emotionality of rats before, during and after drug availability and can be correlated with commonly assessed drug self-administration behavioral data such lever responses, inter-response intervals and locomotor activity. Since USVs can be assessed during intervals prior to drug availability (e.g., anticipatory USVs) and during drug extinction trials, changes in affect associated with drug anticipation and drug abstinence can also be determined. In addition, determining USV changes over the course of short- and long-term drug exposure can provide a more detailed interpretation of drug exposure effects on affective functioning. PMID:20689507

  16. Nutritional status assessment of HIV-positive drug addicts.

    PubMed

    Varela, P; Marcos, A; Ripoll, S; Requejo, A; Herrera, P; Casas, A

    1990-05-01

    Since human immunodeficiency virus (HIV) is known to lead to modifications of immune function and interrelationships among malnutrition, anergy and drug addiction have been shown, the aim of this work was to assess the nutritional status of 36 male heroin addicts under a period of detoxication (3 months). They were divided into two groups: (1) HIV negative (n = 20) and (2) HIV positive (n = 16); heights, weights and serum albumin concentration were measured and immune function was tested, using delayed hypersensitivity skin tests containing 7 antigens. No significant differences in anthropometric measurements were found between both groups, but anthropometric improvement was shown in every patient after the detoxication period. Serum albumin, often used as a classical index of malnutrition, remained within the normal values in both groups. The whole response to skin tests was depressed in both groups and no significant differences were shown between them. Therefore, these results might suggest that in spite of the apparent anthropometric recovery and the normal values of albumin, a subclinical malnutrition was indicated by the depressed immune function, which was more noticeable in the HIV-positive group. PMID:2387276

  17. 75 FR 52765 - Development and Distribution of Patient Medication Information for Prescription Drugs; Public...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-08-27

    ...are needed to ensure distribution of PMI? For example...we ensure adequate distribution of PMI while minimizing...situations where the distribution of PMI would not be...developers, publishers, industry, and any other interested...The Commissioner of Food and Drugs is...

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

    PubMed

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

    2014-10-23

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

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

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ...COMMISSION SPECIFIC DOMESTIC LICENSES TO MANUFACTURE OR TRANSFER CERTAIN ITEMS CONTAINING BYPRODUCT MATERIAL Exempt Concentrations and Items § 32.21 Radioactive drug: Manufacture, preparation, or transfer for commercial distribution of...

  20. 10 CFR 32.21 - Radioactive drug: Manufacture, preparation, or transfer for commercial distribution of capsules...

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    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...

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

    PubMed Central

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

    2014-01-01

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

  2. Assessment of drug transporter function using fluorescent cell imaging.

    PubMed

    Bircsak, Kristin M; Gibson, Christopher J; Robey, Robert W; Aleksunes, Lauren M

    2013-01-01

    ATP-binding cassette (ABC) proteins, including the breast cancer resistance protein (BCRP) and multidrug resistance proteins (MDRs), actively transport structurally diverse chemicals from a number of tissues and are being increasingly cited as mediators of clinically relevant drug-drug interactions. The potential outcomes of concomitantly administering two drugs that interact at the same transporter include altered disposition and toxicity and/or efficacy of one or both of the drugs. Research demonstrating the role of transporters in clinical pharmacokinetics has shed light on the need for in vitro screening methods that detect drug-transporter interactions during preclinical development. This unit describes cell-based procedures for detecting functional inhibitors of BCRP and MDR1 by measuring fluorescent substrate accumulation in suspended cells using an automated cell counter, which offers convenience, sensitivity, and speed in measuring intracellular fluorescence and identifying new inhibitors. An alternative method is provided for making similar measurements using a spectrophotometer with fluorescence detection capabilities. PMID:24510579

  3. US FDA Question-Based Review for Generic Drugs: A New Pharmaceutical Quality Assessment System

    Microsoft Academic Search

    Lawrence X. Yu; Andre Raw; Robert Lionberger; Radhika Rajagopalan; Lai Ming Lee; Frank Holcombe; Rashmikant Patel; Florence Fang; Vilayat Sayeed; Paul Schwartz; Richard Adams; Gary Buehler

    2007-01-01

    The US Food and Drug Administration Office of Generic Drugs has developed a question-based review (QbR) for the Chemistry, Manufacturing, and Controls (CMC) evaluation of an abbreviated new drug application (ANDA). This new QbR system incorporates quality by design and implements risk-based assessment. It recommends that ANDAs be submitted using the Common Technical Document and include the Quality Overall Summary

  4. Quality assessment of drug sales data: the case of antibacterials in Iceland

    Microsoft Academic Search

    Ingunn Björnsdóttir; Ebba Holme Hansen; Almar Grímsson

    1999-01-01

    Background: Two sets of drug sales data, published by the Icelandic Ministry of Health, did not match for antibacterials in 1989. The search for causes turned out to be a project in itself. Objective: To analyze quality problems in the sales data on antibacterials and describe a method for systematic quality assessment of drug sales data. Methods: Documentary analysis based

  5. 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…

  6. 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...

  7. 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...

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

    PubMed

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

    2013-07-01

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

  9. Distribution system reliability assessment due to lightning storms

    Microsoft Academic Search

    Nagaraj Balijepalli; Subrahmanyam S. Venkata; Charles W. Richter; Richard D. Christie; Vito J. Longo

    2005-01-01

    Lightning is a significant cause of faults and outages in many electric power systems and is one of the major causes of poor system reliability. Predictive assessment of distribution reliability indices can be used to identify areas that have poor reliability so that appropriate changes in system design can be implemented. The assessment of distribution system performance under lightning conditions

  10. Cognitive Processes and the Assessment of Subjective Probability Distributions

    Microsoft Academic Search

    Robin M. Hogarth

    1975-01-01

    This article considers the implications of recent research on judgmental processes for the assessment of subjective probability distributions. It is argued that since man is a selective, sequential information processing system with limited capacity, he is ill-suited for assessing probability distributions. Various studies attesting to man's difficulties in acting as an “intuitive statistician” are summarized in support of this contention.

  11. 21 CFR 212.90 - What actions must I take to control the distribution of PET drug products?

    Code of Federal Regulations, 2014 CFR

    2014-04-01

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

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

    PubMed Central

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

    2013-01-01

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

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

    PubMed

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

    2014-11-01

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

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

    PubMed

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

    2010-01-01

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

  15. 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

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

    PubMed Central

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

    2011-01-01

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

  17. On the distribution type of uncertain inputs for probabilistic assessment

    Microsoft Academic Search

    Shin-Jon Ju

    2009-01-01

    The effect of distribution type of uncertain inputs on the probabilistic assessment result of a system is illustrated. The tested systems include linear function, positive exponential function, negative exponential function, and reciprocal function, and a proposed corrosion mechanism for radwaste package in addition. The four types of distributions analyzed are uniform (U), log-uniform (LU), normal (N), and log-normal (LN) distributions.

  18. Parents’ Subjective Assessment of Effects of Antiepileptic Drug Discontinuation

    PubMed Central

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

    2015-01-01

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

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

    PubMed

    Senior, John R

    2014-11-01

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

  20. 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

  1. Assessing resistance costs of antiretroviral therapies via measures of future drug options.

    PubMed

    Jiang, Hongyu; Deeks, Steven G; Kuritzkes, Daniel R; Lallemant, Marc; Katzenstein, David; Albrecht, Mary; DeGruttola, Victor

    2003-10-01

    The emergence of drug-resistant human immunodeficiency virus (HIV) type 1 in the setting of antiretroviral therapy failure limits the number of drugs available for use in subsequent therapy regimens. To quantify the relative HIV-1-resistance costs associated with various antiretroviral therapy strategies, we developed 2 related measures of future drug options (FDOs) by use of rule-based genotype-interpretation systems. The FDO1 metric assesses the number of drug classes that remain useful; the FDO2 metric assesses the number of drug classes that remain useful and the number of active drugs within each class. Application of these methods is illustrated with data from a randomized study of 3 therapy regimens in nucleoside analog-experienced patients. Each therapy regimen resulted in a unique pattern of drug-resistance (and cross-resistance) mutations. The regimen with the highest virologic failure rate preserved greater future drug options. Quantification of future drug options as an outcome of antiretroviral therapy trials may complement traditional clinical, virologic, and immunologic end points, thereby providing novel insights. PMID:14513420

  2. 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

    ...ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) DRUGS: GENERAL CURRENT GOOD MANUFACTURING PRACTICE FOR POSITRON EMISSION TOMOGRAPHY DRUGS (Eff. 12-12-2011) Distribution § 212.90 What actions must I take to control the...

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

    PubMed

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

    2013-12-01

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

  4. 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…

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

    ERIC Educational Resources Information Center

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

    2011-01-01

    Although not originally designed for implementation in correctional settings, researchers and clinicians have begun to use the Personality Assessment Inventory (PAI) to assess offenders. A relatively small number of studies have made attempts to validate the alcohol and drug abuse scales of the PAI, and only a very few studies have validated those…

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

    E-print Network

    Paris-Sud XI, Université de

    Characterization of Lung's Emphysema Distribution: Numerical Assessment of Disease Development M that block airflow and make it increasingly difficult for you to breathe. Emphysema and chronic bronchitis bronchitis. Pulmonary emphysema is defined as a lung disease characterized by "abnormal enlargement

  7. Distribution System Reliability Assessment Incorporating Weather Effects

    Microsoft Academic Search

    R. Billinton; J. Acharya

    2006-01-01

    Electrical distribution systems usually exist in outdoor environments. The weather creates varying degrees of physical stress on system components exposed to fluctuating weather conditions. The failure rate of an element is greatly enhanced in bad weather situations and the likelihood of multiple line failures is much higher in bad weather than in normal weather. The phenomenon of coincident failures of

  8. 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

  9. ARE SCAT SURVEYS A RELIABLE METHOD FOR ASSESSING DISTRIBUTION AND

    E-print Network

    Davison, Angus

    235 Chapter 12 ARE SCAT SURVEYS A RELIABLE METHOD FOR ASSESSING DISTRIBUTION AND POPULATION STATUS Strachan Abstract: Systematic searches for marten feces or `scats' have been used since 1980 for assessing the status of protected populations of pine martens (Martes martes) in Britain. Previous surveys using scats

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

    E-print Network

    Paris-Sud XI, Université de

    Assessing the freshwater distribution of yellow eel Ã?. Lasne(1) , P. Laffaille(1,2) ABSTRACT, such as the European eel, that have complex life cycles, exhibit cryptic behavior, or migrate over long distances. A review of the literature suggests that eel size data could be used to assess and analyze freshwater

  11. 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. PMID:7500226

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

    PubMed

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

    2014-11-01

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

  13. Quantitative analysis of sildenafil and tadalafil in various fake drugs recently distributed in Korea.

    PubMed

    Park, Meejung; Ahn, Suyoun

    2012-11-01

    Illicit distribution of various illicit or counterfeit drugs containing sildenafil and tadalafil has increased and caused noticeable problems in Korea. This study has been performed to determine the content range of sildenafil and tadalafil in various fake drugs. Among the illicit or counterfeit drugs seized by Korean authorities, 105 exhibits were used for the quantification. HPLC-UV analysis of methanol extractions was used for separation and quantitation of the two target compounds. The most abundant type of fake drug was counterfeit Viagra(®) tablets. Sildenafil was found in 73 exhibits, and tadalafil was found in seven exhibits. Twenty-five exhibits out of the 105 contained both sildenafil and tadalafil. The contents of sildenafil ranged from 4.3 to 453.2 mg; for tadalafil, the range was 2.2-40.4 mg. The proportion of cases of having more than 100 mg of sildenafil was 50% and 78% had more than 20 mg of tadalafil. PMID:22620861

  14. 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

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

    PubMed

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

    2008-02-01

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

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

    PubMed Central

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

    2011-01-01

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

  17. 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...

  18. In vivo drug distribution dynamics in thermoablated and normal rabbit livers from biodegradable polymers

    E-print Network

    Gao, Jinming

    In vivo drug distribution dynamics in thermoablated and normal rabbit livers from biodegradable implantation, which was higher than the reported cytotoxic concentration of doxorubicin (6.4 g/g) for liver VX-2 cancer cells. This value dropped to 0.4 g/g at 48 h after implantation due to the depletion

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

    Microsoft Academic Search

    Katja Taxis; Bryony Dean; Nick Barber

    1999-01-01

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

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

    SciTech Connect

    Kennedy, E.; Frischer, H. (Rush Univ., Chicago, IL (USA))

    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.

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

    Microsoft Academic Search

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

    2004-01-01

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

  2. Distribution of drugs of abuse within specific regions of the human brain.

    PubMed

    Stimpfl, T; Reichel, S

    2007-08-01

    Since concentration of drugs of abuse found in the brain better reflect drug concentration at their site of action, brain specimens are useful in the determination of the role of drugs of abuse in the cause of death. In order to allow for the routine use of brain specimens in this field, a comprehensive database with reliable reference values is needed and should include both post-mortem data for cases where drugs have been taken in therapeutic doses as well as for cases of overdose. In this study, a semi-automated extraction procedure, in combination with gas chromatography/mass spectrometry (GC-MS) using stable isotope internal standards was applied to yield reproducible, quantitative results which could be used to investigate the distribution patterns of drugs of abuse within specific regions of the brain, by analyzing several segments of both medulla oblongata and cerebellum. A homogenous distribution of unconjugated morphine, dihydrocodeine, and benzoylecgonine within the investigated segments of medulla oblongata or cerebellum could be found. However, when these two brain regions from the same case were compared to each other, significantly higher concentrations of unconjugated morphine, dihydrocodeine, and benzoylecgonine were found in the cerebellum than in the medulla oblongata. PMID:17629644

  3. Exploiting structural information for drug-target assessment.

    PubMed

    Volkamer, Andrea; Rarey, Matthias

    2014-03-01

    The amount of known protein structures is continuously growing, exhibited in over 95,000 3D structures freely available via the PDB. Over the last decade, pharmaceutical research has sparked interest in computationally extracting information from this large data pool, resulting in a homology-driven knowledge transfer from annotated to new structures. Studying protein structures with respect to understanding and modulating their functional behavior means analyzing their centers of action. Therefore, the detection and description of potential binding sites on the protein surface is a major step towards protein classification and assessment. Subsequently, these representations can be incorporated to compare proteins, and to predict their druggability or function. Especially in the context of target identification and polypharmacology, automated tools for large-scale target comparisons are highly needed. In this article, developments for automated structure-based target assessment are reviewed and remaining challenges as well as future perspectives are discussed. PMID:24575967

  4. Assessing drug exposure in rodent toxicity studies without satellite animals

    Microsoft Academic Search

    Jerry R. Nedelman; Ekaterina Gibiansky; Francis L. S. Tse; Christine Babiuk I

    1993-01-01

    Five major objectives for pharmacokinetic investigations in support of toxicity studies are identified as follows: Assess whether animals exhibited measurable blood concentrations in a dose-dependent manner; estimate average area under the concentration- time curve (AUC)and maximal concentration (Cmax)for each treatment group; elucidate general patterns in the concentration-time (CxT)profile, and summarize relationships between CxTand treatment group; determine CxTdependence on day into

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

    PubMed Central

    2014-01-01

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

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

    PubMed Central

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

    2014-01-01

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

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

    E-print Network

    Gleeson, Joseph G.

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

  8. 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...

  9. Photo-distributed neutrophilic drug eruption and adult respiratory distress syndrome associated with antidepressant therapy.

    PubMed

    Mecca, Patricia; Tobin, Ellis; Andrew Carlson, J

    2004-02-01

    Drug reactions are well-known complications of antidepressant therapy, often related to photosensitization. Herein is reported a singular case of antidepressant (amoxapine and citalopram) and anxiolytic related (perphenazine) photo-distributed neutrophilic dermatosis and adult respiratory distress syndrome (ARDS). The clinicopathologic findings displayed overlapping features with drug-induced Sweet's syndrome, acute generalized exanthematous pustulosis (AGEP), and so-called sterile neutrophilic folliculitis with perifollicular vasculopathy. Of the three medications, only amoxapine has been associated with AGEP. Treatment with high-dose systemic corticosteroids and cessation of drug therapy was followed by rapid resolution of the cutaneous eruption and respiratory distress. The possibility that neutrophil infiltration of the lung and/or accumulation of neutrophils in the skin and blood served as a source for reactive oxygen species, leading to lung injury and subsequent ARDS, is discussed. PMID:14690466

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

    PubMed Central

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

    2011-01-01

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

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

    SciTech Connect

    Chatterjee, Sagnik, E-mail: Sagnik.Chatterjee@pharm.kuleuven.be [Drug Delivery and Disposition, KU Leuven Department of Pharmaceutical and Pharmacological Sciences, O and N2, Herestraat 49 — bus 921, 3000 Leuven (Belgium); Richert, Lysiane, E-mail: l.richert@kaly-cell.com [KaLy-Cell, 20A rue du Général Leclerc, 67115 Plobsheim (France); Augustijns, Patrick, E-mail: Patrick.Augustijns@pharm.kuleuven.be [Drug Delivery and Disposition, KU Leuven Department of Pharmaceutical and Pharmacological Sciences, O and N2, Herestraat 49 — bus 921, 3000 Leuven (Belgium); Annaert, Pieter, E-mail: Pieter.Annaert@pharm.kuleuven.be [Drug Delivery and Disposition, KU Leuven Department of Pharmaceutical and Pharmacological Sciences, O and N2, Herestraat 49 — bus 921, 3000 Leuven (Belgium)

    2014-01-01

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

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

    PubMed

    Stern, L

    1981-11-01

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

  13. 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

  14. QTc prolongation assessment in anticancer drug development: clinical and methodological issues

    PubMed Central

    Curigliano, G; Spitaleri, G; de Braud, F; Cardinale, D; Cipolla, C; Civelli, M; Colombo, N; Colombo, A; Locatelli, M; Goldhirsch, A

    2009-01-01

    Cardiac safety assessments are commonly employed in the clinical development of investigational oncology medications. In anti-cancer drug development there has been increasing consideration for the potential of a compound to cause adverse electrocardiographic changes, especially QT interval prolongation, which can be associated with risk of torsades de pointes and sudden death. Irrespective of overt clinical toxicities, QTc assessment can potentially influence decision making at many levels during the conduct of clinical studies, including eligibility for protocol therapy, dose delivery or discontinuation, and analyses of optimal dose for subsequent development. Given the potential for serious and irreversible morbidity from cardiac adverse events, it is understandable that cardiac safety results can have broad impact on study conduct and patient management. The methodologies for risk management of QTc prolongation for non cardiac drugs have been developed out of experiences primarily from drugs used to treat non life-threatening illnesses in a chronic setting such as antibiotics or antihistamines. Extrapolating these approaches to drugs for treating cancer over an acute period may not be appropriate. Few specific guidelines are available for risk management of cardiac safety in the development and use of oncology drugs. In this manuscript, clinical and methodological issues related to QTc prolongation assessment will be reviewed. Discussions about limitations in phase-I design and oncology drug development will be highlighted. Efforts are needed to refine strategies for risk management, avoiding unintended consequences that negatively affect patient access and clinical development of promising new cancer treatments. A thoughtful risk management plan generated by an organized collaboration between oncologists, cardiologists, and regulatory agencies to support a development programme essential for oncology agents with cardiac safety concerns. PMID:22275999

  15. 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. PMID:24336137

  16. 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. (Faculty of Pharmaceutical Sciences, Setsunan University, Osaka (Japan))

    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.

  17. The Assessment of Prior Distributions in Bayesian Analysis

    Microsoft Academic Search

    Robert L. Winkler

    1967-01-01

    In the Bayesian framework, quantified judgments about uncertainty are an indispensable input to methods of statistical inference and decision. Ultimately, all components of the formal mathematical models underlying inferential procedures represent quantified judgments. In this study, the focus is on just one component, the prior distribution, and on some of the problems of assessment that arise when a person tries

  18. 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...

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

    PubMed Central

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

    2013-01-01

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

  20. 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)-?-cyclodextrin, (2-hydroxypropyl)-?-cyclodextrin, 2,6-di-O-methyl-?-cyclodextrin, hepta-kis(2,3,6-tri-O-methyl)-?-cyclodextrin, ?-cyclodextrin, ?-cyclodextrin, respectively. It is likely that 1:2 complexes are also formed in some cases. This method has also been applied to study the binding behavior as a function of the drug concentration and pH. Binding weakens at higher drug concentration which may be due to the self-association of the drug. An acidic environment decreases the binding constant of CD with the basic econazole. The formation of the 1:2 complexes is completely suppressed in acid as well. This protocol is faster than the phase-solubility method. Moreover, the material requirement is up to four orders of magnitude lower. PMID:18428984

  1. Assessment of a new device for delivering aerosol drugs to asthmatic children.

    PubMed Central

    Hodges, I G; Milner, A D; Stokes, G M

    1981-01-01

    A new device, known as the aero-chamber, for delivering aerosol drugs was compared with a standard aerosol inhaler in asthmatic children aged between 5 years 3 months and 13 years 10 months. The study was conducted under double-blind conditions using fenoterol, a beta 2 stimulant, as the active agent and a placebo. Response to treatment was assessed by measuring the peak expiratory flow rate before and after each inhaler. Seven of 10 children had greater mean improvements in peak expiratory flow rates when receiving the active drug from the aerochamber. The aerochamber offers a method for administering a whole range of canistered packaged drugs to children unable to use the standard inhalers. PMID:7030221

  2. [The characteristics of drug distribution in the body under the influence of different types of electrical current].

    PubMed

    Ulashchik, V S

    1997-01-01

    Rabbit experiments showed that distribution of drugs in the body in intratissue electrophoresis is related to current type. The drugs reach the target organ and are deposited best under the influence of sinusoidal modulated and galvanic currents. The experiments' evidence may serve the basis for differential use of electric currents for intratissue electrophoresis. PMID:9424838

  3. 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

  4. Assessing Drug Use in the Workplace: A Comparison of Self Report, Urinalysis, and Hair Analysis

    Microsoft Academic Search

    Royer F. Cook; Alan D. Bernstein; Christine M. Andrews

    A random sample of 1,200 employees of a steel plant in the western United States was randomly assigned to four different self-report methods of assessing illicit drug use: individual interview in the workplace, group-administered questionnaire in the workplace, telephone interview, and individual interview off the worksite. Urine specimens were collected and analyzed on all 928 subjects participating in the study,

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

    PubMed

    An, Soontae; Muturi, Nancy

    2011-01-01

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

  6. Comparing two types of macrolide antibiotics for the purpose of assessing population-based drug interactions

    PubMed Central

    Fleet, Jamie L; Shariff, Salimah Z; Bailey, David G; Gandhi, Sonja; Juurlink, David N; Nash, Danielle M; Mamdani, Muhammad; Gomes, Tara; Patel, Amit M; Garg, Amit X

    2013-01-01

    Objective Clarithromycin strongly inhibits enzyme cytochrome P450 3A4, preventing the metabolism of some other drugs, while azithromycin is a weak inhibitor. Accordingly, blood concentrations of other drugs increase with clarithromycin coprescription leading to adverse events. These macrolide antibiotics also differ on other properties that may impact outcomes. In this study, we compared outcomes in two groups of macrolide antibiotic users in the absence of potentially interacting drugs. Design Population-based retrospective cohort study. Setting Ontario, Canada, from 2003 to 2010. Patients Patients (mean 74?years) prescribed clarithromycin (n=52?251) or azithromycin (referent group, n=46?618). Main outcomes The primary outcomes were hospital admission within 30?days of a new antibiotic prescription with any of the 12 conditions examined separately (acute kidney injury, acute myocardial infarction, neuroimaging (proxy for delirium), hypotension, syncope, hyperkalaemia, hyponatraemia, hyperglycaemia, arrhythmia, ischaemic stroke, gastrointestinal bleeding and sepsis). The secondary outcome was mortality. Results The baseline characteristics of the two groups, including patient demographics, comorbid conditions, infection type and prescribing physician specialty, were nearly identical. The median daily dose was 1000?mg for clarithromycin and 300?mg for azithromycin and the median duration of dispensing antibiotics was 10 and 5?days, respectively. There was no difference between the groups in the risk of hospitalisation for any condition studied (relative risk ranged from 0.67 to 1.23). Compared with azithromycin, clarithromycin was associated with a slightly higher risk of all-cause mortality (0.46% vs 0.37%, relative risk 1.25, 95% CI 1.03 to 1.52). Conclusions Clarithromycin can be used to assess drug interactions in population-based studies with azithromycin serving as a control group. However, any differences in mortality observed between the two antibiotic groups in the setting of other drug use may be partially attributable to factors beyond the inhibition of drug metabolising enzymes and transporters, as the difference for this outcome was significant. PMID:23847265

  7. Assessment of temperature-induced hERG channel blockade variation by drugs.

    PubMed

    Kauthale, Rahul R; Dadarkar, Shruta S; Husain, Raghib; Karande, Vikas V; Gatne, Madhumanjiri M

    2015-07-01

    Drug-induced QT prolongation has been reported in humans and animals. This potentially lethal effect can be induced by drugs interacting with a cardiac potassium channel, namely hERG (human ether-a go-go-related gene) leading to arrhythmia or torsade de pointes (TdP). Hence, in vitro evaluation of therapeutics for their effects on the rapid delayed rectifier current (IKr ) mediated by the K(+) ion channel encoded by hERG is a valuable tool for identifying potential arrhythmic side effects during drug safety testing. Our objective was to evaluate the temperature-induced hERG channel blockade variation by human and veterinary drugs using the IonFlux 16 system. A panel of eight drugs was tested for IKr inhibition at both ambient (23?°C) and physiological (37?°C) temperatures at various concentrations using IonFlux 16, an automated patch clamp system. Our results established that both amiodarone (IC50 ?=?0.56??M at 23?°C and 0.30??M at 37?°C) and ?-estradiol (IC50 ?=?24.72??M at 23?°C and 8.17??M at 37?°C) showed a dose-dependent IKr blockade with a higher blockade at 37?°C. Whereas, blockade of IKr by both ivermectin (IC50 ?=?12.52??M at 23?°C and 24.41??M at 37?°C) and frusemide (IC50 ?=?12.58??M at 23?°C and 25.55??M at 37?°C) showed a dose-dependent IKr blockade with a lower blockade at 37?°C. Gentamicin, enrofloxacin, xylazine and albendazole did not block IKr at both the assessed temperatures. Collectively, these results demonstrate that the effect of temperature variation should be taken into consideration during the evaluation of test drugs for their hERG channel blockade potential. Copyright © 2014 John Wiley & Sons, Ltd. PMID:25348819

  8. Chemical, genetic and structural assessment of pyridoxal kinase as a drug target in the African trypanosomemmi_8189 51..64

    E-print Network

    Schnaufer, Achim

    Chemical, genetic and structural assessment of pyridoxal kinase as a drug target in the African. These findings suggest that pyridoxal kinase is an essential and druggable target that could lead to much needed targets and the devel- opment of new drugs. Sequencing the T. brucei genome has greatly enhanced our

  9. 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…

  10. 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

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

    PubMed Central

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

    2004-01-01

    Background Hospitalization can significantly disrupt sleeping patterns. In consideration of the previous reports of insomnia and apparent widespread use of benzodiazepines and other hypnotics in hospitalized patients, we conducted a study to assess quality of sleep and hypnotic drug use in our acute care adult patient population. The primary objectives of this study were to assess sleep disturbance and its determinants including the use of drugs with sedating properties. Methods This single-centre prospective study involved an assessment of sleep quality for consenting patients admitted to the general medicine and family practice units of an acute care Canadian hospital. A validated Verran and Snyder-Halpern (VSH) Sleep Scale measuring sleep disturbance, sleep effectiveness, and sleep supplementation was completed daily by patients and scores were compared to population statistics. Patients were also asked to identify factors influencing sleep while in hospital, and sedating drug use prior to and during hospitalization was also assessed. Results During the 70-day study period, 100 patients completed at least one sleep questionnaire. There was a relatively even distribution of males versus females, most patients were in their 8th decade of life, retired, and suffered from multiple chronic diseases. The median self-reported pre-admission sleep duration for participants was 8 hours and our review of PharmaNetR profiles revealed that 35 (35%) patients had received a dispensed prescription for a hypnotic or antidepressant drug in the 3-month period prior to admission. Benzodiazepines were the most common sedating drugs prescribed. Over 300 sleep disturbance, effective and supplementation scores were completed. Sleep disturbance scores across all study days ranged 16–681, sleep effectiveness scores ranged 54–402, while sleep supplementation scores ranged between 0–358. Patients tended to have worse sleep scores as compared to healthy non-hospitalized US adults in all three scales. When compared to US non-hospitalized adults with insomnia, our patients demonstrated sleep disturbance and supplementation scores that were similar on Day 1, but lower (i.e. improved) on Day 3, while sleep effectiveness were higher (i.e. better) on both days. There was an association between sleep disturbance scores and the number of chronic diseases, the presence of pain, the use of bedtime tricyclic antidepressants, and the number of chronic diseases without pain. There was also an association between sleep effectiveness scores and the length of hospitalization, the in hospital use of bedtime sedatives and the presence of pain. Finally, an association was identified between sleep supplementation scores and the in hospital use of bedtime sedatives (tricyclic antidepressants and loxapine), and age. Twenty-nine (29%) patients received a prescription for a hypnotic drug while in hospital, with no evidence of pre-admission hypnotic use. The majority of these patients were prescribed zopiclone, lorazepam or another benzodiazepine. Conclusions The results of this study reveal that quality of sleep is a problem that affects hospitalized adult medical service patients and a relatively high percentage of these patients are being prescribed a hypnotic prior to and during hospitalization. PMID:15040803

  12. Assessment of DNA damage in Japanese nurses handling antineoplastic drugs by the comet assay.

    PubMed

    Sasaki, Makiko; Dakeishi, Miwako; Hoshi, Shigeko; Ishii, Noriko; Murata, Katsuyuki

    2008-01-01

    To clarify genotoxic effects of occupational exposure to antineoplastic drugs in Japan, we examined DNA damage, assessed by the comet assay, in 121 female nurses and 46 female clerks working at three hospitals in the northeast of Japan. The comet assay is considered to be a sensitive and rapid method for DNA strand break detection in individual cells, and tail length and tail moment are used as the comet parameters. Concerning the basal characteristics, the 46 control subjects had higher rates of smoking and coffee-drinking habits and lower hemoglobin than the 121 nurses (p<0.05). The log-transformed tail length in the nurses was significantly longer than that in the control subjects after adjusting for possible covariates such as age and smoking habit (p<0.05). Also, the log-transformed tail length was significantly longer, in the 57 nurses who had handled antineoplastic drugs in the last six months, than that in the 46 control subjects (p<0.05); but, no significant difference in tail length or tail moment was seen between the two nurse groups with and without experience of handling hazardous drugs (p>0.05). These results suggest that Japanese nurses who have worked at hospitals using antineoplastic drugs may have a potential risk of DNA damage. To minimize this risk in Japan, use of biological safety cabinet and appropriate protective equipment, in addition to staff education and training, should be implemented in the healthcare environment. PMID:18285639

  13. Development and evaluation of an in vitro vaginal model for assessment of drug's biopharmaceutical properties: curcumin.

    PubMed

    Berginc, Katja; Skalko-Basnet, Nataša; Basnet, Purusotam; Kristl, Albin

    2012-12-01

    Vaginal administration is a promising alternative to the per-oral route in achieving systemic or local therapeutic effects, when intestinal drug absorption is hindered by problematic biopharmaceutical drug properties. The aim of this study was to establish an in vitro vaginal model and use it to characterize biopharmaceutical properties of liposomally associated curcumin destined for vaginal delivery. The in vitro permeability, metabolism, and tissue retention of high/low permeable compounds were assessed on cow vaginal mucosa and compared to the permeabilities determined through Caco-2 cells and rat jejunum in vitro. The results showed that the intestinal mucosa was superior to the vaginal one in categorizing drugs based on their permeabilities in high/low permeable classes. Passive diffusion was found to be the main mechanism of drug penetration through vaginal mucosa and it was not affected by transporter-enzyme alliance, as their expression/activity was significantly reduced compared to the intestinal tract. Curcumin permeability from the solution form was the lowest of all tested substances due to its significant tissue retention and curcumin-mucus interactions. The permeability of liposomally associated curcumin was even lower but the binding of liposomally associated curcumin to the vaginal tissue was significantly higher. The permeability and tissue retention of liposomal curcumin were vesicle size dependent. Vaginal application of liposomally associated curcumin provides relatively high levels of curcumin in vaginal tissue, with limited systemic absorption. PMID:22899381

  14. Developing and evaluating distributions for probabilistic human exposure assessments

    SciTech Connect

    Maddalena, Randy L.; McKone, Thomas E.

    2002-08-01

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

  15. Effects of established hypolipidemic drugs on HDL concentration, subclass distribution, and function.

    PubMed

    Gomaraschi, Monica; Adorni, Maria Pia; Banach, Maciej; Bernini, Franco; Franceschini, Guido; Calabresi, Laura

    2015-01-01

    The knowledge of an inverse relationship between plasma high-density lipoprotein cholesterol (HDL-C) concentrations and rates of cardiovascular disease has led to the concept that increasing plasma HDL-C levels would be protective against cardiovascular events. Therapeutic interventions presently available to correct the plasma lipid profile have not been designed to specifically act on HDL, but have modest to moderate effects on plasma HDL-C concentrations. Statins, the first-line lipid-lowering drug therapy in primary and secondary cardiovascular prevention, have quite modest effects on plasma HDL-C concentrations (2-10%). Fibrates, primarily used to reduce plasma triglyceride levels, also moderately increase HDL-C levels (5-15%). Niacin is the most potent available drug in increasing HDL-C levels (up to 30%), but its use is limited by side effects, especially flushing.The present chapter reviews the effects of established hypolipidemic drugs (statins, fibrates, and niacin) on plasma HDL-C levels and HDL subclass distribution, and on HDL functions, including cholesterol efflux capacity, endothelial protection, and antioxidant properties. PMID:25523003

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

    PubMed Central

    Lim, Roxanne; Conner, Kim; Karnsakul, Wikrom

    2014-01-01

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

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

    NASA Astrophysics Data System (ADS)

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

    2011-03-01

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

  18. 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

    ...the Controlled Substances Act. Drugs with abuse potential generally include drugs...under medical supervision. If a drug has abuse potential, the Secretary of Health...with the National Institute on Drug Abuse (NIDA), as described in a...

  19. 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.

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

  1. Admixed Phylogenetic Distribution of Drug Resistant Mycobacterium tuberculosis in Saudi Arabia

    PubMed Central

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

    2013-01-01

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

  2. 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

  3. [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. PMID:21465764

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

    Microsoft Academic Search

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

    2008-01-01

    Penetration and distribution of thiocolchicoside from a commercially available foam (Miotens® 0.25%, w\\/v) through human excised full-thickness skin were evaluated using two different in vitro apparatus: a Franz diffusion cell and a Saarbruecken penetration model-based cell. In order to evaluate the intrinsic capability\\u000a of the drug to penetrate into the skin, a simple drug aqueous solution prepared at the same

  5. Beta-adrenergic blockade affects initial drug distribution due to decreased cardiac output and altered blood flow distribution.

    PubMed

    Avram, Michael J; Krejcie, Tom C; Henthorn, Thomas K; Niemann, Claus U

    2004-11-01

    Beta-adrenergic receptor blockers decrease intravenous anesthetic dose requirements. The present study determined the effect of propranolol on indocyanine green and antipyrine disposition from the moment of rapid intravenous injection. Anti-pyrine is a physiological marker that distributes to a volume as large as total body water in a blood flow-dependent manner and is a pharmacokinetic surrogate for many lipophilic drugs, including intravenous anesthetics. Antipyrine and indocyanine green disposition were determined twice in five healthy adult males in this Institutional Review Board-approved study, once during propranolol infusion. After rapid indocyanine green and antipyrine injection, arterial blood samples were collected frequently for 2 min and less frequently thereafter. Plasma indocyanine green and antipyrine concentrations were measured by high-performance liquid chromatography. Indocyanine green and antipyrine disposition were characterized, using SAAM II, by a recirculatory pharmacokinetic model that describes drug disposition from the moment of injection. Parameters were compared using the paired t test. The disposition of indocyanine green demonstrated that propranolol decreased cardiac output at the expense of the fast peripheral (nonsplanchnic) intravascular circuit. The area under the antipyrine concentration versus time relationship was doubled for at least the first 3 min after injection due to both decreased cardiac output and maintenance of nondistributive blood flow at the expense of a two-thirds reduction of blood flow (intercompartmental clearance) to the rapidly equilibrating (fast, splanchnic) tissue volume. The increase in antipyrine area under the curve due to propranolol-induced alteration of initial antipyrine disposition could explain decreased intravenous anesthetic dose requirements in the presence of beta-adrenergic receptor blockade. PMID:15197245

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

    Microsoft Academic Search

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

    2004-01-01

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

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

    PubMed

    Vaishnav, K G; Patel, I C

    2006-03-01

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

  8. New Approach to Assessment of Cardioselectivity of Beta-blocking Drugs

    PubMed Central

    Kumana, C. R.; Marlin, G. E.; Kaye, C. M.; Smith, D. M.

    1974-01-01

    Propranolol, practolol, and placebo were each given intravenously at weekly intervals to six normal subjects, and their effects on respiratory function tests and heart rates assessed. The reduction in the exercise heart rate after each of the two drugs was most comparable at six hours, indicating a similar degree of cardiac beta-blockade, when the plasma concentration ratio of practolol to propranolol was 28:1. The peak flow rate (PFR) was higher at all times during exercise than at rest. There were significant differences between the changes in resting and exercise PFR after placebo and the reductions after propranolol (except at 24 hours), but not after practolol—and the latter's influence on PFR seemed to be intermediate to that of propranolol and placebo. At six hours, when the cardiac beta-blocking activity of the two drugs was almost the same, there was a significant difference (P 0·025) between the reductions in exercise PFR associated with each drug. PMID:4425917

  9. 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 may be the natural variation in these techniques. But other explanations are possible and are discussed. PMID:20537190

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

    Microsoft Academic Search

    Annpey Pong; Damaraju Raghavarao

    2002-01-01

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

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

    Microsoft Academic Search

    E P Brass; R Lofstedt; O Renn

    2011-01-01

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

  12. Discussion of risks of platinum resources based on a function orientated criticality assessment - shown by cytostatic drugs and automotive catalytic converters

    Microsoft Academic Search

    Andrea Thorenz; Armin Reller

    2011-01-01

    Purpose  The purpose of the study is the enhancement of criticality assessments for resources in order to address function specific\\u000a factors like dissipation, recycling, bio-activity and toxicity. The developed methodology is applied to platinum-containing\\u000a cytostatic drugs and automotive catalytic converters.\\u000a \\u000a \\u000a \\u000a \\u000a Methods  The study is methodically based on an analysis of resource specific factors like exploration rates, reserves-to-production\\u000a ratio and regional distribution of

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

    PubMed Central

    Rocchi, Angela; Chabot, Isabelle; Glennie, Judith

    2015-01-01

    Background In 2007, Canada chose to develop a separate and distinct path for oncology drug health technology assessment (HTA). In 2013, the decision was made to transfer the pan-Canadian Oncology Drug Review (pCODR) to the Canadian Agency for Drugs and Technologies in Health (CADTH), to align the pCODR and CADTH Common Drug Review processes while building on the best practices of both. The objective of this research was to conduct an examination of the best practices established by the pCODR. Methods A qualitative research approach was taken to assess the policies, processes, and practices of the pCODR, based on internationally accepted best practice “principles” in HTA, with a particular focus on stakeholder engagement. Publicly available information regarding the approach of the pCODR was used to gauge the agency’s performance against these principles. In addition, stakeholder observations and real-world experiences were gathered through key informant interviews to be inclusive of perspectives from patient advocacy groups, provincial and/or cancer agency decision-makers, community and academic oncologists, industry, expert committee members, and health economists. Results This analysis indicated that, through the pCODR, oncology stakeholders have had a voice in and have come to trust the quality and relevance of oncology HTA as a vital tool to ensure the best decisions for Canadians with cancer and their health care system. It could be expected that adoption of the principles and processes of the pCODR would bring a similar level of engagement and trust to other HTA organizations in Canada and elsewhere. Conclusion The results of this research led to recommendations for improvement and potential extrapolation of these best practices to other HTA organizations worldwide, along with suggestions for continued evolution of the pCODR in conjunction with its integration into the CADTH. It is clear that the transition of the pCODR to CADTH provides an opportunity for practices initiated by the pCODR to become the standard for these newly amalgamated HTA agencies in Canada. PMID:26082654

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

    PubMed Central

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

    2013-01-01

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

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

    PubMed

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

    2013-12-01

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

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

    PubMed Central

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

    2013-01-01

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

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

    ERIC Educational Resources Information Center

    Libby, David L.; Novick, Melvin R.

    1982-01-01

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

  18. Towards the Assessment of Distributed Vulnerabilities in Autonomic Networks and Systems

    E-print Network

    Paris-Sud XI, Université de

    Towards the Assessment of Distributed Vulnerabilities in Autonomic Networks and Systems Mart. In this work, we present a novel approach for describing and assessing distributed vulner- abilities a framework for assessing dis- tributed vulnerabilities in autonomic environments that exploits the knowledge

  19. DMAS: a web-based distributed mathematics assessment system (abstract only)

    Microsoft Academic Search

    Saleh Al-shomrani; Paul Wang

    2008-01-01

    Assessing student performance and understanding is very important in education generally and in Mathematics education in particular. DMAS is a Web-based Distributed Mathematics Assessment system that can be of great value to teachers and students of Mathematics. Features of DMAS include: DMAD (the core Distributed Mathematics Assessment database), test authoring tool for teachers, online taking of tests, grading and results

  20. “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

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

    E-print Network

    Eustice, Ryan

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

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

    PubMed

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

    1993-01-01

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

  3. Performance Assessment of OVERFLOW on Distributed Computing Environment

    NASA Technical Reports Server (NTRS)

    Djomehri, M. Jahed; Rizk, Yehia M.

    2000-01-01

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

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

    PubMed Central

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

    2013-01-01

    Objectives In vivo experimentation is costly and time-consuming, and presents a major bottleneck in anti-tuberculosis drug development. Conventional methods rely on the enumeration of bacterial colonies, and it can take up to 4 weeks for Mycobacterium tuberculosis to grow on agar plates. Light produced by recombinant bacteria expressing luciferase enzymes can be used as a marker of bacterial load, and disease progression can be easily followed non-invasively in live animals by using the appropriate imaging equipment. The objective of this work was to develop a bioluminescence-based mouse model of tuberculosis to assess antibiotic efficacy against M. tuberculosis in vivo. Methods We used an M. tuberculosis strain carrying a red-shifted derivative of the firefly luciferase gene (FFlucRT) to infect mice, and monitored disease progression in living animals by bioluminescence imaging before and after treatment with the frontline anti-tuberculosis drug isoniazid. The resulting images were analysed and the bioluminescence was correlated with bacterial counts. Results Using bioluminescence imaging we detected as few as 1.7?×?103 and 7.5?×?104 reporter bacteria ex vivo and in vivo, respectively, in the lungs of mice. A good correlation was found between bioluminescence and bacterial load in both cases. Furthermore, a marked reduction in luminescence was observed in living mice given isoniazid treatment. Conclusions We have shown that an improved bioluminescent strain of M. tuberculosis can be visualized by non-invasive imaging in live mice during an acute, progressive infection and that this technique can be used to rapidly visualize and quantify the effect of antibiotic treatment. We believe that the model presented here will be of great benefit in early drug discovery as an easy and rapid way to identify active compounds in vivo. PMID:23633686

  5. Recent developments in the risk assessment of potentially genotoxic impurities in pharmaceutical drug substances.

    PubMed

    Humfrey, Charles D N

    2007-11-01

    Controlling the quality of medicines is just as important as demonstrating efficacy. The International Conference on Harmonisation has published general guidance on the quality and safety assessment of impurities in pharmaceutical drug substances and drug products. More recently, the European Medicines Evaluation Agency has published a guideline focusing on limits for genotoxic impurities. This is based on a Threshold of Toxicological Concern (TTC) derived from animal carcinogenicity data using multiple worst case assumptions to estimate a daily dose (1.5 microg/day) associated with a lifetime cancer risk of 1 in 100,000, a risk level considered acceptable for genotoxic impurities in human medicines. Based on these assumptions, presentation of the TTC as a single figure infers an unwarranted level of precision and supports the adoption of a more flexible approach by regulatory authorities when evaluating new drug products; a range within fivefold of the TTC limit would seem sensible. Furthermore, the limit is based on 70 years continuous daily exposure, a scenario that is uncommon for most medicines and irrelevant to the preregistration clinical development phase. To address this latter point, a staged TTC has been developed that proposes limits based on shorter durations of treatment, e.g., up to 1 year. Based on recent history, this approach has been acceptable to some authorities but not to others, and it is imperative that steps are taken to reach a common agreement between the pharmaceutical industry and regulatory authorities globally in order that new medicines can continue to be developed and delivered to benefit patients in a safe and timely manner. PMID:17656486

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

    Microsoft Academic Search

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

    1985-01-01

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

  7. 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 [Center for Physiology and Pharmacology, Department of Neurophysiology and -pharmacology, Medical University of Vienna, 1090 Vienna (Austria); Hilber, Karlheinz, E-mail: karlheinz.hilber@meduniwien.ac.at [Center for Physiology and Pharmacology, Department of Neurophysiology and -pharmacology, Medical University of Vienna, 1090 Vienna (Austria); Sandtner, Walter [Center for Physiology and Pharmacology, Institute of Pharmacology, Medical University of Vienna, 1090 Vienna (Austria)

    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 ?M) even shortened the AP. These findings can be explained by the drug's calcium channel inhibition, which counteracts the AP-prolonging effect generated by hERG blockade. Implementation of ibogaine's inhibitory effects on human ion channels in a computer model of a ventricular cardiomyocyte, on the other hand, suggested that ibogaine does prolong the AP in the human heart. We conclude that therapeutic concentrations of ibogaine have the propensity to prolong the QT interval of the electrocardiogram in humans. In some cases this may lead to cardiac arrhythmias. - Highlights: • We study effects of anti-addiction drug ibogaine on ionic currents in cardiomyocytes. • We assess the cardiac ion channel profile of ibogaine. • Ibogaine inhibits hERG potassium, sodium and calcium channels. • Ibogaine’s effects on ion channels are a potential source of cardiac arrhythmias. • 18-Methoxycoronaridine has a lower affinity for cardiac ion channels than ibogaine.

  8. Quantitative assessment of cumulative carcinogenic risk for multiple genotoxic impurities in a new drug substance.

    PubMed

    Bercu, Joel P; Hoffman, Wherly P; Lee, Cindy; Ness, Daniel K

    2008-08-01

    In pharmaceutical development, significant effort is made to minimize the carcinogenic potential of new drug substances (NDS). This involves appropriate genotoxicity and carcinogenicity testing of the NDS, and understanding the genotoxic potential of its impurities. Current available guidance recommends the use of the threshold of toxicological concern (TTC) for a single impurity where mutagenicity but no carcinogenicity information exists. Despite best efforts, the presence of more than one genotoxic impurity in an NDS may occur at trace levels. This paper repeats the analysis performed by others for a single genotoxic compound, but also uses statistical simulations to assess the impact on cancer risk for a mixture of genotoxic compounds. In summary, with the addition of multiple impurities all controlled to the TTC, an increase in cancer risk was observed. This increase is relatively small when considering the conservative assumptions of the TTC. If structurally similar compounds had an assumed strong correlation (+/-10-fold from the first randomly selected impurity) in cancer potency, the resulting cancer risk was not negatively impacted. Findings based on probabilistic analysis here can be very useful in making appropriate decisions about risk management of multiple genotoxic impurities measured in the final drug substance. PMID:18550240

  9. A novel method for assessing in vitro oncology drug combinations using growth rates.

    PubMed

    Pashkevich, Maksim; Iversen, Philip; Brooks, Harold

    2012-01-01

    We propose a new method that allows screening oncology drug combinations using data from in vitro studies to select agents that have the promise of showing a synergistic effect in vivo. In contrast to known approaches that define combination effects either on the concentration scale or on the percent inhibition scale, we use the growth rate of treated cells as a primary indicator of treatment activity. The developed method is based on a novel statistical model that describes the growth of cancer cells that are subject to treatment with a combination of compounds. The model assumes a multicompartment cell population with transition rates between compartments modeled according to biochemical reaction properties, and cells in each compartment growing according to exponential law. This translates to a linear system of ordinary differential equations, whose solution is accurately approximated by a closed-form expression using rapid equilibrium assumptions. Special cases of the aforementioned model represent situations when the combination effect is absent or when the considered drugs act as the same compound. Assuming the normal distribution for the growth rate measurement error, we describe a formal statistical testing procedure to distinguish between different mechanisms of action for the considered compounds, and to test if a significant combination effect is being observed. PMID:22416837

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

    Microsoft Academic Search

    Gene M Heyman; Brian Dunn

    2002-01-01

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

  11. Functional ATP-binding cassette drug efflux transporters in isolated human and rat hepatocytes significantly affect assessment of drug disposition.

    PubMed

    Lundquist, Patrik; Englund, Gunilla; Skogastierna, Cristine; Lööf, Johan; Johansson, Jenny; Hoogstraate, Janet; Afzelius, Lovisa; Andersson, Tommy B

    2014-03-01

    Freshly isolated hepatocytes are considered the gold standard for in vitro studies of hepatic drug disposition. To ensure a reliable supply of cells, cryopreserved human hepatocytes are often used. ABC-superfamily drug efflux transporters are key elements in hepatic drug disposition. These transporters are often considered lost after isolation of hepatocytes. In the present study, the expression and activity of ABC transporters BCRP, BSEP, P-gp, MRP2, MRP3, and MRP4 in human and rat cryopreserved hepatocytes were investigated. In commercially available human cryopreserved hepatocytes, all drug efflux transporters except human BCRP (hBCRP) exhibited similar expression levels as in fresh liver biopsies. Expression levels of hBCRP were 60% lower in cryopreserved human hepatocytes than in liver tissue, which could lead to, at most, a 2.5-fold reduction in hBCRP-mediated efflux. Fresh rat hepatocytes showed significantly lower levels of rat BCRP compared with liver expression levels; expression levels of other ABC transporters were unchanged. ABC transporters in human cryopreserved cells were localized to the plasma membrane. Functional studies could demonstrate P-gp and BCRP activity in both human cryopreserved and fresh rat hepatocytes. Inhibiting P-gp-mediated efflux by elacridar in in vitro experiments significantly decreased fexofenadine efflux from hepatocytes, resulting in an increase in apparent fexofenadine uptake. The results from the present study clearly indicate that ABC transporter-mediated efflux in freshly isolated as well as cryopreserved rat and human hepatocytes should be taken into account in in vitro experiments used for modeling of drug metabolism and disposition. PMID:24396144

  12. Development of a Questionnaire to Assess Drug Abuse among High School Students of Isfahan Province, Iran: An Action Research

    PubMed Central

    Geramian, Nahid; Gharaat, Leila; Taheri, Shohreh Akhavan; Mohebpour, Fatemeh; Nahvizadeh, Mahmonir; Farajzadegan, Ziba; Heidari, Kamal

    2014-01-01

    Background: Considering the problem of drug abuse in Iran especially in adolescents and the youth, recent alterations in drug abuse rate and its trend, the necessity to have local information about this problem, applied research has a determining role in management of this problem and making proper decisions. Therefore, the current study was conducted to develop a questionnaire to assess the status of drug abuse among high school students of Isfahan Province, Iran. Methods: This cross-sectional study was conducted out in 2009 in 20 cities of Isfahan Province. A researcher-made questionnaire was developed to determine knowledge, attitude, and practice of high school students regarding addictive drugs and their associated causes. This was accomplished by recruiting 7137 students who were selected by multistage random cluster sampling. Results: The designed questionnaire identified the status quo of drug abuse according to age, gender, and different cities of Isfahan Province. We also accessed information about the type of abused drug, the most common causes of drug abuse for the first time, the most important causes of drug abuse, mean age of abusers and mean age at the first abuse, common time and locations of drug abuse, and the most common routes of drug abuse according to gender as well as urban and rural areas of Isfahan Province. Reliability of the questionnaire, based on the calculated Cronbach's alpha coefficient, was 77% considering a cut-off point of 0.07. Conclusions: According to the obtained results, the designed questionnaire is capable to assess the drug abuse status among high school students of Isfahan Province. Regarding the importance of teenage years in forming the future behaviors of adolescents and the opportunities provided at schools, it is prudent to pay more attention to interventions in this age group in order to increase their knowledge and correct their attitude toward illegal drugs and strengthening their confidence in this regard. These interventions can have an important role in decreasing the rate of drug abuse in this age group and consequently in the whole community.

  13. Detecting drug-induced prolongation of the QRS complex: New insights for cardiac safety assessment

    SciTech Connect

    Cros, C., E-mail: caroline.cros@hotmail.co.uk [Safety Pharmacology, Global Safety Assessment, Safety Assessment UK, AstraZeneca R and D, Alderley Park, Macclesfield, SK10 4TG (United Kingdom); Skinner, M., E-mail: Matthew.Skinner@astrazeneca.com [Safety Pharmacology, Global Safety Assessment, Safety Assessment UK, AstraZeneca R and D, Alderley Park, Macclesfield, SK10 4TG (United Kingdom); Moors, J. [Safety Pharmacology, Global Safety Assessment, Safety Assessment UK, AstraZeneca R and D, Alderley Park, Macclesfield, SK10 4TG (United Kingdom)] [Safety Pharmacology, Global Safety Assessment, Safety Assessment UK, AstraZeneca R and D, Alderley Park, Macclesfield, SK10 4TG (United Kingdom); Lainee, P. [Sanofi-Aventis R and D, 371, rue du Pr Joseph Blayac, 34184 Montpellier Cedex 04 (France)] [Sanofi-Aventis R and D, 371, rue du Pr Joseph Blayac, 34184 Montpellier Cedex 04 (France); Valentin, J.P. [Safety Pharmacology, Global Safety Assessment, Safety Assessment UK, AstraZeneca R and D, Alderley Park, Macclesfield, SK10 4TG (United Kingdom)] [Safety Pharmacology, Global Safety Assessment, Safety Assessment UK, AstraZeneca R and D, Alderley Park, Macclesfield, SK10 4TG (United Kingdom)

    2012-12-01

    Background: Drugs slowing the conduction of the cardiac action potential and prolonging QRS complex duration by blocking the sodium current (I{sub Na}) may carry pro-arrhythmic risks. Due to the frequency-dependent block of I{sub Na}, this study assesses whether activity-related spontaneous increases in heart rate (HR) occurring during standard dog telemetry studies can be used to optimise the detection of class I antiarrhythmic-induced QRS prolongation. Methods: Telemetered dogs were orally dosed with quinidine (class Ia), mexiletine (class Ib) or flecainide (class Ic). QRS duration was determined standardly (5 beats averaged at rest) but also prior to and at the plateau of each acute increase in HR (3 beats averaged at steady state), and averaged over 1 h period from 1 h pre-dose to 5 h post-dose. Results: Compared to time-matched vehicle, at rest, only quinidine and flecainide induced increases in QRS duration (E{sub max} 13% and 20% respectively, P < 0.01–0.001) whereas mexiletine had no effect. Importantly, the increase in QRS duration was enhanced at peak HR with an additional effect of + 0.7 ± 0.5 ms (quinidine, NS), + 1.8 ± 0.8 ms (mexiletine, P < 0.05) and + 2.8 ± 0.8 ms (flecainide, P < 0.01) (calculated as QRS at basal HR-QRS at high HR). Conclusion: Electrocardiogram recordings during elevated HR, not considered during routine analysis optimised for detecting QT prolongation, can be used to sensitise the detection of QRS prolongation. This could prove useful when borderline QRS effects are detected. Analysing during acute increases in HR could also be useful for detecting drug-induced effects on other aspects of cardiac function. -- Highlights: ? We aimed to improve detection of drug-induced QRS prolongation in safety screening. ? We used telemetered dogs to test class I antiarrhythmics at low and high heart rate. ? At low heart rate only quinidine and flecainide induced an increase in QRS duration. ? At high heart rate the effects of two out of three antiarrhythmics were enhanced. ? Detection of a drug-induced prolongation of QRS was improved at high heart rate.

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

    PubMed

    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. PMID:24967688

  15. 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

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

    PubMed

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

    2010-01-01

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

  17. Clustered distribution of natural product leads of drugs in the chemical space as influenced by the privileged target-sites.

    PubMed

    Tao, Lin; Zhu, Feng; Qin, Chu; Zhang, Cheng; Chen, Shangying; Zhang, Peng; Zhang, Cunlong; Tan, Chunyan; Gao, Chunmei; Chen, Zhe; Jiang, Yuyang; Chen, Yu Zong

    2015-01-01

    Some natural product leads of drugs (NPLDs) have been found to congregate in the chemical space. The extent, detailed patterns, and mechanisms of this congregation phenomenon have not been fully investigated and their usefulness for NPLD discovery needs to be more extensively tested. In this work, we generated and evaluated the distribution patterns of 442?NPLDs of 749 pre-2013 approved and 263 clinical trial small molecule drugs in the chemical space represented by the molecular scaffold and fingerprint trees of 137,836 non-redundant natural products. In the molecular scaffold trees, 62.7% approved and 37.4% clinical trial NPLDs congregate in 62 drug-productive scaffolds/scaffold-branches. In the molecular fingerprint tree, 82.5% approved and 63.0% clinical trial NPLDs are clustered in 60 drug-productive clusters (DCs) partly due to their preferential binding to 45 privileged target-site classes. The distribution patterns of the NPLDs are distinguished from those of the bioactive natural products. 11.7% of the NPLDs in these DCs have remote-similarity relationship with the nearest NPLD in their own DC. The majority of the new NPLDs emerge from preexisting DCs. The usefulness of the derived knowledge for NPLD discovery was demonstrated by the recognition of the new NPLDs of 2013-2014 approved drugs. PMID:25790752

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

    EPA Science Inventory

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

  19. 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. PMID:24962255

  20. Clinical drug-drug interaction assessment of ivacaftor as a potential inhibitor of cytochrome P450 and P-glycoprotein.

    PubMed

    Robertson, Sarah M; Luo, Xia; Dubey, Neeraj; Li, Chonghua; Chavan, Ajit B; Gilmartin, Geoffrey S; Higgins, Mark; Mahnke, Lisa

    2015-01-01

    Ivacaftor is approved in the USA for the treatment of cystic fibrosis (CF) in patients with a G551D-CFTR mutation or one of eight other CFTR mutations. A series of in vitro experiments conducted early in the development of ivacaftor indicated ivacaftor and metabolites may have the potential to inhibit cytochrome P450 (CYP) 2C8, CYP2C9, CYP3A, and CYP2D6, as well as P-glycoprotein (P-gp). Based on these results, a series of clinical drug-drug interaction (DDI) studies were conducted to evaluate the effect of ivacaftor on sensitive substrates of CYP2C8 (rosiglitazone), CYP3A (midazolam), CYP2D6 (desipramine), and P-gp (digoxin). In addition, a DDI study was conducted to evaluate the effect of ivacaftor on a combined oral contraceptive, as this is considered an important comedication in CF patients. The results indicate ivacaftor is a weak inhibitor of CYP3A and P-gp, but has no effect on CYP2C8 or CYP2D6. Ivacaftor caused non-clinically significant increases in ethinyl estradiol and norethisterone exposure. Based on these results, caution and appropriate monitoring are recommended when concomitant substrates of CYP2C9, CYP3A and/or P-gp are used during treatment with ivacaftor, particularly drugs with a narrow therapeutic index, such as warfarin. PMID:25103957

  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. Risk assessment and distribution of soil Pb in Guangdong, China.

    PubMed

    Yang, C L; Wu, Z F; Zhang, H H; Guo, R P; Wu, Y Q

    2009-12-01

    In this study, the spatial distributions of soil lead (Pb) concentration in three horizontal soils in Guangdong, China, were surveyed and analyzed using geostatistics and geography information systems (GIS). Findings indicated that the Pb geometric mean concentration of 23.3 mg/kg in surface soils was found to be higher than those in global soils, which ranged from 2.3-235 mg/kg. In addition, the Pb geometric mean concentrations from A- to C-horizon were found to be 23.3, 27.2, and 28.6 mg/kg, respectively. The classification of a soil Pb environmental risk in an area was likewise presented based on the different levels of environmental quality of Pb and was done by GIS technology. Accordingly, there is a higher local concentration of Pb in the surrounding areas of Guangzhou where there is higher population density and in the north of Guangdong, which is a historic mining area. The results obtained by the environmental risk assessment reveal that about 46% of total surveyed area was above the background value, that is, 2.7% of the total area was at risk of pollution. PMID:19058022

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

    PubMed

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

    2013-10-01

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

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

    PubMed

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

    2014-11-01

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

  5. 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

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

    E-print Network

    Sterk, Joseph P. (Sterk, Joseph Phillip)

    2011-01-01

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

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

    PubMed Central

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

    2014-01-01

    Causality assessment of suspected drug induced liver injury (DILI) and herb induced liver injury (HILI) is hampered by the lack of a standardized approach to be used by attending physicians and at various subsequent evaluating levels. The aim of this review was to analyze the suitability of the liver specific Council for International Organizations of Medical Sciences (CIOMS) scale as a standard tool for causality assessment in DILI and HILI cases. PubMed database was searched for the following terms: drug induced liver injury; herb induced liver injury; DILI causality assessment; and HILI causality assessment. The strength of the CIOMS lies in its potential as a standardized scale for DILI and HILI causality assessment. Other advantages include its liver specificity and its validation for hepatotoxicity with excellent sensitivity, specificity and predictive validity, based on cases with a positive reexposure test. This scale allows prospective collection of all relevant data required for a valid causality assessment. It does not require expert knowledge in hepatotoxicity and its results may subsequently be refined. Weaknesses of the CIOMS scale include the limited exclusion of alternative causes and qualitatively graded risk factors. In conclusion, CIOMS appears to be suitable as a standard scale for attending physicians, regulatory agencies, expert panels and other scientists to provide a standardized, reproducible causality assessment in suspected DILI and HILI cases, applicable primarily at all assessing levels involved. PMID:24653791

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

    PubMed Central

    2011-01-01

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

  9. Causality Assessment in Drug-Induced Liver Injury Using a Structured Expert Opinion Process: Comparison to the Roussel-Uclaf Causality Assessment Method

    PubMed Central

    Rockey, Don C.; Seeff, Leonard B.; Rochon, James; Freston, James; Chalasani, Naga; Bonacini, Maurizio; Fontana, Robert J.; Hayashi, Paul H.

    2011-01-01

    Drug-induced liver injury (DILI) is largely a diagnosis of exclusion and is therefore challenging. The US Drug-Induced Liver Injury Network (DILIN) prospective study used two methods to assess DILI causality: a structured expert opinion process and the Roussel-Uclaf Causality Assessment Method (RUCAM). Causality assessment focused on detailed clinical and laboratory data from patients with suspected DILI. The adjudication process used standardized numerical and descriptive definitions and scored cases as definite, highly likely, probable, possible, or unlikely. Results of the structured expert opinion procedure were compared with those derived by the RUCAM approach. Among 250 patients with suspected DILI, the expert opinion adjudication process scored 78 patients (31%) as definite, 102 (41%) as highly likely, 37 (15%) as probable, 25 (10%) as possible, and 8 (3%) as unlikely. Among 187 enrollees who had received a single implicated drug, initial complete agreement was reached for 50 (27%) with the expert opinion process and for 34 (19%) with a five-category RUCAM scale (P = 0.08), and the two methods demonstrated a modest correlation with each other (Spearman's r = 0.42, P = 0.0001). Importantly, the RUCAM approach substantially shifted the causality likelihood toward lower probabilities in comparison with the DILIN expert opinion process. Conclusion The structured DILIN expert opinion process produced higher agreement rates and likelihood scores than RUCAM in assessing causality, but there was still considerable interobserver variability in both. Accordingly, a more objective, reliable, and reproducible means of assessing DILI causality is still needed. PMID:20512999

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

    Microsoft Academic Search

    Robert T. O'Neill; Ana Szarfman

    2001-01-01

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

  11. 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.

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

    NASA Technical Reports Server (NTRS)

    Schmeckpeper, K. R.

    1988-01-01

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

  13. 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 component in the high throughput assessment of demethylation and risk of chromatin reorganization in epigenetic-drug screening tasks. PMID:20813111

  14. 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

  15. Learn More about Normal Distribution | Dietary Assessment Primer

    Cancer.gov

    In statistics, the "distribution function" of a random variable is a function that specifies the probability that the variable's observed value will lie in any given region of possible values. The "normal distribution" is the most commonly used distribution in statistics. A variable that is normally distributed has a histogram (or "density function") that is bell-shaped, with only one peak, and is symmetric around the mean.

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

    NASA Astrophysics Data System (ADS)

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

    2014-05-01

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

  17. Pharmacology of antithrombotic drugs: an assessment of oral antiplatelet and anticoagulant treatments.

    PubMed

    Mega, Jessica L; Simon, Tabassome

    2015-07-18

    Antithrombotic drugs, which include antiplatelet and anticoagulant therapies, prevent and treat many cardiovascular disorders and, as such, are some of the most commonly prescribed drugs worldwide. The first drugs designed to inhibit platelets or coagulation factors, such as the antiplatelet clopidogrel and the anticoagulant warfarin, significantly reduced the risk of thrombotic events at the cost of increased bleeding in patients. However, both clopidogrel and warfarin have some pharmacological limitations including interpatient variability in antithrombotic effects in part due to the metabolism, interactions (eg, drug, environment, and genetic), or targets of the drugs. Increased knowledge of the pharmacology of antithrombotic drugs and the mechanisms underlying thrombosis has led to the development of newer drugs with faster onset of action, fewer interactions, and less interpatient variability in their antithrombotic effects than previous antithrombotic drugs. Treatment options now include the next-generation antiplatelet drugs prasugrel and ticagrelor, and, in terms of anticoagulants, inhibitors that directly target factor IIa (dabigatran) or Xa (rivaroxaban, apixaban, edoxaban) are available. In this Series paper we review the pharmacological properties of these most commonly used oral antithrombotic drugs, and explore the development of antiplatelet and anticoagulant therapies. PMID:25777662

  18. Illicit Drug Use Among South Korean Offenders: Assessing the Generality of Social Learning Theory.

    PubMed

    Yun, Minwoo; Kim, Eunyoung

    2014-04-21

    Since the mid-1990s, illicit drug use has become a problem in Korean society. This trend is likely due to the rapid globalization and expansion that occurred with the Internet revolution, which led to greater numbers of people socially learning about drug culture. The current study attempts to uncover criminogenic causality of such social learning about drug use by studying adult felony drug offenders in South Korea. The data used for the study were obtained from self-reported surveys, originally collected by the Korean Institution of Criminology (KIC). The final sample comprised 1,452 felony offenders convicted of illicit drug use, and their responses were analyzed with a set of multiple logistic regression tests. The current study found supportive evidence for the generalizability of social learning theory from the sample of the South Korean adult drug offenders. We argue that the current study provides additional empirical evidence that supports the generalizability of social learning theory. PMID:24752638

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

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ...or licensed with a state agency as a drug manufacturer; (iii) Licensed as a pharmacy by a State Board of Pharmacy; (iv) Operating as a nuclear pharmacy within a Federal medical institution; or (v) A Positron Emission...

  20. 45 CFR 156.295 - Prescription drug distribution and cost reporting.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ...that were provided under the QHP through retail pharmacies compared to mail order pharmacies, and the percentage of prescriptions for which...compared to all drugs dispensed, broken down by pharmacy type, which includes an independent...

  1. 10 CFR 32.72 - Manufacture, preparation, or transfer for commercial distribution of radioactive drugs containing...

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ...or licensed with a state agency as a drug manufacturer; (iii) Licensed as a pharmacy by a State Board of Pharmacy; (iv) Operating as a nuclear pharmacy within a Federal medical institution; or (v) A Positron Emission...

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

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ...that were provided under the QHP through retail pharmacies compared to mail order pharmacies, and the percentage of prescriptions for which...compared to all drugs dispensed, broken down by pharmacy type, which includes an independent...

  3. 10 CFR 32.72 - Manufacture, preparation, or transfer for commercial distribution of radioactive drugs containing...

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ...or licensed with a state agency as a drug manufacturer; (iii) Licensed as a pharmacy by a State Board of Pharmacy; (iv) Operating as a nuclear pharmacy within a Federal medical institution; or (v) A Positron Emission...

  4. 10 CFR 32.72 - Manufacture, preparation, or transfer for commercial distribution of radioactive drugs containing...

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ...or licensed with a state agency as a drug manufacturer; (iii) Licensed as a pharmacy by a State Board of Pharmacy; (iv) Operating as a nuclear pharmacy within a Federal medical institution; or (v) A Positron Emission...

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

    PubMed

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

    2012-05-01

    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 de-risking 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

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

    PubMed

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

    2008-12-01

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

  7. The assessment of efficacy, toxicity and quality of care in long-term drug treatment.

    PubMed

    Dollery, C T

    1976-01-01

    Drug studies in man are usually divided into four phases. The first phase is to establish that the drug has a pharmacological action in man and in which dose range it occurs. The second phase is a study of the therapeutic effect of the drug in small numbers of closely observed patients. The third phase consists of large-scale studies which may involve hundreds or thousands of patients; such studies are designed to accumulate less detailed information about efficacy and to provide information about low frequency toxic events. At the end of this stage the drug is submitted to a regulatory body for a license to market it. Information derived from these studies usually has several important deficiencies. There is unlikely to be much evidence about the efficacy of the drug in relation to that of other substances used to treat the same condition. The carefully regulated conditions of the clinical trial may bear little relationship to the way the drug will be used in practice. Most important, the evidence obtained on efficacy may relate chiefly to the pharmacological action of the drug, e.g. in lowering blood pressure or blood sugar, or reducing inflammation, and may not bear directly upon therapeutic outcome. For these reasons much attention is being focused on monitoring of the way drugs are used after marketing. To provide evidence of therapeutic efficacy may require studies of such large scale and high cost that they are beyond the research of individual pharmaceutical companies and will require national or international action. Monitoring of the way drugs are used inevitably means studying not just the performance of the drug but also of the doctors who prescribe it. Studies that have been made of the quality of care of patients treated with anti-hypertensive drugs and those requiring anticoagulants are not reassuring concerning the general level of such quality. PMID:829769

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

    Microsoft Academic Search

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

    2012-01-01

    Land Use Regression (LUR) models have been widely used to characterize the spatial distribution of urban air pollution and estimate exposure in epidemiologic studies. However, spatial patterns of air pollution vary greatly between cities due to local source type and distribution. London is a medium sized city with relatively few and isolated industrial point sources, which allowed the study to

  9. Assessment of Distributed Generation Potential in JapaneseBuildings

    Microsoft Academic Search

    Nan Zhou; Chris Marnay; Masaru Nishida

    2005-01-01

    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

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

    PubMed Central

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

    2014-01-01

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

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

    PubMed

    Allen, Tim; Parker, Melissa

    2011-01-01

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

  12. Combining ESI, ASL and PET for quantitative assessment of drug-resistant focal epilepsy.

    PubMed

    Storti, Silvia Francesca; Boscolo Galazzo, Ilaria; Del Felice, Alessandra; Pizzini, Francesca Benedetta; Arcaro, Chiara; Formaggio, Emanuela; Mai, Roberto; Manganotti, Paolo

    2014-11-15

    When localization of the epileptic focus is uncertain, the epileptic activity generator may be more accurately identified with non-invasive imaging techniques which could also serve to guide stereo-electroencephalography (sEEG) electrode implantation. The aim of this study was to assess the diagnostic value of perfusion magnetic resonance imaging with arterial spin labeling (ASL) in the identification of the epileptogenic zone, as compared to the more invasive positron-emission tomography (PET) and other established investigation methods for source imaging of electroencephalography (EEG) data. In 6 patients with drug-resistant focal epilepsy, standard video-EEG was performed to identify clinical seizure semeiology, and high-density EEG, ASL and FDG-PET to non-invasively localize the epileptic focus. A standardized source imaging procedure, low-resolution brain electromagnetic tomography constrained to the individual matter, was applied to the averaged spikes of high-density EEG. Quantification of current density, cerebral blood flow, and standardized uptake value were compared over the same anatomical areas. In most of the patients, source in the interictal phase was associated with an area of hypoperfusion and hypometabolism. Conversely, in the patients presenting with early post-ictal discharges, the brain area identified by electrical source imaging (ESI) as the generating zone appeared to be hyperperfused. In 2 patients in whom the focus remained uncertain, the postoperative follow-up showed the disappearance of epileptic activity. As an innovative and more comprehensive approach to the study of epilepsy, the combined use of ESI, perfusion MRI, and PET may play an increasingly important role in the non-invasive evaluation of patients with refractory focal epilepsy. PMID:23792219

  13. HVAC Modeling for Cost of Ownership Assessment in Biotechnology & Drugs Manufacturing

    Microsoft Academic Search

    Peter Broomes

    Heating, ventilation, and air conditioning (HVAC) systems used in the clean room environment of biotechnology and drug development and manufacturing, are extremely energy and water intensive and represent a significant operating cost for these facilities (1). HVAC systems are also the primary source of environmental emissions for the majority of companies operating within the biotechnology and drugs sector. While the

  14. A colorimetric field method to assess the authenticity of drugs sold as the antimalarial artesunate

    Microsoft Academic Search

    Michael D Green; Dwight L Mount; Robert A Wirtz; Nicholas J White

    2000-01-01

    Artesunate is the most widely used of the artemisinin derivatives. These drugs are being used increasingly throughout the tropical world, and are an essential component of the treatment of multi-drug resistant malaria. The recent and widespread appearance of counterfeit artesunate tablets in several countries in Southeast Asia poses a serious threat to health in this region. We have developed a

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

    ERIC Educational Resources Information Center

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

    2003-01-01

    Evaluations of prison-based drug treatment programs typically focus on one or two dichotomous outcome variables related to recidivism. In contrast, this paper uses multiple measures of outcomes related to crime and drug use to examine the impact of prison treatment. Crime variables included self-report data of time to first illegal activity,…

  16. 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…

  17. 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.

  18. Diversity, distribution and conservation status assessment of Paraguayan palms (Arecaceae)

    Microsoft Academic Search

    Irene GautoRodolphe; Rodolphe E. Spichiger; Fred W. Stauffer

    Indigenous palm species of Paraguay are presented with data on their diversity, distribution, threats and conservation status.\\u000a The Paraguayan palm flora consists of 23 native species in 11 genera, representing two of the five subfamilies recognized\\u000a in the group. The palm distribution in the country is strongly related to the different ecoregions present in Paraguay, with\\u000a number of species by

  19. Considerations for assessing the potential effects of antidiabetes drugs on cardiac ventricular repolarization: A report from the Cardiac Safety Research Consortium.

    PubMed

    Heller, Simon; Darpö, Börje; Mitchell, Malcolm I; Linnebjerg, Helle; Leishman, Derek J; Mehrotra, Nitin; Zhu, Hao; Koerner, John; Fiszman, Mónica L; Balakrishnan, Suchitra; Xiao, Shen; Todaro, Thomas G; Hensley, Ingrid; Guth, Brian D; Michelson, Eric L; Sager, Philip

    2015-07-01

    Thorough QT studies conducted according to the International Council on Harmonisation E14 guideline are required for new nonantiarrhythmic drugs to assess the potential to prolong ventricular repolarization. Special considerations may be needed for conducting such studies with antidiabetes drugs as changes in blood glucose and other physiologic parameters affected by antidiabetes drugs may prolong the QT interval and thus confound QT/corrected QT assessments. This review discusses potential mechanisms for QT/corrected QT interval prolongation with antidiabetes drugs and offers practical considerations for assessing antidiabetes drugs in thorough QT studies. This article represents collaborative discussions among key stakeholders from academia, industry, and regulatory agencies participating in the Cardiac Safety Research Consortium. It does not represent regulatory policy. PMID:26093861

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

    PubMed

    Raucy, Judy L; Lasker, Jerome M

    2013-02-01

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

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

    Microsoft Academic Search

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

    2009-01-01

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

  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. Monthly spatial distributed water resources assessment: a case study

    NASA Astrophysics Data System (ADS)

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

    2012-08-01

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

  4. In vivo assessment of the impact of efflux transporter on oral drug absorption using portal vein-cannulated rats.

    PubMed

    Matsuda, Yoshiki; Konno, Yoshihiro; Hashimoto, Takashi; Nagai, Mika; Taguchi, Takayuki; Satsukawa, Masahiro; Yamashita, Shinji

    2013-08-01

    The purpose of this study was to evaluate the impact of intestinal efflux transporters on the in vivo oral absorption process. Three model drugs-fexofenadine (FEX), sulfasalazine (SASP), and topotecan (TPT)-were selected as P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), and P-gp and BCRP substrates, respectively. The drugs were orally administered to portal vein-cannulated rats after pretreatment with zosuquidar (ZSQ), P-gp inhibitor, and/or Ko143, BCRP inhibitor. Intestinal availability (Fa·Fg) of the drugs was calculated from the difference between portal and systemic plasma concentrations. When rats were orally pretreated with ZSQ, Fa·Fg of FEX increased 4-fold and systemic clearance decreased to 75% of the control. In contrast, intravenous pretreatment with ZSQ did not affect Fa·Fg of FEX, although systemic clearance decreased significantly. These data clearly show that the method presented herein using portal vein-cannulated rats can evaluate the effects of intestinal transporters on Fa·Fg of drugs independently of variable systemic clearance. In addition, it was revealed that 71% of FEX taken up into enterocytes underwent selective efflux via P-gp to the apical surface, while 79% of SASP was effluxed by Bcrp. In the case of TPT, both transporters were involved in its oral absorption. Quantitative analysis indicated a 3.5-fold higher contribution from Bcrp than P-gp. In conclusion, the use of portal vein-cannulated rats enabled the assessment of the impact of efflux transporters on intestinal absorption of model drugs. This experimental system is useful for clarifying the cause of low bioavailability of various drugs. PMID:23686319

  5. INITIAL INTERNAL RELIABILITY AND DESCRIPTIVE STATISTICS FOR A BRIEF ASSESSMENT TOOL FOR THE LIFE SKILLS TRAINING DRUG-ABUSE PREVENTION PROGRAM

    Microsoft Academic Search

    ARAXI P. MACAULAY; KENNETH W. GRIFFIN; GILBERT J. BOTVIN

    2002-01-01

    Summary.-Adolescent drug use in the United States remains the highest in the industrialized world. Fortunately there have been significant advances in developing effective prevention programs for adolescent drug use. An important issue in evaluat- ing such programs is that the self-report surveys have adequate psychometric proper- ties and assess constructs targeted by an intervention. A questionnaire focusing on knowledge and

  6. Action of Penetration Enhancers on Human Skin as Assessed by the Permeation of Model Drugs 5Fluorouracil and Estradiol. I. Infinite Dose Technique

    Microsoft Academic Search

    Michael Goodman; Brian William Barry

    1988-01-01

    We have conducted permeation studies to assess the effectiveness of accelerants Azone, oleic acid (OA), decylmethyl sulfoxide (DCMS) and propylene glycol (PG) in promoting the absorption through human skin of model drugs 5-fluorouracil (5FU) and estradiol (ES). Drug permeation from saturated aqueous solutions was monitored before and after accelerant treatment (applied in aqueous and PG vehicles). With ES, the study

  7. Comparative QSAR-and Fragments Distribution Analysis of Drugs, Druglikes, Metabolic Substances, and Antimicrobial Compounds

    E-print Network

    , and Antimicrobial Compounds Emre Karakoc, S. Cenk Sahinalp, and Artem Cherkasov*, School of Computing Science, Simon that include conventional drugs, inactive druglikes, antimicrobial substituents, and bacterial and human QSAR descriptors which allowed up to 99% accurate separation of the studied groups of activities

  8. Determination of drug-like properties of a novel antileishmanial compound: In vitro absorption, distribution, metabolism, and excretion studies

    PubMed Central

    Mondal, Susanta Kumar; Mondal, Nirup B.; Banerjee, Sukdeb; Mazumder, Upal Kanti

    2009-01-01

    In drug discovery research, the compounds should not only to be potent and selective but also must possess acceptable pharmacokinetic properties such as absorption, distribution, metabolism, and excretion (ADME) to increase success rate in clinical studies. Objective: Exploration of drug-like properties of 2-(2-methylquinolin-4-ylamino)-N-phenyl acetamide, a potent antileishmanial compound by performing some in vitro ADME experiments along with validation of such studies. Materials and Methods: Experimental protocols were established and validated for stability (in PBS pH7.4, simulated gastric and intestinal fluid), solubility, permeability, distribution coefficient (Log D), plasma protein binding and metabolism by rat liver microsomes by using spectrophotometer or HPLC. Methods were considered valid if the results of the standard compounds matched with reported results or within acceptable range or with proper ranking (high-medium-low). Results: The compound was found to be stable (>95% remaining) in all stability studies and aqueous solubility was 299.7 ± 6.42 ?M. The parallel artificial membrane permeability assay (PAMPA) indicated its medium permeability (Log Pe = ?5.53 ± 0.01). The distribution coefficients (Log D) in octanol/PBS and cyclohexane/PBS systems were found to be 0.54 and ?1.33, respectively. The plasma protein binding study by the equilibrium dialysis method was observed to be 78.82 ± 0.13% while metabolism by Phase-I enzymes for 1 hour at 37°C revealed that 36.07 ± 4.15% of the compound remained after metabolism. Conclusion: The methods were found to be very useful for day-to-day ADME studies. All the studies with the antileishmanial compound ascertained that the compound bears optimum pharmacokinetic properties to be used orally as a potential drug for the treatment of leishmaniasis. PMID:20523869

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

    PubMed Central

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

    2006-01-01

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

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

    PubMed

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

    2011-06-01

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

  11. Assessment of Pediatric asthma drug use in three European countries; a TEDDY study

    PubMed Central

    Verhamme, Katia M. C.; Neubert, Antje; Hsia, Yingfen; Murray, Macey; Felisi, Mariagrazia; Giaquinto, Carlo; ‘t Jong, Geert W.; Picelli, Gino; Baraldi, Eugenio; Nicolosi, Alfredo; Ceci, Adriana; Wong, Ian C.; Sturkenboom, Miriam C. J. M.

    2010-01-01

    Asthma drugs are amongst the most frequently used drugs in childhood, but international comparisons on type and indication of use are lacking. The aim of this study was to describe asthma drug use in children with and without asthma in the Netherlands (NL), Italy (IT), and the United Kingdom (UK). We conducted a retrospective analysis of outpatient medical records of children 0–18 years from 1 January 2000 until 31 December 2005. For all children, prescription rates of asthma drugs were studied by country, age, asthma diagnosis, and off-label status. One-year prevalence rates were calculated per 100 children per patient-year (PY). The cohort consisted of 671,831 children of whom 49,442 had been diagnosed with asthma at any time during follow-up. ß2-mimetics and inhaled steroids were the most frequently prescribed asthma drug classes in NL (4.9 and 4.1/100 PY), the UK (8.7 and 5.3/100 PY) and IT (7.2 and 16.2/100 PY), respectively. Xanthines, anticholinergics, leukotriene receptor antagonists, and anti-allergics were prescribed in less than one child per 100 per year. In patients without asthma, ß2-mimetics were used most frequently. Country differences were highest for steroids, (Italy highest), and for ß2-mimetics (the UK highest). Off-label use was low, and most pronounced for ß2-mimetics in children <18 months (IT) and combined ß2-mimetics?+?anticholinergics in children <6 years (NL). Conclusion: This study shows that among all asthma drugs, ß2-mimetics and inhaled steroids are most often used, also in children without asthma, and with large variability between countries. Linking multi-country databases allows us to study country specific pediatric drug use in a systematic manner without being hampered by methodological differences. This study underlines the potency of healthcare databases in rapidly providing data on pediatric drug use and possibly safety. PMID:20811908

  12. Interobserver variation in assessment of gastroduodenal lesions associated with non-steroidal anti-inflammatory drugs.

    PubMed Central

    Hudson, N; Everitt, S; Hawkey, C J

    1994-01-01

    Video endoscopic images were used to investigate whether gastroenterologists could agree on the definition of lesions within the stomach seen at endoscopy, with particular reference to those seen in patients taking non-steroidal anti-inflammatory drugs. Seven experienced endoscopists, unaware of the patients' clinical history or drug consumption, recorded their classification for 93 randomised video images of gastric lesions. There was complete agreement in the diagnosis of ulceration for nine images from patients who were not taking non-steroidal anti-inflammatory drugs; eight of nine were classified as deep ulcers, with 86% agreement for this subclassification. By contrast, the overall agreement for lesions in patients taking non-steroidal anti-inflammatory drugs was only 55%. Only nine of 44 ulcers were subclassified as deep, and there was considerable cross classification of non-haemorrhagic erosions and ulcers. In conclusion, ulcers that occur in patients taking non-steroidal anti-inflammatory drugs differ from those in patients who are not taking these drugs in that they are often more superficial and difficult to distinguish from erosions. The prognostic importance of these lesions is, therefore, uncertain. PMID:7926900

  13. Rapid Assessment Response (RAR) study: drug use, health and systemic risks—Emthonjeni Correctional Centre, Pretoria, South Africa

    PubMed Central

    2014-01-01

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

  14. Noninvasive in vivo optical assessment of blood brain barrier permeability and brain tissue drug deposition in rabbits

    NASA Astrophysics Data System (ADS)

    Ergin, Aysegul; Wang, Mei; Zhang, Jane; Bigio, Irving; Joshi, Shailendra

    2012-05-01

    Osmotic disruption of the blood brain barrier (BBB) by intraarterial mannitol injection is sometimes the key step for the delivery of chemotherapeutic drugs to brain tissue. BBB disruption (BBBD) with mannitol, however, can be highly variable and could impact local drug deposition. We use optical pharmacokinetics, which is based on diffuse reflectance spectroscopy, to track in vivo brain tissue concentrations of indocyanine green (ICG), an optical reporter used to monitor BBBD, and mitoxantrone (MTX), a chemotherapy agent that does not deposit in brain tissue without BBBD, in anesthetized New Zealand white rabbits. Results show a significant increase in the tissue ICG concentrations with BBBD, and our method is able to track the animal-to-animal variation in tissue ICG and MTX concentrations after BBBD. The tissue concentrations of MTX increase with barrier disruption and are found to be correlated to the degree of disruption, as assessed by the ICG prior to the injection of the drug. These findings should encourage the development of tracers and optical methods capable of quantifying the degree of BBBD, with the goal of improving drug delivery.

  15. Noninvasive in vivo optical assessment of blood brain barrier permeability and brain tissue drug deposition in rabbits

    PubMed Central

    Ergin, Aysegul; Wang, Mei; Zhang, Jane; Bigio, Irving; Joshi, Shailendra

    2012-01-01

    Abstract. Osmotic disruption of the blood brain barrier (BBB) by intraarterial mannitol injection is sometimes the key step for the delivery of chemotherapeutic drugs to brain tissue. BBB disruption (BBBD) with mannitol, however, can be highly variable and could impact local drug deposition. We use optical pharmacokinetics, which is based on diffuse reflectance spectroscopy, to track in vivo brain tissue concentrations of indocyanine green (ICG), an optical reporter used to monitor BBBD, and mitoxantrone (MTX), a chemotherapy agent that does not deposit in brain tissue without BBBD, in anesthetized New Zealand white rabbits. Results show a significant increase in the tissue ICG concentrations with BBBD, and our method is able to track the animal-to-animal variation in tissue ICG and MTX concentrations after BBBD. The tissue concentrations of MTX increase with barrier disruption and are found to be correlated to the degree of disruption, as assessed by the ICG prior to the injection of the drug. These findings should encourage the development of tracers and optical methods capable of quantifying the degree of BBBD, with the goal of improving drug delivery. PMID:22612147

  16. Image quality assessment based on local orientation distributions

    Microsoft Academic Search

    Yue Wang; Tingting Jiang; Siwei Ma; Wen Gao

    2010-01-01

    Image quality assessment (IQA) is very important for many image and video processing applications, e.g. compression, archiving, restoration and enhancement. An ideal image quality metric should achieve consistency between image distortion prediction and psychological perception of human visual system (HVS). Inspired by that HVS is quite sensitive to image local orientation features, in this paper, we propose a new structural

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

    EPA Science Inventory

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

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

    EPA Science Inventory

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

  19. 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...

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

    PubMed Central

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

    2013-01-01

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

  1. RESEARCH ARTICLE Source, distribution, and health risk assessment of polycyclic

    E-print Network

    Ma, Lena

    hydrocarbons in urban street dust from Tianjin, China Binbin Yu & Xiujie Xie & Lena Q. Ma & Haidong Kan, with the development of economy and urbanization, urban areas have been expanded quickly in China and other countries of urban residents exposed to urban street dust, the total concentration, sources, and distribution of 16

  2. ASSESSMENT AND IMPLICATIONS OF BACTERIAL REGROWTH IN WATER DISTRIBUTION SYSTEMS

    EPA Science Inventory

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

  3. Assessing a Tornado Climatology from Global Tornado Intensity Distributions

    Microsoft Academic Search

    Bernold Feuerstein; Nikolai Dotzek; Jürgen Grieser

    2005-01-01

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

  4. Residual Antimalarials in Malaria Patients from Tanzania – Implications on Drug Efficacy Assessment and Spread of Parasite Resistance

    PubMed Central

    Hodel, Eva Maria; Kabanywanyi, Abdunoor Mulokozi; Malila, Aggrey; Zanolari, Boris; Mercier, Thomas; Beck, Hans-Peter; Buclin, Thierry; Olliaro, Piero; Decosterd, Laurent Arthur; Genton, Blaise

    2009-01-01

    Background Repeated antimalarial treatment for febrile episodes and self-treatment are common in malaria-endemic areas. The intake of antimalarials prior to participating in an in vivo study may alter treatment outcome and affect the interpretation of both efficacy and safety outcomes. We report the findings from baseline plasma sampling of malaria patients prior to inclusion into an in vivo study in Tanzania and discuss the implications of residual concentrations of antimalarials in this setting. Methods and Findings In an in vivo study conducted in a rural area of Tanzania in 2008, baseline plasma samples from patients reporting no antimalarial intake within the last 28 days were screened for the presence of 14 antimalarials (parent drugs or metabolites) using liquid chromatography-tandem mass spectrometry. Among the 148 patients enrolled, 110 (74.3%) had at least one antimalarial in their plasma: 80 (54.1%) had lumefantrine above the lower limit of calibration (LLC?=?4 ng/mL), 7 (4.7%) desbutyl-lumefantrine (4 ng/mL), 77 (52.0%) sulfadoxine (0.5 ng/mL), 15 (10.1%) pyrimethamine (0.5 ng/mL), 16 (10.8%) quinine (2.5 ng/mL) and none chloroquine (2.5 ng/mL). Conclusions The proportion of patients with detectable antimalarial drug levels prior to enrollment into the study is worrying. Indeed artemether–lumefantrine was supposed to be available only at government health facilities. Although sulfadoxine–pyrimethamine is only recommended for intermittent preventive treatment in pregnancy (IPTp), it was still widely used in public and private health facilities and sold in drug shops. Self-reporting of previous drug intake is unreliable and thus screening for the presence of antimalarial drug levels should be considered in future in vivo studies to allow for accurate assessment of treatment outcome. Furthermore, persisting sub-therapeutic drug levels of antimalarials in a population could promote the spread of drug resistance. The knowledge on drug pressure in a given population is important to monitor standard treatment policy implementation. PMID:20011529

  5. Uncertainty Analysis of the Adequacy Assessment Model of a Distributed Generation System

    E-print Network

    Paris-Sud XI, Université de

    1 Uncertainty Analysis of the Adequacy Assessment Model of a Distributed Generation System Yanfu Li of distributed generation (DG) systems have been particularly focused on the probabilistic modeling of random1 , Enrico Zio1,2 1 Chair on Systems Science and the Energetic challenge, European Foundation

  6. 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...

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

    SciTech Connect

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

    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.

  8. Prescription Drug Monitoring Program Inquiry in Psychiatric Assessment: Detection of High Rates of Opioid Prescribing to a Dual Diagnosis Population

    PubMed Central

    Hackman, Daniel T.; Greene, Marion S.; Fernandes, Taya J.; Brown, Ashley M.; Wright, Eric R.; Chambers, R. Andrew

    2015-01-01

    Objective An epidemic of prescription drug abuse is disproportionately impacting the mentally ill. We examined the utility of a state prescription drug monitoring database for assessing recent controlled substance prescribing to patients presenting for dual diagnosis treatment. Method In a community mental health center that provides integrated dual diagnosis care, we queried the Indiana Scheduled Prescription Electronic Collection and Tracking (INSPECT) system for all cases that were open as of August 2, 2011, and had been practitioner-diagnosed (per DSM-IV criteria) by January 2, 2012. INSPECT provided a record of controlled substance dispensations to each patient; diagnostic evaluation was conducted blind from prescription data compilation covering the prior 12 months. Demographic data, insurance status, and DSM-IV diagnoses were compiled from the clinic's electronic medical record. Results The sample (N = 201) was 51% female, 56% white, and two-thirds uninsured. Over 80% were dually diagnosed with substance use disorders and psychotic, mood, or anxiety disorders. Nicotine and alcohol disorders were identified in most, with about a third diagnosed with cannabis, cocaine, or opioid disorders. A majority of patients (n = 115) had been prescribed opioids in the prior year, with nearly 1 in 5 prescribed an opioid and benzodiazepine simultaneously. Patients were dispensed a mean of 4 opioid prescriptions and 213 opioid pills. More opioid prescriptions correlated with opioid dependence (OR = 1.08; 95% CI, 1.016–1.145), and more prescribers correlated with personality disorder diagnoses (OR = 1.112; 95% CI, 1.001–1.235). Higher rates and riskier patterns of controlled substance prescribing were identified in patients with Medicaid/Medicare insurance compared to uninsured patients. Conclusions Prescription drug monitoring is a powerful tool for assessing addictions and high frequencies of patient exposures to prescribed opioids in a dual diagnosis clinic. Improved prevention and treatment strategies for addictions as facilitated by more research and clinical use of prescription drug monitoring in psychiatric care are warranted. PMID:25093472

  9. The role of pharmacodynamic research in the assessment and development of new antibacterial drugs.

    PubMed

    Lister, Philip D

    2006-03-30

    Antibacterial resistance continues to increase world wide, with some bacterial pathogens exhibiting resistance to virtually all available drugs. As the plague of antibacterial resistance continues to grow and create serious therapeutic problems, it is essential that the development of new antibacterial agents continue. Pharmacodynamic research plays an important role in the development of new antibacterial agents, as pharmacodynamic data can help define the clinical potential of a new drug and identify the strengths and weaknesses in comparison to other drugs already on the market. Furthermore, pharmacodynamic experiments can help focus the clinical phases of drug development by providing key information on the pharmacodynamic parameters that influence efficacy and the pharmacodynamic targets that should be achieved to optimize clinical success. Characterization of these pharmacodynamic properties for a new drug in development can help direct the design of the best dose and dosing strategy for clinical trials. This review will focus on the tools, methods, and strategies used to characterize the pharmacodynamics of antibacterial agents and aide in their development for clinical use. PMID:16316633

  10. In vitro assessment of antiretroviral drugs demonstrates potential for ototoxicity.

    PubMed

    Thein, Pru; Kalinec, Gilda M; Park, Channy; Kalinec, Federico

    2014-04-01

    Several studies have reported an increased incidence of auditory dysfunction among HIV/AIDS patients. We used auditory HEI-OC1 cells in cell viability, flow cytometry and caspases 3/7-activation studies to investigate the potential ototoxicity of fourteen HIV antiretroviral agents: Abacavir, AZT, Delavirdine, Didenosine, Efavirenz, Emtricitabine, Indinavir, Lamivudine, Nefinavir, Nevirapine, Tenofovir, Ritonavir, Stavudine and Zalcitabine, as well as combinations of these agents as used in the common anti-HIV cocktails Atripla™, Combivir™, Epzicom™, Trizivir™, and Truvada™. Our results suggested that most of the single assayed anti-HIV drugs are toxic for HEI-OC1 auditory cells. The cocktails, on the other hand, decreased auditory cells' viability with high significance, with the following severity gradient: Epzicom ? Trizivir > Atripla ? Combivir > Truvada. Interestingly, our results suggest that Trizivir- and Epzicom-induced cell death would be mediated by a caspase-independent mechanism. l-Carnitine, a natural micronutrient known to protect HEI-OC1 cells against some ototoxic drugs as well as to decrease neuropathies associated with anti-HIV treatments, increased viability of cells treated with Lamivudine and Tenofovir as well as with the cocktail Atripla, but had only minor effects on cells treated with other drugs and drug combinations. Altogether, these results suggest that some frequently used anti-HIV agents could have deleterious effects on patients' hearing, and provide arguments in favor of additional studies aimed at elucidating the potential ototoxicity of current as well as future anti-HIV drugs. PMID:24487230

  11. Self-microemulsifying drug delivery system (SMEDDS) of vinpocetine: formulation development and in vivo assessment.

    PubMed

    Chen, Ying; Li, Gao; Wu, Xianggen; Chen, Zhiyu; Hang, Jiangeng; Qin, Bei; Chen, Song; Wang, Ruihua

    2008-01-01

    A new self-microemulsifying drug delivery system (SMEDDS) has been developed to increase the solubility, dissolution rate and oral bioavailability of vinpocetine (VIP), a poor water-soluble drug. The formulations of VIP-SMEDDS were optimized by solubility assay, compatibility tests, and pseudo-ternary phase diagrams analysis. The optimal ratio in the formulation of SMEDDS was found to be Labrafac : oleic acid : Cremophor EL : Transcutol P=40 : 10 : 40 : 10 (w/w). The average particle diameter of VIP was less than 50 nm. In vitro dissolution study indicated that the dialysis method in reverse was better than the ultrafiltration method and the dialysis method in simulating the drug in vivo environment. Comparing with VIP crude drug power and commercial tablets, (-)VIP-SMEDDS caused a 3.4- and 2.9-fold increase in the percent of accumulated dissolution at 3 h. Further study on the absorption property of VIP-SMEDDS employing in situ intestine of rats demonstrated that VIP in SMEDDS could be well-absorbed in general intestinal tract without specific absorption sites. In addition, the developed SMEDDS formulations significantly improved the oral bioavailability of VIP in rats. Relative bioavailability of (-)VIP-SMEDDS and (+)VIP-SMEDDS increased by 1.85- and 1.91-fold, respectively, in relative of VIP crude powder suspension. The mechanisms of enhanced bioavailability of VIP might contribute to the improved release, enhanced lymphatic transport, and increased intestinal permeability of the drug. PMID:18175953

  12. 10 CFR 32.21 - Radioactive drug: Manufacture, preparation, or transfer for commercial distribution of capsules...

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ...commercial distribution of capsules containing carbon-14 urea each for âin vivoâ diagnostic...commercial distribution of capsules containing carbon-14 urea each for “in vivo” diagnostic...capsules containing 37 kBq (1 µCi) carbon-14 urea (allowing for nominal...

  13. 10 CFR 32.21 - Radioactive drug: Manufacture, preparation, or transfer for commercial distribution of capsules...

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ...commercial distribution of capsules containing carbon-14 urea each for âin vivoâ diagnostic...commercial distribution of capsules containing carbon-14 urea each for “in vivo” diagnostic...capsules containing 37 kBq (1 µCi) carbon-14 urea (allowing for nominal...

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

    PubMed Central

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

    2008-01-01

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

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

    PubMed Central

    2011-01-01

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

  16. 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

  17. 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

  18. Distribution of the most Common Genetic Variants Associated with a Variable Drug Response in the Population of the Republic of Macedonia.

    PubMed

    Kapedanovska Nestorovska, A; Jakovski, K; Naumovska, Z; Hiljadnikova Bajro, M; Sterjev, Z; Eftimov, A; Matevska Geskovska, N; Suturkova, L; Dimitrovski, K; Labacevski, N; Dimovski, A J

    2014-12-01

    Genetic variation in the regulation, expression and activity of genes coding for Phase I, Phase II drug metabolizing enzymes (DMEs) and drug targets, can be defining factors for the variability in both the effectiveness and occurrence of drug therapy side effects. Information regarding the geographic structure and multi-ethnic distribution of clinically relevant genetic variations is becoming increasingly useful for improving drug therapy and explaining inter-individual and inter-ethnic differences in drug response. This study summarizes our current knowledge about the frequency distribution of the most common allelic variants in three broad gene categories: the Phase I oxidation-cytochrome P450 (CYP450) family (CYP2C9, CYP2C19, CYP3A5, CYP2D6); the Phase II conjugation (GSTT1, SULT1A1; UGT1A1) and drug target (TYMS-TSER, MTHFR and VKORC1) in the population of the Republic of Macedonia and compares the information obtained with data published for other indigenous European populations. Our findings define the population of the Republic of Macedonia as an ethnic group with a highly polymorphic genetic profile. These results add to the evidence regarding the distribution of clinically important variant alleles in DME and drug target genes in populations of European ancestry. PMID:25937793

  19. "Patients, not criminals"? An assessment of Thailand's compulsory drug dependence treatment system.

    PubMed

    Pearshouse, Richard

    2009-05-01

    Since the enactment of a new law on addiction treatment in 2002, Thailand has sharply increased the number of people in compulsory drug treatment programs. This article provides an overview of the system, particularly the custodial programs. It also provides some preliminary observations on the implementation of the legislation on its own terms--namely, that people who are dependent on drugs should be "treated as patients and not criminals." While diverting people with drug dependence from the criminal justice system is important, this stated approach is undermined in a number of ways by the law's implementation. This article is based on a longer report released by the Canadian HIV/AIDS Legal Network in 2009. PMID:19606547

  20. Assessment of knowledge of pediatric nurses related with drug administration and preparation

    PubMed Central

    Bülbül, Ali; Kunt, Ay?e; Selalmaz, Melek; Sözeri, ?ehrinaz; Uslu, Sinan; Nuho?lu, Asiye

    2014-01-01

    Aim: Aim of this study is to determine the levels of knowledge related with drug administration and drug administration errors of nurses who care for pediatric patients. Material and Methods: The study data were obtained from the nurses who were working in the departments of pediatrics in two education and research hospitals in the province of ?stanbul and who accepted to participate in the study. The questionnaire form of the study was established by the investigators in accordance with the experiences and literature information. A total of 31 questions related with drug preparation, calculation and administration together with the general working properties of the individual were filled out by face to face interview. The data were evaluated using percent and chi-square tests. The study was initiated after ethics committee approval was obtained from ?i?li Hamidiye Etfal Education and Research Hospital (365/2013). Results: The study was conducted with 98 nurses who accepted the questionnaire. The education levels of the participants were as follows: undergraduate (48%), high school (32.7%), associate degree (12.2%), master’s degree (6.1%) and postgraduate (1%). It was found that 88.8% of the participants worked in a patient-centered fashion and 11.2% worked in a work-centered fashion. The frequency of interruption/distraction during preparation of treatment was found to be 92.9%. It was found that the frequency of checking by two people during preparation or administration of high risk drugs was 64.3% and the conditions under which drugs should be kept were found to known correctly with a rate of 76.5%. It was found that undergraduate healthcare workers were more successful in converting units (p= 0.000). It was found that powder weight of drugs was considered with a rate of 85.7% in calculation. Conclusions: Conclusively, it was found that nurses who worked in pediatric wards did not receive a standard education in terms of drug administration and preparation. It was found that undergraduate nurses were more successful in calculating doses, the process of drug preparation was interrupted with a rate of >90% and the rate of checking by two people was low.

  1. 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.

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

    PubMed

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

    2015-03-01

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

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

    PubMed

    Cauwels, Vanessa; Vanhavere, Filip; Reginatto, Marcel

    2014-10-01

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

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

    NASA Astrophysics Data System (ADS)

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

    2014-03-01

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

  5. 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

    ...test sample collection systems for drugs of abuse testing. 809.40 Section...sample collection systems for drugs of abuse testing. (a) Over-the-counter...sample collection systems for drugs of abuse testing (§ 864.3260 of...

  6. 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

    ...test sample collection systems for drugs of abuse testing. 809.40 Section...sample collection systems for drugs of abuse testing. (a) Over-the-counter...sample collection systems for drugs of abuse testing (§ 864.3260 of...

  7. Ketoconazole, an oral antifungal: laboratory and clinical assessment of imidazole drugs

    Microsoft Academic Search

    D. Borelli; J. L. Bran; J. Fuentes; R. Legendre; E. Leiderman; H. B. Levine; A. Restrepo; D. A. Stevens

    1979-01-01

    Miconazole, a parenterally administered imidazole antifungal agent has been shown to produce responses in systemic fungal infections in man. Ketoconazole, an analogue, can be given by mouth. It is inhibitory in vitro at low concentrations to most fungi. Blood levels after oral administration to animals and man greatly exceed these inhibitory concentrations for several hours. The efficacy of this drug

  8. Double Jeopardy: An Assessment of the Felony Drug Provision of the Welfare Reform Act.

    ERIC Educational Resources Information Center

    Adams, Rukaiyah; Onek, David; Riker, Alissa

    In 1996 the Aid to Families with Dependent Children program was replaced with a federal block grant program called Temporary Assistance for Needy Families (TANF), which imposed time limits and work requirements on welfare recipients. The welfare legislation placed a lifetime ban on TANF and food stamp benefits for convicted drug felons, although…

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

    Microsoft Academic Search

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

    The stability of 30 common antipsychotics (APs) in spiked whole blood was investigated over ten weeks in a preliminary experiment (designated “P experiment”). Pools of blank blood spiked with drugs at two different therapeutic levels were stored at four different temperatures: 20°C, 4°C, ?20°C, and ?60°C and extracted once weekly in duplicate, using a previously published method. A loss of

  10. Illicit Drugs and Alcohol in Breast Milk: Assessing Risk to Infants

    Microsoft Academic Search

    Henry C. Nipper

    There is no question that breast-feeding is beneficial to both mother and infant. Manifold advantages ensue from the process; protection against infection and reduced risk of exposure to external sources of food contamination are only two of the many. Yet, the degree and risk involved from in vivo contamination of this precious fluid through maternal use of illicit drugs, tobacco

  11. Assessment of multiparametric MRI in a human glioma model to monitor cytotoxic and antiangiogenic drug effects

    E-print Network

    Paris-Sud XI, Université de

    anti-tumoral drugs Key words: Apparent diffusion coefficient of water (ADC), blood volume fraction (BVf, Apparent Diffusion Coefficient of water; BVf, Blood Volume fraction; CE, Contrast Enhancement; VSI, Vessel no treatment. Tumor volume, apparent diffusion coefficient (ADC) of water, blood volume fraction (BVf

  12. A General Causal Model to Guide Alcohol, Tobacco, and Illicit Drug Prevention: Assessing the Research Evidence

    ERIC Educational Resources Information Center

    Birckmayer, Johanna D.; Holder, Harold D.; Yacoubian, George S., Jr.; Friend, Karen B.

    2004-01-01

    The problems associated with the use of alcohol, tobacco, and other drugs (ATOD) extract a significant health, social, and economic toll on American society. While the field of substance abuse prevention has made great strides during the past decade, two major challenges remain. First, the field has been disorganized and fragmented with respect to…

  13. A novel assay to assess the effectiveness of antiangiogenic drugs in human breast cancer.

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Many cytotoxic drugs maintain antiangiogenic properties, but there are no human, tumor-based assays to evaluate their antiangiogenic potential. We used a fibrin-thrombin clot-based angiogenesis model to evaluate the angiogenic response of human breast cancer to various cytotoxic agents commonly used...

  14. drug discovery drug discovery

    E-print Network

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

  15. Reliability and Validity of Drug Use Items Differing in the Nature of Their Response Options.

    ERIC Educational Resources Information Center

    Hays, Ron D.; Huba, George J.

    1988-01-01

    Considered techniques to assess self-reported drug use. Evaluated the effects of different response options on the distribution, reliability, and validity of scores on drug-use items. Suggests that more quantitative measures are not necessarily more reliable or valid than less quantitative measures of drug use. (Author/KS)

  16. A First Assessment of Mycobacterium tuberculosis Genetic Diversity and Drug-Resistance Patterns in Twelve Caribbean Territories

    PubMed Central

    Millet, Julie; Baboolal, Shirematee; Akpaka, Patrick E.

    2014-01-01

    With the exception of some French-speaking islands, data on tuberculosis (TB) in the Caribbean are scarce. In this study, we report a first assessment of genetic diversity of a convenience sample of Mycobacterium tuberculosis strains received from twelve Caribbean territories by spoligotyping and describe their drug-resistance patterns. Of the 480 isolates, 40 (8.3%) isolates showed resistance to at least one anti-TB drug. The proportion of drug-resistant strains was significantly higher in The Bahamas (21.4%; P = 0.02), and Guyana (27.5%; P < 0.0001), while it was significantly lower in Jamaica (2.4%; P = 0.03) than in other countries of the present study. Regarding genetic diversity, 104 distinct spoligotype patterns were observed: 49 corresponded to clustered strains (2 to 93 strains per cluster), while 55 remained unclustered among which 16 patterns were not reported previously. Combining the study results with regional data retrieved from the international SITVIT2 database underlined a connection between frequency of certain M. tuberculosis phylogenetic lineages and the language spoken, suggesting historical (colonial) and ongoing links (trade, tourism, and migratory flows) with European countries with which they shared a common past. PMID:24795893

  17. In vitro and in vivo assessment of renal drug transporters in the disposition of mesna and dimesna.

    PubMed

    Cutler, M J; Urquhart, B L; Velenosi, T J; Meyer Zu Schwabedissen, H E; Dresser, G K; Leake, B F; Tirona, R G; Kim, R B; Freeman, D J

    2012-04-01

    Mesna and its dimer, dimesna, are coadministered for mitigation of ifosfamide- and cisplatin-induced toxicities, respectively. Dimesna is selectively reduced to mesna in the kidney, producing its protective effects. In vitro screens of uptake and efflux transporters revealed saturable uptake by renal organic anion transporters OAT1, OAT3, and OAT4. Efflux transporters breast cancer resistance protein; multidrug and toxin extrusion 1 (MATE1); multidrug resistance proteins MRP1, MRP2, MRP4, and MRP5; and P-glycoprotein (Pgp) significantly reduced dimesna accumulation. Further investigation demonstrated that renal apical efflux transporters MATE1, MRP2, and Pgp were also capable of mesna efflux. Administration of OAT inhibitor probenecid to healthy subjects significantly increased combined mesna and dimesna plasma exposure (91% ± 34%) while decreasing the renal clearance due to net secretion (67.0% ± 12.7%) and steady-state volume of distribution (45.2% ± 13.4%). Thus, the kidney represents a significant sink of total mesna, whereas function of renal drug transporters facilitates clearance in excess of glomerular filtration rate and likely the presence of active mesna in the urine. Loss of renal transporter function due to genetic variability or drug-drug interactions may decrease the efficacy of chemoprotectants, increasing the risk of ifosfamide- and cisplatin-induced toxicities. PMID:21505084

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

    NASA Astrophysics Data System (ADS)

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

    2013-10-01

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

  19. Cell culture-selected substitutions in influenza A(H3N2) neuraminidase affect drug susceptibility assessment.

    PubMed

    Tamura, Daisuke; Nguyen, Ha T; Sleeman, Katrina; Levine, Marnie; Mishin, Vasiliy P; Yang, Hua; Guo, Zhu; Okomo-Adhiambo, Margaret; Xu, Xiyan; Stevens, James; Gubareva, Larisa V

    2013-12-01

    Assessment of drug susceptibility has become an integral part of influenza virus surveillance. In this study, we describe the drug resistance profile of influenza A(H3N2) virus, A/Mississippi/05/2011, collected from a patient treated with oseltamivir and detected via surveillance. An MDCK cell-grown isolate of this virus exhibited highly reduced inhibition by the neuraminidase (NA) inhibitors (NAIs) oseltamivir (8,005-fold), zanamivir (813-fold), peramivir (116-fold), and laninamivir (257-fold) in the NA inhibition assay. Sequence analysis of its NA gene revealed a known oseltamivir-resistance marker, the glutamic acid-to-valine substitution at position 119 (E119V), and an additional change, threonine to isoleucine at position 148 (T148I). Unlike E119V, T148I was not detected in the clinical sample but acquired during viral propagation in MDCK cells. Using recombinant proteins, T148I by itself was shown to cause only a 6-fold increase in the zanamivir 50% inhibitory concentration (IC50) and had no effect on inhibition by other drugs. The T148I substitution reduced NA activity by 50%, most likely by affecting the positioning of the 150 loop at the NA catalytic site. Using pyrosequencing, changes at T148 were detected in 35 (23%) of 150 MDCK cell-grown A(H3N2) viruses tested, which was lower than the frequency of changes at D151 (85%), an NA residue previously implicated in cell selection. We demonstrate that culturing of the A(H3N2) viruses (n = 11) at a low multiplicity of infection delayed the emergence of the NA variants with changes at position 148 and/or 151, especially when conducted in MDCK-SIAT1 cells. Our findings highlight the current challenges in monitoring susceptibility of influenza A(H3N2) viruses to the NAI class of antiviral drugs. PMID:24080660

  20. Performance of an In-House Human Immunodeficiency Virus Type 1 Genotyping System for Assessment of Drug Resistance in Cuba

    PubMed Central

    Alemán, Yoan; Vinken, Lore; Kourí, Vivian; Pérez, Lissette; Álvarez, Alina; Abrahantes, Yeissel; Fonseca, Carlos; Pérez, Jorge; Correa, Consuelo; Soto, Yudira; Schrooten, Yoeri; Vandamme, Anne-Mieke; Van Laethem, Kristel

    2015-01-01

    As commercial human immunodeficiency virus type 1 drug resistance assays are expensive, they are not commonly used in resource-limited settings. Hence, a more affordable in-house procedure was set up taking into account the specific epidemiological and economic circumstances of Cuba. The performance characteristics of the in-house assay were evaluated using clinical samples with various subtypes and resistance patterns. The lower limit of amplification was determined on dilutions series of 20 clinical isolates and ranged from 84 to 529 RNA copies/mL. For the assessment of trueness, 14 clinical samples were analyzed and the ViroSeq HIV-1 Genotyping System v2.0 was used as the reference standard. The mean nucleotide sequence identity between the two assays was 98.7% ± 1.0. Additionally, 99.0% of the amino acids at drug resistance positions were identical. The sensitivity and specificity in detecting drug resistance mutations was respectively 94.1% and 99.5%. Only few discordances in drug resistance interpretation patterns were observed. The repeatability and reproducibility were evaluated using 10 clinical samples with 3 replicates per sample. The in-house test was very precise as nucleotide sequence identity among paired nucleotide sequences ranged from 98.7% to 99.9%. The acceptance criteria were met by the in-house test for all performance characteristics, demonstrating a high degree of accuracy. Subsequently, the applicability in routine clinical practice was evaluated on 380 plasma samples. The amplification success rate was 91% and good quality consensus sequences encoding the entire protease and the first 335 codons in reverse transcriptase could be obtained for 99% of the successful amplicons. The reagent cost per sample using the in-house procedure was around € 80 per genotyping attempt. Overall, the in-house assay provided good results, was feasible with equipment and reagents available in Cuba and was half as expensive as commercial assays. PMID:25671421

  1. Performance of an in-house human immunodeficiency virus type 1 genotyping system for assessment of drug resistance in Cuba.

    PubMed

    Alemán, Yoan; Vinken, Lore; Kourí, Vivian; Pérez, Lissette; Álvarez, Alina; Abrahantes, Yeissel; Fonseca, Carlos; Pérez, Jorge; Correa, Consuelo; Soto, Yudira; Schrooten, Yoeri; Vandamme, Anne-Mieke; Van Laethem, Kristel

    2015-01-01

    As commercial human immunodeficiency virus type 1 drug resistance assays are expensive, they are not commonly used in resource-limited settings. Hence, a more affordable in-house procedure was set up taking into account the specific epidemiological and economic circumstances of Cuba. The performance characteristics of the in-house assay were evaluated using clinical samples with various subtypes and resistance patterns. The lower limit of amplification was determined on dilutions series of 20 clinical isolates and ranged from 84 to 529 RNA copies/mL. For the assessment of trueness, 14 clinical samples were analyzed and the ViroSeq HIV-1 Genotyping System v2.0 was used as the reference standard. The mean nucleotide sequence identity between the two assays was 98.7% ± 1.0. Additionally, 99.0% of the amino acids at drug resistance positions were identical. The sensitivity and specificity in detecting drug resistance mutations was respectively 94.1% and 99.5%. Only few discordances in drug resistance interpretation patterns were observed. The repeatability and reproducibility were evaluated using 10 clinical samples with 3 replicates per sample. The in-house test was very precise as nucleotide sequence identity among paired nucleotide sequences ranged from 98.7% to 99.9%. The acceptance criteria were met by the in-house test for all performance characteristics, demonstrating a high degree of accuracy. Subsequently, the applicability in routine clinical practice was evaluated on 380 plasma samples. The amplification success rate was 91% and good quality consensus sequences encoding the entire protease and the first 335 codons in reverse transcriptase could be obtained for 99% of the successful amplicons. The reagent cost per sample using the in-house procedure was around € 80 per genotyping attempt. Overall, the in-house assay provided good results, was feasible with equipment and reagents available in Cuba and was half as expensive as commercial assays. PMID:25671421

  2. An integrated approach to improved toxicity prediction for the safety assessment during preclinical drug development using Hep G2 cells

    SciTech Connect

    Noor, Fozia [Biochemical Engineering Institute, Saarland University, Campus A 1.5, D-66123 Saarbruecken (Germany)], E-mail: fozia.noor@mx.uni-saarland.de; Niklas, Jens [Biochemical Engineering Institute, Saarland University, Campus A 1.5, D-66123 Saarbruecken (Germany)], E-mail: j.niklas@mx.uni-saarland.de; Mueller-Vieira, Ursula [Pharmacelsus GmbH, Science Park 2, D-66123 Saarbruecken (Germany)], E-mail: mueller@pharmacelsus.de; Heinzle, Elmar [Biochemical Engineering Institute, Saarland University, Campus A 1.5, D-66123 Saarbruecken (Germany)], E-mail: e.heinzle@mx.uni-saarland.de

    2009-06-01

    Efficient and accurate safety assessment of compounds is extremely important in the preclinical development of drugs especially when hepatotoxicty is in question. Multiparameter and time resolved assays are expected to greatly improve the prediction of toxicity by assessing complex mechanisms of toxicity. An integrated approach is presented in which Hep G2 cells and primary rat hepatocytes are compared in frequently used cytotoxicity assays for parent compound toxicity. The interassay variability was determined. The cytotoxicity assays were also compared with a reliable alternative time resolved respirometric assay. The set of training compounds consisted of well known hepatotoxins; amiodarone, carbamazepine, clozapine, diclofenac, tacrine, troglitazone and verapamil. The sensitivity of both cell systems in each tested assay was determined. Results show that careful selection of assay parameters and inclusion of a kinetic time resolved assay improves prediction for non-metabolism mediated toxicity using Hep G2 cells as indicated by a sensitivity ratio of 1. The drugs with EC{sub 50} values 100 {mu}M or lower were considered toxic. The difference in the sensitivity of the two cell systems to carbamazepine which causes toxicity via reactive metabolites emphasizes the importance of human cell based in-vitro assays. Using the described system, primary rat hepatocytes do not offer advantage over the Hep G2 cells in parent compound toxicity evaluation. Moreover, respiration method is non invasive, highly sensitive and allows following the time course of toxicity. Respiration assay could serve as early indicator of changes that subsequently lead to toxicity.

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

    PubMed Central

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

    2011-01-01

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

  4. A definitive or thorough phase 1 QT ECG trial as a requirement for drug safety assessment.

    PubMed

    Morganroth, Joel

    2004-01-01

    Prolongation of the QT interval by noncardiac drugs is the commonest cause of drug delays in development, nonapprovals and withdrawal from after marketing. The new regulatory guidance issued by the FDA-Health Canada ECG Concept document, requires irrespective of preclinical cardiac findings a definitive or thorough Phase I trial for all bioactive agents powered to exclude a 5-ms QTc effect (upper confidence interval = 10 ms) since such resolution is usually not possible with the variability inherent in ECG data from the usual trials in the target population. To design a definitive QT trial attention must be given to the sources of QTc duration spontaneous variability. The sources include the proper selection of the sample size, frequency of and method to analyze ECGs, proper correction formula for QT duration, choice of the supratherapeutic dose (required since the trail must be conducted in healthy volunteers rather than the target population) and proper use of a placebo and positive control groups. The positive control group is essential to define the sensitivity of the trial to detect a drug's effect on cardiac repolarization. An approach to interpretation of the resulting ECG data from the trial is provided. PMID:15132366

  5. The NIfETy method for environmental assessment of neighborhood-level indicators of violence, alcohol, and other drug exposure.

    PubMed

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

    2008-12-01

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

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

    PubMed

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

    2011-12-15

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

  7. 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…

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

    PubMed

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

    2014-05-28

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

  9. An assessment of drug information sheets for diabetic patients: only active involvement by patients is helpful.

    PubMed

    Kumana, C R; Ma, J T; Kung, A; Kou, M; Lauder, I

    1988-09-01

    Insulin/sulphonylurea-treated diabetics attending a busy university diabetic clinic were studied to determine whether issuing drug information sheets and/or age influenced understanding and behaviour regarding their disease and its treatment, especially with respect to avoiding hypoglycaemia. Patients were each asked 10 basic questions (each correct answer scoring 1), stratified by age (20 were less than or equal to 45 years and 91 greater than 45 years). According to a single-blind randomised protocol, they were issued or not issued with drug information sheets (providing information to correctly answer all 10 questions). After 2-3 months, 107 (88 aged greater than 45 years) were retested and asked whether they recalled an information sheet, read it themselves or had it read to them. Whether or not patients received sheets, corresponding mean aggregate scores were very similar in both age groups and there was no correlation with age. Second test scores yielded clinically and statistically significant increments in both the sheet and no sheet groups, respective mean aggregate scores increasing from 4.48 to 5.80 and 5.14 to 6.27 (P less than 0.001). Among patients issued with sheets, 32 who recalled reading them achieved the greatest improvement in mean scores (4.53 to 6.16, P less than 0.001). Active interaction/communication (participation in first test, recall and reading of information sheet) had a favourable educational impact irrespective of age, but merely issuing drug information sheets had no benefit. PMID:3219992

  10. Just another drug? A philosophical assessment of randomised controlled studies on intercessory prayer

    PubMed Central

    Turner, D D

    2006-01-01

    The empirical results from recent randomised controlled studies on remote, intercessory prayer remain mixed. Several studies have, however, appeared in prestigious medical journals, and it is believed by many researchers, including apparent sceptics, that it makes sense to study intercessory prayer as if it were just another experimental drug treatment. This assumption is challenged by (1) discussing problems posed by the need to obtain the informed consent of patients participating in the studies; (2) pointing out that if the intercessors are indeed conscientious religious believers, they should subvert the studies by praying for patients randomised to the control groups; and (3) showing that the studies in question are characterised by an internal philosophical tension because the intercessors and the scientists must take incompatible views of what is going on: the intercessors must take a causation?first view, whereas the scientists must take a correlation?first view. It therefore makes no ethical or methodological sense to study remote, intercessory prayer as if it were just another drug. PMID:16877631

  11. Functional connectome assessed using graph theory in drug-naive Parkinson's disease.

    PubMed

    Luo, Chun Yan; Guo, Xiao Yan; Song, Wei; Chen, Qin; Cao, Bei; Yang, Jing; Gong, Qi Yong; Shang, Hui-Fang

    2015-06-01

    The purpose of this study is to investigate whether the topological organization of whole-brain functional network is disrupted in patients with Parkinson's disease (PD). We employed resting-state functional MRI (R-fMRI) and graph theory to investigate the topological organization of the functional connectome in 47 early-stage drug-naïve PD patients and 47 healthy control subjects. Correlations between network properties and clinical variables were tested. Both the PD and control groups showed small-world architecture in brain functional networks. However, the PD patients had lower clustering coefficient and local efficiency relative to control subjects, indicating disrupted topologic organization and a shift toward randomization in their functional brain network. At node and connection level, reduced node centralities and connectivity strength were found mainly in temporal-occipital regions and also in sensorimotor regions of PD patients. In PD patients, altered global network properties correlated with cognitive function, while motor impairment was correlated with local connection changes. This study demonstrates a disruption of whole-brain topological organization of the functional brain networks in early-stage drug-naïve PD patients and this disruption might contribute to preclinical changes in cognitive process in these patients. PMID:25929663

  12. Attitudes, knowledge, and perceptions of Chinese doctors toward drug abuse

    Microsoft Academic Search

    Yi-lang Tang; Anna Wiste; Pei-xian Mao; Ye-zhi Hou

    2005-01-01

    We assessed the attitudes, knowledge, and perceptions of Chinese doctors who worked with drug abusers to provide direction for planned drug and alcohol education and training. A 34-item questionnaire was developed; 523 copies were distributed and 446 (84.5%) validated copies were collected. Half of the respondents (50.0%) had no formal training before they started treating drug abusers. Among them, only

  13. Assessing camera traps for surveying the European mink, Mustela lutreola (Linnaeus, 1761), distribution

    Microsoft Academic Search

    J. González-Esteban; I. Villate; I. Irizar

    2004-01-01

    This study assesses the suitability of camera trapping as a method for detecting the European mink and determining its distribution in a region located in southwestern Europe. Using this technique, 98 river stretches were surveyed, resulting in the detection of 11 species of carnivores. A high photographic rate was obtained for the European mink, and we were able to get

  14. M&SENABLED TESTING OF DISTRIBUTED SYSTEMS: BEYOND INTEROPERABILITY TO COMBAT EFFECTIVENESS ASSESSMENT

    E-print Network

    testing that can expand the perspective to support a combat effectiveness assessment. Starting fromM&S­ENABLED TESTING OF DISTRIBUTED SYSTEMS: BEYOND INTEROPERABILITY TO COMBAT EFFECTIVENESS Information Technology Team Joint Interoperability Test Command Fort Huachuca, AZ 85613-7051 zeiglerb

  15. Assessment of species diversity from species abundance distributions at different localities

    E-print Network

    Engen, Steinar

    by analysing similarities of communities of rare and endangered species of oak-living beetles in southAssessment of species diversity from species abundance distributions at different localities, Norway. We show how the spatial structure of species diversity can be analyzed using the correlation

  16. Development of Risk Assessment Methodology for Land Application and Distribution and Marketing of Municipal Sludge

    EPA Science Inventory

    This is one of a series of reports that present methodologies for assessing the potential risks to humans or other organisms from the disposal or reuse of municipal sludge. The sludge management practices addressed by this series include land application practices, distribution a...

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

    E-print Network

    Zhang, Minghua

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

  18. Using Quantitative CT to Assess Adipose Distribution in Adult Men with Acquired Hypogonadism

    Microsoft Academic Search

    Laurence Katznelson; Daniel I. Rosenthal; Michael S. Rosol; Ellen J. Anderson; Douglas L. Hayden; David A. Schoenfeld; Anne Klibanski

    OBJECTIVE. Quantitative CT is a powerful tool that may be used to assess distribution of adipose and lean mass and bone mineral density in specific anatomic compartments. Tes- tosterone deficiency (hypogonadism) is increasingly recognized in adult men and is associ- ated with osteoporosis, diminished strength, and an increase in cardiovascular risk. We used quantitative CT to determine whether hypogonadism is

  19. Evaluating score distributions in the revised Dutch version of the Childhood Health Assessment Questionnaire

    Microsoft Academic Search

    Jessika W Ouwerkerk; Philomine A van Pelt; Tim Takken; Paul JM Helders; Janjaap Net

    2008-01-01

    OBJECTIVES: Evaluating the original, and the revised version of the Dutch Childhood Health Assessment Questionnaire (CHAQ). To explore the effect of different score calculation methods and eight more challenging items as proposed by Lam et al. (2004) on the score distribution in a population of patients with Juvenile Idiopathic Arthritis (JIA). METHODS: Two convenience samples of 59 and 31 children

  20. EFFECTS OF PRESSURE DEPENDENT ANALYSIS ON QUALITY PERFORMANCE ASSESSMENT OF WATER DISTRIBUTION NETWORKS

    Microsoft Academic Search

    M. TABESH; A. DOLATKHAHI

    Water network performance is defined as the ability to deliver a required quantity of water under sufficient pressure and an acceptable level of quality. A sound performance indicator is a powerful tool for more efficient management of water systems. This paper introduces a methodology for performance assessment of water distribution networks based on quality parameters (such as residual chlorine, water

  1. Non-parametric pharmacokinetic method for assessment of the variance of lifespan distribution of blood cells

    Microsoft Academic Search

    W. Krzyzanski

    2005-01-01

    Backround: The description of lifespan distribution of blood cells (RBC, platelets) is commonly limited to its mean that can be calculated from the initial slope of the survival curve. The standard deviation (SD) can be determined from the area under survival curve. Similar descriptors (slope, area) are used in non-compartmental analysis of pharmacokinetic data. These methods were adopted to assess

  2. Use of In Vitro Absorption, Distribution, Metabolism, and Excretion (ADME) Data in Bioaccumulation Assessments for Fish

    Microsoft Academic Search

    John W. Nichols; Susan Erhardt; Scott Dyer; Margaret O. James; Margo Moore; Kathleen Plotzke; Helmut Segner; Irvin R. Schultz; Karluss Thomas; Luba Vasiluk; Anne V. Weisbrod

    2007-01-01

    A scientific workshop was held in 2006 to discuss the use of in vitro Absorption, Distribution, Metabolism, and Excretion (ADME) data in chemical bioaccumulation assessments for fish. Computer-based (in silico) modeling tools are widely used to estimate chemical bioaccumulation. These in silico methods have inherent limitations that result in inaccurate estimates for many compounds. Based on a review of the

  3. Governance and assessment in a widely distributed medical education program in Australia.

    PubMed

    Solarsh, Geoff; Lindley, Jennifer; Whyte, Gordon; Fahey, Michael; Walker, Amanda

    2012-06-01

    The learning objectives, curriculum content, and assessment standards for distributed medical education programs must be aligned across the health care systems and community contexts in which their students train. In this article, the authors describe their experiences at Monash University implementing a distributed medical education program at metropolitan, regional, and rural Australian sites and an offshore Malaysian site, using four different implementation models. Standardizing learning objectives, curriculum content, and assessment standards across all sites while allowing for site-specific implementation models created challenges for educational alignment. At the same time, this diversity created opportunities to customize the curriculum to fit a variety of settings and for innovations that have enriched the educational system as a whole.Developing these distributed medical education programs required a detailed review of Monash's learning objectives and curriculum content and their relevance to the four different sites. It also required a review of assessment methods to ensure an identical and equitable system of assessment for students at all sites. It additionally demanded changes to the systems of governance and the management of the educational program away from a centrally constructed and mandated curriculum to more collaborative approaches to curriculum design and implementation involving discipline leaders at multiple sites.Distributed medical education programs, like that at Monash, in which cohorts of students undertake the same curriculum in different contexts, provide potentially powerful research platforms to compare different pedagogical approaches to medical education and the impact of context on learning outcomes. PMID:22643380

  4. Assessing the impact of a high-intensity partnership between the police and drug treatment service in addressing the offending of problematic drug users

    Microsoft Academic Search

    David Best; Deborah Walker; Elizabeth Aston; Charlotte Pegram; Geraldine ODonnell

    2010-01-01

    While there is a considerable evidence base showing links between drug use and offending and clear evidence of the impact of treatment engagement on drug-related offending, there is a much smaller UK evidence base on ‘what works’ in treatment and criminal justice partnerships, particularly in the UK. The current study used police arrest data to measure changes in offending behaviour

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

    PubMed Central

    Billioux, Veena G.; Sherman, Susan G.; Latkin, Carl A.

    2012-01-01

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

  6. Use of cellular electrical impedance sensing to assess in vitro cytotoxicity of anticancer drugs in a human kidney cell nephrotoxicity model.

    PubMed

    Xie, Fengbo; Xu, Youchun; Wang, Lei; Mitchelson, Keith; Xing, Wanli; Cheng, Jing

    2012-03-21

    Nephrotoxicity is one of the major concerns for anticancer drug safety because most drugs are metabolized and excreted by the kidneys. Convenient tools able to perform rapid in vitro cytotoxicity analysis and identify drug side effects in kidney cells during early phases of drug discovery could be beneficial to drug development programs. Here we developed an electrical cell-substrate impedance sensing system (ECIS) capable of continuously measuring the dosage and time response of human proximal tubular epithelial (HK2) cells exposed to four drugs throughout the experimental period. These drugs induced HK2 cell apoptosis/death in a dose-dependent manner, although with very different dose-response effects. DDP (50 ?M) was the most cytotoxic and induced obvious HK2 cell apoptosis rapidly after exposure. The other three drugs had much lower cytotoxicity, even at concentrations approaching 1 mM. The results obtained from our ECIS system correlated well with conventional in vitro assays such as flow cytometry and cell viability assays. Notably, the continuous and automatic measurements provided by ECIS system allow for better resolution for drugs with different temporal toxicity profiles. Furthermore, we investigated the effect of DDP's antidotes, glutathione and sodium subsulfite, on DDP-induced cytotoxicity, both of which decreased nephrotoxicity of DDP in a dose-dependent manner. Overall this study illustrates the convenience of ECIS for direct, continuous assessment of the cytotoxicity of anticancer drugs in vitro. ECIS has the potential to become a useful, non-invasive analytical method for early evaluation of drugs and antidotes of toxins. PMID:22214987

  7. Enhanced characterization of contractility in cardiomyocytes during early drug safety assessment.

    PubMed

    Butler, Larissa; Cros, Caroline; Oldman, Karen L; Harmer, Alex R; Pointon, Amy; Pollard, Christopher E; Abi-Gerges, Najah

    2015-06-01

    We sought to investigate whether drug-induced changes in contractility were affected by pacing rates that represent the range of heart rates encountered in vivo. Using the cell geometry measurement system (IonOptix), we paced dog cardiomyocytes at different cycle lengths (CLs) of 2000, 1000, 500, and 333.3?ms, before and after exposure to 13 inotropic drugs. Time course data using vehicle control (0.1% dimethyl sulfoxide (DMSO)) demonstrated stability of the system at all CLs tested. Seven positive inotropes (eg isoproterenol) exerted rate-dependent increases in sarcomere shortening (Sarc. short.; maximal effect at a CL of 333.3?ms [0.1?µM isoproterenol increased Sarc. short. by 41.1% and 145.9% at 2000 and 333.3?ms, respectively]). Omecamtiv mecarbil showed an atypical profile (increased Sarc. short. at 2000?ms [106.9%] and decreased at 333.3?ms [IC50?=?0.64?µM]). Four negative inotropes (eg flecainide) showed rate-independent inhibition of Sarc. short. (IC50s: 3.3?µM [2000 ms] versus 2.3?µM [333.3 ms]). The remaining negative inotropes, verapamil, and BTS (N-benzyl-p-toluene sulphonamide) produced an increase (IC50s: 3.9?µM [2000 ms] versus 0.043?µM [333.3ms]) and decrease (IC50s: 18.3?µM [2000 ms] versus 34.0?µM [333.3ms]) in potency, respectively. Negative inotropes (eg flecainide, BTS, and verapamil) decreased the area of the Ca(2+) transient versus Sarc. short. hysteresis loop, although rate dependency was seen with verapamil only. Positive inotropes (eg isoproterenol and levosimendan) induced a rate-dependent increase in the area, however Omecamtiv mecarbil increased and decreased the area at CLs of 2000 and 333.3?ms, respectively. Thus, the use of different pacing rates may improve the detection of inotropes in early drug discovery and illustrate the potential for finger-printing different mechanisms of action. PMID:25820236

  8. Health technology assessment of cancer drugs in Canada, the United kingdom and australia: should the United States take notice?

    PubMed

    Dranitsaris, George; Papadopoulos, George

    2015-06-01

    Cancer remains a global problem, with 7.5 million deaths annually, making it responsible for approximately 13 % of deaths from all causes. Cancer also becomes more prevalent as the population ages, making it a major health policy challenge for many countries around the world. However, the encouraging news is that the number of cancer-related deaths has stabilized in many countries. At least part of this success may be attributed to improved diagnosis, early intervention strategies and the development of a newer class of anticancer agents, collectively called "targeted therapies", that are more specific in inhibiting key pathways in tumour genesis. However, these newer drugs are associated with a higher cost. As a result, expenditures for agents and cancer in general have been rising rapidly, far beyond the rate of inflation. Some view this as threatening the very health care systems themselves, which are integral to the modern social contract. Different countries have adopted unique mechanisms to facilitate patient access to these newer agents, with the intent of ensuring value for money and sustainability. In this review, cancer care policies and mechanisms for patient access to new drugs will be discussed and compared between select countries. Given its position as a country that allows free pharmaceutical pricing and multi-payer health insurance, the USA will be the reference country and will be compared with the UK, Canada and Australia, three countries with socialized health care systems and active health technology assessment programmes. PMID:25274258

  9. Analysis of drugs of abuse by online SPE-LC high resolution mass spectrometry: communal assessment of consumption.

    PubMed

    Heuett, Nubia V; Ramirez, Cesar E; Fernandez, Adolfo; Gardinali, Piero R

    2015-04-01

    An online SPE-LC-HRMS method was developed to monitor the consumption of 18 drugs of abuse (DOAs) including amphetamines, opioids, cocainics, cannabinoids, lysergics, and their corresponding metabolites in a well characterized college campus setting via wastewater analysis. Filtered and diluted (10×) sewage water samples (5 mL inj.) were automatically pre-concentrated and analyzed in 15 min using a Thermo EQuan MAX online SPE system equipped with a HyperSep™ Retain PEP (20×2.1 mm×12 ?m) SPE column and a Hypersil Gold™ aQ (150×2.1 mm×3 ?m) analytical column. A Q Exactive™ Hybrid Quadrupole-Orbitrap HRMS was used in full scan mode (R=140,000) for positive identification, and quantitation of target compounds. Method detection limits for all analytes ranged between 0.6 and 1.7 ng/L in sewage. A total of 14 DOAs were detected from two different locations (dorms and main college campus) within a one-year period. Most frequently detected drugs throughout the entire study were amphetamine (>96%) and THC's metabolite 11-nor-9-carboxy-?-9-THC (>100%) with maximum concentrations of 5956 and 2413 ng/L respectively. Daily doses per 1000 people were determined in order to assess consumption of THC, amphetamine, heroin and cocaine, in both dorms and main campus. PMID:25553546

  10. Substandard antimalarials available in afghanistan: a case for assessing the quality of drugs in resource poor settings.

    PubMed

    Lalani, Mirza; Kaur, Harparkash; Mohammed, Nader; Mailk, Naiela; Wyk, Albert van; Jan, Sakhi; Kakar, Rishtya Meena; Mojadidi, Mohammed Khalid; Leslie, Toby

    2015-06-01

    Good-quality antimalarials are crucial for the effective treatment and control of malaria. A total of 7,740 individual and packaged tablets, ampoules, and syrups were obtained from 60 randomly selected public (N = 35) and private outlets (N = 25) in Afghanistan. Of these, 134 samples were screened using the Global Pharma Health Fund (GPHF) MiniLab(®) in Kabul with 33/126 (26%) samples failing the MiniLab(®) disintegration test. The quality of a subsample (N = 37) of cholorquine, quinine, and sulfadoxine/pyrimethamine tablets was assessed by in vitro dissolution testing following U.S. Pharmacopeia (USP) monographs at a bioanalytical laboratory in London, United Kingdom. Overall, 12/32 (32%) samples of sulfadoxine/pyrimethamine and quinine were found not to comply with the USP tolerance limits. Substandard antimalarials were available in Afghanistan demonstrating that continuous monitoring of drug quality is warranted. However, in Afghanistan as in many low-income countries, capacity to determine and monitor drug quality using methods such as dissolution testing needs to be established to empower national authorities to take appropriate action in setting up legislation and regulation. PMID:25897070

  11. Comparative risk assessment of alcohol, tobacco, cannabis and other illicit drugs using the margin of exposure approach

    PubMed Central

    Lachenmeier, Dirk W.; Rehm, Jürgen

    2015-01-01

    A comparative risk assessment of drugs including alcohol and tobacco using the margin of exposure (MOE) approach was conducted. The MOE is defined as ratio between toxicological threshold (benchmark dose) and estimated human intake. Median lethal dose values from animal experiments were used to derive the benchmark dose. The human intake was calculated for individual scenarios and population-based scenarios. The MOE was calculated using probabilistic Monte Carlo simulations. The benchmark dose values ranged from 2?mg/kg bodyweight for heroin to 531?mg/kg bodyweight for alcohol (ethanol). For individual exposure the four substances alcohol, nicotine, cocaine and heroin fall into the “high risk” category with MOE < 10, the rest of the compounds except THC fall into the “risk” category with MOE < 100. On a population scale, only alcohol would fall into the “high risk” category, and cigarette smoking would fall into the “risk” category, while all other agents (opiates, cocaine, amphetamine-type stimulants, ecstasy, and benzodiazepines) had MOEs > 100, and cannabis had a MOE > 10,000. The toxicological MOE approach validates epidemiological and social science-based drug ranking approaches especially in regard to the positions of alcohol and tobacco (high risk) and cannabis (low risk). PMID:25634572

  12. Substandard Antimalarials Available in Afghanistan: A Case for Assessing the Quality of Drugs in Resource Poor Settings

    PubMed Central

    Lalani, Mirza; Kaur, Harparkash; Mohammed, Nader; Mailk, Naiela; van Wyk, Albert; Jan, Sakhi; Kakar, Rishtya Meena; Mojadidi, Mohammed Khalid; Leslie, Toby

    2015-01-01

    Good-quality antimalarials are crucial for the effective treatment and control of malaria. A total of 7,740 individual and packaged tablets, ampoules, and syrups were obtained from 60 randomly selected public (N = 35) and private outlets (N = 25) in Afghanistan. Of these, 134 samples were screened using the Global Pharma Health Fund (GPHF) MiniLab® in Kabul with 33/126 (26%) samples failing the MiniLab® disintegration test. The quality of a subsample (N = 37) of cholorquine, quinine, and sulfadoxine/pyrimethamine tablets was assessed by in vitro dissolution testing following U.S. Pharmacopeia (USP) monographs at a bioanalytical laboratory in London, United Kingdom. Overall, 12/32 (32%) samples of sulfadoxine/pyrimethamine and quinine were found not to comply with the USP tolerance limits. Substandard antimalarials were available in Afghanistan demonstrating that continuous monitoring of drug quality is warranted. However, in Afghanistan as in many low-income countries, capacity to determine and monitor drug quality using methods such as dissolution testing needs to be established to empower national authorities to take appropriate action in setting up legislation and regulation. PMID:25897070

  13. A New Experimental Model for Assessing Drug Efficacy against Trypanosoma cruzi Infection Based on Highly Sensitive In Vivo Imaging

    PubMed Central

    Lewis, Michael D.; Francisco, Amanda Fortes; Taylor, Martin C.

    2015-01-01

    The protozoan Trypanosoma cruzi is the causative agent of Chagas disease, one of the world’s major neglected infections. Although development of improved antiparasitic drugs is considered a priority, there have been no significant treatment advances in the past 40 years. Factors that have limited progress include an incomplete understanding of pathogenesis, tissue tropism, and disease progression. In addition, in vivo models, which allow parasite burdens to be tracked throughout the chronic stage of infection, have been lacking. To address these issues, we have developed a highly sensitive in vivo imaging system based on bioluminescent T. cruzi, which express a red-shifted luciferase that emits light in the tissue-penetrating orange-red region of the spectrum. The exquisite sensitivity of this noninvasive murine model has been exploited to monitor parasite burden in real time throughout the chronic stage, has allowed the identification of the gastrointestinal tract as the major niche of long-term infection, and has demonstrated that chagasic heart disease can develop in the absence of locally persistent parasites. Here, we review the parameters of the imaging system and describe how this experimental model can be incorporated into drug development programs as a valuable tool for assessing efficacy against both acute and chronic T. cruzi infections. PMID:25296657

  14. Controversies in ASSAY and drug development technologies: a focus on assessing irreproducibility.

    PubMed

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

    2014-10-01

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

  15. Development of an in vitro cytochrome P450 cocktail inhibition assay for assessing the inhibition risk of drugs of abuse.

    PubMed

    Dinger, Julia; Meyer, Markus R; Maurer, Hans H

    2014-10-01

    Drugs of abuse are not tested for cytochrome P450 (CYP) inhibition potential before distribution. Therefore, a cocktail assay should be developed for testing the inhibition potential for all relevant CYPs. The following CYP test substrates and selective inhibitors were incubated in pooled human liver microsomes: phenacetin (alpha-naphthoflavone for CYP1A2), coumarin (tranylcypromine, CYP2A6), bupropion (sertraline, CYP2B6), amodiaquine (trimethoprim, CYP2C8), diclofenac (sulfaphenazole, CYP2C9), omeprazole (fluconazole, CYP2C19), dextromethorphan (quinidine, CYP2D6), chlorzoxazone (clomethiazole, CYP2E1), testosterone (verapamil, CYP3A). Samples were analyzed after protein precipitation using a Thermo Fisher Q-Exactive LC-high-resolution-MS/MS. The IC50 values were calculated by plotting the concentration of the formed metabolite, relative to the control sample, over the logarithm of the inhibitor concentration. They were determined either for single substrate or the cocktail incubation. Unfortunately, the cocktail assay had to be split because of interferences during incubation caused by substrates or metabolites, but the mixture of both incubates could be analyzed in one analytical run. The IC50 values determined in the single substrate or both cocktail incubations were comparable among themselves and with published data. In conclusion, the new inhibition cocktail assay was reproducible and applicable for testing the inhibition potential of drugs of abuse as exemplified for 2,5-dimethoxy-4-iodo-amfetamine (DOI). PMID:25111188

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

    PubMed Central

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

    2013-01-01

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

  17. Effect of sampling and diagnostic effort on the assessment of schistosomiasis and soil-transmitted helminthiasis and drug efficacy: a meta-analysis of six drug efficacy trials and one epidemiological survey.

    PubMed

    Levecke, Bruno; Brooker, Simon J; Knopp, Stefanie; Steinmann, Peter; Sousa-Figueiredo, Jose Carlos; Stothard, J Russell; Utzinger, Jürg; Vercruysse, Jozef

    2014-12-01

    It is generally recommended to perform multiple stool examinations in order to improve the diagnostic accuracy when assessing the impact of mass drug administration programmes to control human intestinal worm infections and determining efficacy of the drugs administered. However, the collection and diagnostic work-up of multiple stool samples increases costs and workload. It has been hypothesized that these increased efforts provide more accurate results when infection and drug efficacy are summarized by prevalence (proportion of subjects infected) and cure rate (CR, proportion of infected subjects that become egg-negative after drug administration), respectively, but not when these indicators are expressed in terms of infection intensity and egg reduction rate (ERR). We performed a meta-analysis of six drug efficacy trials and one epidemiological survey. We compared prevalence and intensity of infection, CR and ERR based on collection of one or two stool samples that were processed with single or duplicate Kato-Katz thick smears. We found that the accuracy of prevalence estimates and CR was lowest with the minimal sampling effort, but that this was not the case for estimating infection intensity and ERR. Hence, a single Kato-Katz thick smear is sufficient for reporting infection intensity and ERR following drug treatment. PMID:24725546

  18. A novel QSAR model of Salmonella mutagenicity and its application in the safety assessment of drug impurities

    SciTech Connect

    Valencia, Antoni; Prous, Josep; Mora, Oscar [Prous Institute for Biomedical Research, Rambla de Catalunya, 135, 3-2, Barcelona 08008 (Spain); Sadrieh, Nakissa [Office of Pharmaceutical Science, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, 10903 New Hampshire Avenue, Silver Spring, MD 20993-0002 (United States); Valerio, Luis G., E-mail: luis.valerio@fda.hhs.gov [Office of Pharmaceutical Science, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, 10903 New Hampshire Avenue, Silver Spring, MD 20993-0002 (United States)

    2013-12-15

    As indicated in ICH M7 draft guidance, in silico predictive tools including statistically-based QSARs and expert analysis may be used as a computational assessment for bacterial mutagenicity for the qualification of impurities in pharmaceuticals. To address this need, we developed and validated a QSAR model to predict Salmonella t. mutagenicity (Ames assay outcome) of pharmaceutical impurities using Prous Institute's Symmetry?, a new in silico solution for drug discovery and toxicity screening, and the Mold2 molecular descriptor package (FDA/NCTR). Data was sourced from public benchmark databases with known Ames assay mutagenicity outcomes for 7300 chemicals (57% mutagens). Of these data, 90% was used to train the model and the remaining 10% was set aside as a holdout set for validation. The model's applicability to drug impurities was tested using a FDA/CDER database of 951 structures, of which 94% were found within the model's applicability domain. The predictive performance of the model is acceptable for supporting regulatory decision-making with 84 ± 1% sensitivity, 81 ± 1% specificity, 83 ± 1% concordance and 79 ± 1% negative predictivity based on internal cross-validation, while the holdout dataset yielded 83% sensitivity, 77% specificity, 80% concordance and 78% negative predictivity. Given the importance of having confidence in negative predictions, an additional external validation of the model was also carried out, using marketed drugs known to be Ames-negative, and obtained 98% coverage and 81% specificity. Additionally, Ames mutagenicity data from FDA/CFSAN was used to create another data set of 1535 chemicals for external validation of the model, yielding 98% coverage, 73% sensitivity, 86% specificity, 81% concordance and 84% negative predictivity. - Highlights: • A new in silico QSAR model to predict Ames mutagenicity is described. • The model is extensively validated with chemicals from the FDA and the public domain. • Validation tests show desirable high sensitivity and high negative predictivity. • The model predicted 14 reportedly difficult to predict drug impurities with accuracy. • The model is suitable to support risk evaluation of potentially mutagenic compounds.

  19. Assessment of New Immunosuppressive Drugs in a Rat Cardiac Allograft Heterotopic Model

    Microsoft Academic Search

    B. Walpoth; J. Galdikas; T. Vorburger; H. J. Altermatt; T. Schaffner; U. Althaus; M. Billingham; R. Morris

    1992-01-01

    We assessed FK506 (FK) and rapamycin (RPM) in a heterotopic abdominal rat heart transplant model using a major histocompatibility mismatch (DA to LEW). The end point of our study was histologic grading of rejection (Billingham and working formulation) at 1 week. Two doses of FK (2.0 and 8.0mg\\/kg p.o., q.d.) and RPM (1.5 and 6.0mg\\/kg i.p., q.d.) were compared to

  20. Antineoplastic Drugs

    NASA Astrophysics Data System (ADS)

    Sadée, Wolfgang; El Sayed, Yousry Mahmoud

    The limited scope of therapeutic drug-level monitoring in cancer chemotherapy results from the often complex biochemical mechanisms that contribute to antineoplastic activity and obscure the relationships among drug serum levels and therapeutic benefits. Moreover, new agents for cancer chemotherapy are being introduced at a more rapid rate than for the treatment of other diseases, although the successful application of therapeutic drug-level monitoring may require several years of intensive study of the significance of serum drug levels. However, drug level monitoring can be of considerable value during phase I clinical trials of new antineoplastic agents in order to assess drug metabolism, bioavailability, and intersubject variability; these are important parameters in the interpretation of clinical studies, but have no immediate benefit to the patient. High performance liquid chromatography (HPLC) probably represents the most versatile and easily adaptable analytical technique for drug metabolite screening (1). HPLC may therefore now be the method of choice during phase I clinical trials of antineoplastic drugs. For example, within a single week we developed an HPLC assay—using a C18 reverse-phase column, UV detection, and direct serum injection after protein precipitation—for the new radiosensitizer, misonidazole (2).

  1. Spatial point pattern analysis of aerial survey data to assess clustering in wildlife distributions

    NASA Astrophysics Data System (ADS)

    Khaemba, Wilson Mwale

    Assessing clustering in wildlife populations is crucial for understanding their dynamics. This assessment is made difficult for data obtained through aerial surveys because the shape and size of sampling units (strip transects) result in poor data supports, which generally hampers spatial analysis of these data. The problem may be solved by having more detailed data where exact locations of observed animal groups are recorded. These data, obtainable through GPS technology, are amenable to spatial analysis, thereby allowing spatial point pattern analysis to be used to assess observed spatial patterns relative to environmental factors like vegetation. Distance measures like the G-statistic and K-function classify such patterns into clustered, regular or completely random patterns, while independence between species is assessed through a multivariate extension of the K-function. Quantification of clustering is carried out using spatial regression. The techniques are illustrated with field data on three ungulates observed in an ecosystem in Kenya. Results indicate a relation between species spatial distribution and their dietary requirements, thereby concluding the usefulness of spatial point pattern analysis in investigating species spatial distribution. It also provides a technique for explaining and differentiating the distribution of wildlife species.

  2. Toward oral delivery of biopharmaceuticals: an assessment of the gastrointestinal stability of 17 peptide drugs.

    PubMed

    Wang, Jie; Yadav, Vipul; Smart, Alice L; Tajiri, Shinichiro; Basit, Abdul W

    2015-03-01

    A major barrier to successful oral delivery of peptide and protein molecules is their inherent instability in the lumen of the gastrointestinal tract. The aim of this study was to determine the stability of 17 disparate peptide drugs (insulin, calcitonin, glucagon, secretin, somatostatin, desmopressin, oxytocin, [Arg(8)]-vasopressin, octreotide, ciclosporin, leuprolide, nafarelin, buserelin, histrelin, [d-Ser](4)-gonadorelin, deslorelin, and goserelin) in gastric and small intestinal fluids from both humans and pigs, and in simulated gastric and intestinal fluids. In human gastric fluid, the larger peptides including somatostatin, calcitonin, secretin, glucagon, and insulin were metabolized rapidly, while the smaller peptides showed good stability. In human small intestinal fluid, however, both small and large peptides degraded rapidly with the exception of the cyclic peptide ciclosporin and the disulfide-bridge containing peptides octreotide and desmopressin, which showed good stability. The stability of peptides in both simulated gastric fluid and pig gastric fluid correlated well with stability in human gastric fluid. However, it was not possible to establish such a correlation with the small intestinal fluids because of the rapid rate of peptide degradation. This work has identified the molecular features in the structure of a wide range of peptides that influence their stability in the environment of the gastrointestinal tract, which in turn will allow for better selection of peptide candidates for oral delivery. PMID:25612507

  3. The Assessment of Drug-Dependent and Isoimmune Antiplatelet Antibodies by the Use of Platelet Aggregometry

    PubMed Central

    Deykin, Daniel; Hellerstein, Lewis J.

    1972-01-01

    The technique of platelet aggregometry provides a simple, quantitative, and specific method for the detection of drug-dependent and isoimmune antiplatelet antibodies. In the presence of antiquinidine antibody, quinidine causes lysis of normal platelets in platelet-rich plasma. The resulting changes in optical density are readily detected in the aggregometer. The initial rate of lysis is a function of the antibody titer, but is relatively independent of the platelet count. In vitro, quinidine produces platelet swelling and inhibits aggregation of platelets by adenosine diphosphate, epinephrine, and collagen. Isoimmune antibodies cause aggregation of platelets in platelet-rich plasma. In studies of a single family the rate of aggregation is proportional to the number of HL-A antigens present on the normal platelets against which the antibody is directed. The simple technique of platelet aggregometry may be a useful adjunct in the selection of compatible donors for platelet transfusion. Serum derived from patients with idiopathic thromboytopenic purpura did not cause platelet aggregation. Images PMID:4674399

  4. ECG in neonate mice with spinal muscular atrophy allows assessment of drug efficacy.

    PubMed

    Heier, Christopher R; DiDonato, Christine J

    2015-01-01

    Molecular technologies have produced diverse arrays of animal models for studying genetic diseases and potential therapeutics. Many have neonatal phenotypes. Spinal muscular atrophy (SMA) is a neuromuscular disorder primarily affecting children, and is of great interest in translational medicine. The most widely used SMA mouse models require all phenotyping to be performed in neonates since they do not survive much past weaning. Pre-clinical studies in neonate mice can be hindered by toxicity and a lack of quality phenotyping assays, since many assays are invalid in pups or require subjective scoring with poor inter-rater variability. We find, however, that passive electrocardiography (ECG) recording in conscious 11-day old SMA mice provides sensitive outcome measures, detecting large differences in heart rate, cardiac conduction, and autonomic control resulting from disease. We find significant drug benefits upon treatment with G418, an aminoglycoside targeting the underlying protein deficiency, even in the absence of overt effects on growth and survival. These findings provide several quantitative physiological biomarkers for SMA preclinical studies, and will be of utility to diverse disease models featuring neonatal cardiac arrhythmias. PMID:25553367

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

    PubMed Central

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

    2015-01-01

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

  6. 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

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

    PubMed

    Dansereau, Raymond N

    2014-11-01

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

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

    PubMed Central

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

    2012-01-01

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

  9. Time-of-flight secondary ion mass spectrometry study on the distribution of alendronate sodium in drug-loaded ultra-high molecular weight polyethylene.

    PubMed

    Liu, Xiaomin; Qu, Shuxin; Lu, Xiong; Ge, Xiang; Leng, Yang

    2009-12-01

    The aim of this study was to investigate the drug distribution in ultra-high molecular weight polyethylene (UHMWPE) loaded with alendronate sodium (ALN), which was developed to treat particle-induced osteolysis after artificial joint replacements, since the drug distribution in UHMWPE could play a key role in controlling drug release. A mixture of UHMWPE powder and ALN was dried and hot pressed to prepare UHMWPE loaded with ALN (UHMWPE-ALN). Fourier transform infrared spectroscopy analysis demonstrated that the hot press had no effect on the functional groups of ALN in UHMWPE-ALN. X-ray diffraction indicated that there was no phase change of the UHMWPE after hot pressing. Time-of-flight secondary ion mass spectrometry (ToF-SIMS) spectra revealed the existence of characteristic elements and functional groups from ALN in UHMWPE-ALN, such as Na+, C3H8N+, PO3(-) and PO3H(-). In addition, SIMS images suggested that ALN did not agglomerate in UHMWPE-ALN. A small punch test and hardness test were carried out and the results indicated that ALN did not affect the mechanical properties at the present content level. The present study demonstrated that it was feasible to fabricate the un-agglomerated distributed drug in UHMWPE with good mechanical properties. This ALN loaded UHMWPE would have potential application in clinics. PMID:19966382

  10. Examining the Relationship between Gender and Drug-Using Behaviors in Adolescents: The Use of Diagnostic Assessments and Biochemical Analyses of Urine Samples.

    ERIC Educational Resources Information Center

    James, William H.; Moore, David D.

    1999-01-01

    Examines the relationship between gender and drug use among adolescents using diagnostic assessments and biochemical analyses of urine samples. Statistical significance was found in the relationship between gender and marijuana use. The study confirms that more research is needed in this area. (Author/MKA)

  11. Assessment of re-aggregated human pancreatic islets for secondary drug screening

    PubMed Central

    Ramachandran, K; Peng, X; Bokvist, K; Stehno-Bittel, L

    2014-01-01

    BACKGROUND AND PURPOSE Insulin secretion from isolated pancreatic islets is a pivotal assay in developing novel insulin secretagogues, given its good correlation with in vivo efficacy. Because the supply of human islets is limited, this assay is typically run with rodent islets, which do not address species differences and are low-throughput, because of the size matching or volume normalization required. Here we have evaluated the suitability of human re-aggregated islets for this assay. EXPERIMENTAL APPROACH We generated re-aggregated human islets of a consistent size, using micromolds and compared their responses with those of native human and rat islets, to known secretagogues and inhibitors of insulin release. KEY RESULTS Insulin secretion from rat islets, human islets and human re-aggregated cell clusters was concentration-dependently increased by glucose. The calcium channel agonist, Bay K 8644, stimulated insulin secretion in native rat islets and human re-aggregated islets, but not native human islets. Glibenclamide and tolbutamide were more effective and potent in re-aggregated human clusters compared with the other two preparations. Rat islets outperformed both human preparations of islets in response to caffeine, carbachol and glucagon-like peptide-1. Re-aggregated human islet clusters were more sensitive to somatostatin, diazoxide and sodium azide, but rodent islets were more sensitive to nifedipine. CONCLUSIONS AND IMPLICATIONS Human re-aggregated clusters of islet cells, of a constant size were more responsive to all compounds tested than native human islets. Importantly, the assay variability was less in the re-aggregated cluster preparations, which suggests that such re-aggregated cells could be useful for drug development. PMID:24641508

  12. 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

  13. Computational techniques in fragment based drug discovery.

    PubMed

    Villar, Hugo O; Hansen, Mark R

    2007-01-01

    Fragment based drug discovery is gaining acceptance as a complement to other more established techniques to identify leads and optimize drug candidates. In this review we illustrate areas where fragment based drug discovery has had an impact and point to some examples that show how fragment based analysis is being applied to new arenas. The traditional uses of computational methods in fragment based for lead discovery and optimization and for risk assessment are briefly summarized. The application of fragment analysis for the definition of bioisosteric replacements are discussed together with techniques to characterize the diversity of chemical libraries based on fragment distribution. PMID:17897037

  14. [The development from drug to designer drug.

    PubMed

    Askaa, Bjarke; Horwitz, Henrik; Wøien, Vidar André; Høgberg, Lotte C G; Jürgens, Gesche

    2014-10-13

    Synthetic "designer drugs" with hallucinogenic properties have become increasingly popular among recreational drug users in recent years. Some of the designer drugs are chemically modified drugs previously used in treatment of depression and chronic fatigue. The drugs are available from a large number of internet distributers. There is very little knowledge of the clinical symptoms and how intoxicated people should be treated. We present a review of published literature (including 284 intoxicated patients) and experiences from the Danish poison centre concerning two chemical derivatives of earlier registered drugs. PMID:25316367

  15. 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.

  16. The use of flow cytometry to assess a novel drug efficacy in multiple sclerosis.

    PubMed

    Benedek, Gil; Meza-Romero, Roberto; Bourdette, Dennis; Vandenbark, Arthur A

    2015-08-01

    Applying different technologies to monitor disease activity and treatment efficacy are essential in a complex disease such as multiple sclerosis. Combining current assays with flow cytometry could create a powerful tool for such analyses. The cell surface expression level of CD74, the MHC class II invariant chain, is a potential disease biomarker that could be monitored by FACS analysis in order to assess disease progression and the clinical efficacy of partial MHC class II constructs in treating MS. These constructs, which can bind to and down-regulate CD74 cell-surface expression on monocytes and inhibit macrophage migration inhibitory factor (MIF) effects, can reverse clinical and histological signs of EAE. These properties of partial class II constructs are highly compatible with a flow cytometry approach for monitoring CD74 expression as a possible biomarker for disease activity/progression and as a treatment response marker. PMID:25502010

  17. Assessment of HIV antiretroviral therapy adherence by measuring drug concentrations in hair among children in rural Uganda.

    PubMed

    Olds, Peter K; Kiwanuka, Julius P; Nansera, Denis; Huang, Yong; Bacchetti, Peter; Jin, Chengshi; Gandhi, Monica; Haberer, Jessica E

    2015-01-01

    Current tools for measuring medication adherence have significant limitations, especially among pediatric populations. We conducted a prospective observational study to assess the use of antiretroviral (ARV) drug levels in hair for evaluating antiretroviral therapy (ART) adherence among HIV-infected children in rural Uganda. Three-day caregiver recall, 30-day visual analog scale (VAS), Medication Event Monitoring System (MEMS), and unannounced pill counts and liquid formulation weights (UPC) were collected monthly over a one-year period. Hair samples were collected quarterly and analyzed for nevirapine (NVP) levels, and plasma HIV RNA levels were collected every six months. Among children with at least one hair sample collected, we used univariable random intercept linear regression models to compare log transformed NVP concentrations with each adherence measure, and the child's age, sex, and CD4 count percentage (CD4%). One hundred and twenty-one children aged 2-10 years were enrolled in the study; 74 (61%) provided at least one hair sample, and the mean number of hair samples collected per child was 1.9 (standard deviation [SD] 1.0). Three-day caregiver recall, VAS, and MEMS were found to be positively associated with increasing NVP concentration in hair, although associations were not statistically significant. UPC was found to have a nonsignificant negative association with increasing hair NVP concentration. In conclusion, NVP drug concentrations in hair were found to have nonsignificant, although generally positive, associations with other adherence measures in a cohort of HIV-infected children in Uganda. Hair collection in this population proved challenging, suggesting the need for community education and buy-in with the introduction of novel methodologies. PMID:25483955

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

    PubMed Central

    2011-01-01

    Background The increasing popularity and use of the internet makes it an attractive option for providing health information and treatment, including alcohol/other drug use. There is limited research examining how people identify and access information about alcohol or other drug (AOD) use online, or how they assess the usefulness of the information presented. This study examined the strategies that individuals used to identify and navigate a range of AOD websites, along with the attitudes concerning presentation and content. Methods Members of the general community in Brisbane and Roma (Queensland, Australia) were invited to participate in a 30-minute search of the internet for sites related to AOD use, followed by a focus group discussion. Fifty one subjects participated in the study across nine focus groups. Results Participants spent a maximum of 6.5 minutes on any one website, and less if the user was under 25 years of age. Time spent was as little as 2 minutes if the website was not the first accessed. Participants recommended that AOD-related websites should have an engaging home or index page, which quickly and accurately portrayed the site's objectives, and provided clear site navigation options. Website content should clearly match the title and description of the site that is used by internet search engines. Participants supported the development of a portal for AOD websites, suggesting that it would greatly facilitate access and navigation. Treatment programs delivered online were initially viewed with caution. This appeared to be due to limited understanding of what constituted online treatment, including its potential efficacy. Conclusions A range of recommendations arise from this study regarding the design and development of websites, particularly those related to AOD use. These include prudent use of text and information on any one webpage, the use of graphics and colours, and clear, uncluttered navigation options. Implications for future website development are discussed. PMID:21545748

  19. Assessing the availability of the teratogenic drug isotretinoin outside the pregnancy prevention programme: a survey of e-pharmacies†

    PubMed Central

    Lagan, Briege M; Dolk, Helen; White, Bronagh; Uges, Donald R A; Sinclair, M

    2014-01-01

    Purpose The increase in online purchasing of medications raises safety concerns regarding teratogenic drugs. The use of the teratogenic drug ‘isotretinoin’ for women of childbearing age requires strict adherence to the Pregnancy Prevention Programme (PPP), a risk minimisation measure imposed on prescribers and users. We sought to determine how readily consumers can purchase isotretinoin online and the associated safety procedures and information. Methods A descriptive cross-sectional survey was conducted of 50 e-pharmacies identified from commonly used search engines. E-pharmacy characteristics and isotretinoin PPP specific criteria were evaluated. Purchases of isotretinoin from seven e-pharmacies not bearing authentication logos and not requiring a prescription were assessed for PPP policy adherence, purchasing procedures and compound quality. Results Forty-three (86%) of the e-pharmacies did not have an authentication seal/logo. Isotretinoin could be purchased from 42 sites without a valid prescription. Information on isotretinoin causing birth defects was lacking in 25 of the 50 sites, on not taking isotretinoin in pregnancy in 24 sites and not taking isotretinoin if planning or at risk of a pregnancy in 33 sites. Of the eight attempted purchases, seven arrived, all without any patient information leaflet. All were verified as isotretinoin. Conclusion The Internet provides a loophole for purchasing of medications known to cause congenital abnormalities, which needs to be addressed by medicines regulatory agencies worldwide. The current PPP for isotretinoin may be failing to protect mothers and babies from preventable harm—clinicians need to be aware of this, and the public needs to be educated about the potential risks. PMID:24493556

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

    Microsoft Academic Search

    Feng Wang; Wenning Pang; Patrick Duffy

    2012-01-01

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

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

    E-print Network

    Lanthaler, Karin; Bilsland, Elizabeth; Dobson, Paul D; Moss, Harry J; Pir, Pinar; Kell, Douglas B; Oliver, Stephen G

    2011-10-24

    Abstract 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...

  2. HIGH VOLUME BIOASSAYS TO ASSESS CYP3A4-MEDIATED DRUG INTERACTIONS: INDUCTION AND INHIBITION IN A SINGLE CELL LINE

    Microsoft Academic Search

    Mei-Fei Yueh; Marleen Kawahara; Judy Raucy

    2005-01-01

    Exposure to certain xenochemicals can alter the catalytic activity of the major drug-metabolizing enzyme, CYP3A4, either by en- hancing expression of this cytochrome P450 or inhibiting its activ- ity. Such alterations can result in adverse consequences stemming from drug-drug interactions. A simplified and reliable tool for de- tecting the ability of candidate drugs to alter CYP3A4 levels or inhibit catalytic

  3. Effects of age on noninvasive assessments of vascular function in nonhuman primates: implications for translational drug discovery

    PubMed Central

    2013-01-01

    Background Endothelium-dependent flow mediated dilation (FMD) and pulse-wave velocity (PWV), are used as measures of vascular health and predictors of cardiovascular risk in clinical studies, and both are age-dependent. Numbers of circulating endothelial microparticles (EMPs) and endothelial progenitor cells (EPCs) are also associated with cardiovascular risk, but independent of age in humans. The use of these measurements for pre-clinical assessment of drug cardiovascular safety and efficacy in non-human primates (NHPs) may promote the translation of drug-induced effects on vascular function to clinic outcomes. However, in NHPs, the age effects on the non-invasive measurements of FMD and PWV and the relationship of EMPs/EPCs with FMD are unknown. Methods A non-invasive, clinically-relevant approach to assess FMD and PWV was used to examine their relationship with age and with EMPs/EPCs in NHPs. The effects on FMD of nicotine and rosiglitazone were evaluated in senescent primates in an effort to validate our FMD method for pre-clinical assessment of vascular function. Results FMD and PWV methods were established in a colony (n?=?25) of metabolically healthy, cynomolgus monkeys ranging in age from 6 to 26 years. FMD, defined as the percent change, at 1 min of cuff release, from baseline vascular diameter (0.15?±?0.03 cm), had a strong, negative correlation with age (r?=?-0.892, p?assessed with FMD, together with EMPs/EPCs assessment, may serve as a novel approach for translational research and therapeutic discovery. Age should be considered in the study design or data analyses when FMD or PWV is used in NHPs. PMID:23607770

  4. Drug Distribution to Human Tissues: Prediction and Examination of the Basic Assumption in In Vivo Pharmacokinetics-Pharmacodynamics (PK/PD) Research.

    PubMed

    Poulin, Patrick

    2015-06-01

    The tissue:plasma partition coefficients (Kp ) are good indicators of the extent of tissue distribution. Therefore, advanced tissue composition-based models were used to predict the Kp values of drugs under in vivo conditions on the basis of in vitro and physiological input data. These models, however, focus on animal tissues and do not challenge the predictions with human tissues for drugs. The first objective of this study was to predict the experimentally determined Kp values of seven human tissues for 26 drugs. In all, 95% of the predicted Kp values are within 2.5-fold error of the observed values in humans. Accordingly, these results suggest that the tissue composition-based model used in this study is able to provide accurate estimates of drug partitioning in the studied human tissues. Furthermore, as the Kp equals to the ratio of total concentration between tissue and plasma, or the ratio of unbound fraction between plasma (fup ) and tissue (fut ), this parameter Kp would deviate from the unity. Therefore, the second objective was to examine the corresponding relationships between fup and fut values experimentally determined in humans for several drugs. The results also indicate that fup may significantly deviate to fut ; the discrepancies are governed by the dissimilarities in the binding and ionization on both sides of the membrane, which were captured by the tissue composition-based model. Hence, this violated the basic assumption in in vivo pharmacokinetics-pharmacodynamics (PK/PD) research, since the free drug concentration in tissue and plasma was not equal particularly for the ionizable drugs due to the pH gradient effect on the fraction of unionized drug in plasma (fuip ) and tissue (fuit ) (i.e., fup × fuip × total plasma concentration = fut × fuit × total tissue concentration, and, hence, the free drug concentration in plasma and tissue differed by fuip/fuit). Therefore, this assumption should be adjusted for the ionized drugs, and, hence, a mathematical correction to the basic assumption of similar free drug concentration in plasma and tissues can be derived from the tissue composition-based model. Note that this assumption will be further challenged in a dynamic in vivo system in a companion manuscript. Overall, this study was a first attempt to predict the in vivo Kp values for specific human tissues by considering separately the effect of fup and fut , with the aim of facilitating the use of physiologically-based PK (PBPK) model in PK/PD studies. © 2015 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 104:2110-2118, 2015. PMID:25808270

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

    SciTech Connect

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

    1994-06-01

    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.

  6. 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).

  7. Assessment of size-dependent mercury distribution in King Mackerel, Scomberomorus cavalla

    SciTech Connect

    Voit, E.O. [Medical Univ. of South Carolina, Charleston, SC (United States). Dept. of Biometry and Epidemiology; Balthis, W.L. [Medical Univ. of South Carolina, Charleston, SC (United States). Dept. of Biometry and Epidemiology]|[National Marine Fisheries Service, Charleston, SC (United States). Southeast Fisheries Science Center

    1994-12-31

    The assessment of health risks from fish contamination and the issuance of advisories require accurate characterizations of the actual contaminant concentrations in fish of every relevant size. Such characterizations should not only contain statistical measures of location and variation, but provide a complete parameterization of the contaminant distribution for each given size class. This paper proposes two methods for determining such distributions from scatter diagrams of contaminant concentration versus fish length and illustrates them with an analysis of mercury contaminant in king mackerel, Scomberomorus cavalla. The first method consists of fitting contamination data with a family of S-distributions. This family shows trends in its defining parameter values, and these trends provide a comprehensive characterization of the measured contaminant concentrations. Each S-distribution has a rather simple mathematical structure from which one readily obtains secondary characteristics like quantiles, which are necessary for advanced simulation purposes. The second method takes into account that contaminant accumulation is the outcome of a metabolic process. When this process is modeled as a system of differential equations, it can be reformulated in such a way that it describes how the contaminant distribution changes over a given period of time. The resulting distributions have a more complicated structure than those obtained with the first method, but they allow them to bridge the gap between individual metabolic accumulation processes and trends in populations.

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

    PubMed Central

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

    2014-01-01

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

  9. Do Drug Treatment Facilities Increase Clients’ Exposure to Potential Neighborhood-Level Triggers for Relapse? A Small-Area Assessment of a Large, Public Treatment System

    PubMed Central

    2006-01-01

    Research on drug treatment facility locations has focused narrowly on the issue of geographic proximity to clients. We argue that neighborhood conditions should also enter into the facility location decision and illustrate a formal assessment of neighborhood conditions at facilities in a large, metropolitan area, taking into account conditions clients already face at home. We discuss choice and construction of small-area measures relevant to the drug treatment context, including drug activity, disadvantage, and violence as well as statistical comparisons of clients’ home and treatment locations with respect to these measures. Analysis of 22,707 clients discharged from 494 community-based outpatient and residential treatment facilities that received public funds during 1998–2000 in Los Angeles County revealed no significant mean differences between home and treatment neighborhoods. However, up to 20% of clients are exposed to markedly higher levels of disadvantage, violence, or drug activity where they attend treatment than where they live, suggesting that it is not uncommon for treatment locations to increase clients’ exposure to potential environmental triggers for relapse. Whereas on average both home and treatment locations exhibit higher levels of these measures than the household locations of the general population, substantial variability in public treatment clients’ home neighborhoods calls into question the notion that they hail exclusively from poor, high drug activity areas. Shortcomings of measures available for neighborhood assessment of treatment locations and implications of the findings for other areas of treatment research are also discussed. PMID:16736365

  10. 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.

  11. Spatio-temporal assessment of food safety risks in Canadian food distribution systems using GIS.

    PubMed

    Hashemi Beni, Leila; Villeneuve, Sébastien; LeBlanc, Denyse I; Côté, Kevin; Fazil, Aamir; Otten, Ainsley; McKellar, Robin; Delaquis, Pascal

    2012-09-01

    While the value of geographic information systems (GIS) is widely applied in public health there have been comparatively few examples of applications that extend to the assessment of risks in food distribution systems. GIS can provide decision makers with strong computing platforms for spatial data management, integration, analysis, querying and visualization. The present report addresses some spatio-analyses in a complex food distribution system and defines influence areas as travel time zones generated through road network analysis on a national scale rather than on a community scale. In addition, a dynamic risk index is defined to translate a contamination event into a public health risk as time progresses. More specifically, in this research, GIS is used to map the Canadian produce distribution system, analyze accessibility to contaminated product by consumers, and estimate the level of risk associated with a contamination event over time, as illustrated in a scenario. PMID:22749207

  12. Reliability and Validity of the Functional Assessment of Human Immunodeficiency Virus Infection (FAHI) in patients with drug and alcohol use disorders

    PubMed Central

    Byrne, Shannon; Petry, Nancy M.

    2012-01-01

    HIV and substance use disorders can both significantly impact a patient’s quality of life (QOL), and it is therefore important to assess QOL throughout treatments for these chronic conditions. This study evaluated the psychometric properties of the Functional Assessment of Human Immunodeficiency Virus (HIV) Infection (FAHI) in 170 HIV-positive patients who participated in a substance abuse treatment study. Internal consistency of the FAHI was good. Convergent and discriminant validity were generally supported with comparisons to other patient-reported measures. FAHI scores were not significantly associated with viral loads or CD4 counts, and they were similar in patients with and without AIDS. Patients who achieved longer durations of drug and alcohol abstinence during treatment reported better quality of life post-treatment. The FAHI appears to be a reliable and valid measure for assessing quality of life in HIV-positive patients with concurrent drug and alcohol use disorders. PMID:22646736

  13. Drug Filtering

    NSDL National Science Digital Library

    Lawrence F. Iles

    2010-01-01

    In this math meets health science activity, learners observe a model of exponential decay, and how kidneys filter blood. Learners will calculate the amount of a drug in the body over a period of time. Then, they will make and analyze the graphical representation of this exponential function. This lesson guide includes questions for learners, assessment options, extensions, and reflection questions.

  14. Counterfeit Drug Penetration into Global Legitimate Medicine Supply Chains: A Global Assessment

    PubMed Central

    Mackey, Tim K.; Liang, Bryan A.; York, Peter; Kubic, Thomas

    2015-01-01

    Counterfeit medicines are a global public health risk. We assess counterfeit reports involving the legitimate supply chain using 2009–2011 data from the Pharmaceutical Security Institute Counterfeit Incident System (PSI CIS) database that uses both open and nonpublic data sources. Of the 1,510 identified CIS reports involving counterfeits, 27.6% reported China as the source country of the incident/detection. Further, 51.3% were reported as counterfeit but the specific counterfeit subcategory was not known or verifiable. The most prevalent therapeutic category was anti-infectives (21.1%) with most reports originating from health-related government agencies. Geographically, Asian and Latin American regions and, economically, middle-income markets were most represented. A total of 127 (64.8%) of a total of 196 countries had no legitimate supply chain CIS counterfeit reports. Improvements in surveillance, including detection of security breaches, data collection, analysis, and dissemination are urgently needed to address public health needs to combat the global counterfeit medicines trade. PMID:25897059

  15. Counterfeit drug penetration into global legitimate medicine supply chains: a global assessment.

    PubMed

    Mackey, Tim K; Liang, Bryan A; York, Peter; Kubic, Thomas

    2015-06-01

    Counterfeit medicines are a global public health risk. We assess counterfeit reports involving the legitimate supply chain using 2009-2011 data from the Pharmaceutical Security Institute Counterfeit Incident System (PSI CIS) database that uses both open and nonpublic data sources. Of the 1,510 identified CIS reports involving counterfeits, 27.6% reported China as the source country of the incident/detection. Further, 51.3% were reported as counterfeit but the specific counterfeit subcategory was not known or verifiable. The most prevalent therapeutic category was anti-infectives (21.1%) with most reports originating from health-related government agencies. Geographically, Asian and Latin American regions and, economically, middle-income markets were most represented. A total of 127 (64.8%) of a total of 196 countries had no legitimate supply chain CIS counterfeit reports. Improvements in surveillance, including detection of security breaches, data collection, analysis, and dissemination are urgently needed to address public health needs to combat the global counterfeit medicines trade. PMID:25897059

  16. A Network-Based Classification Model for Deriving Novel Drug-Disease Associations and Assessing Their Molecular Actions

    PubMed Central

    Oh, Min; Ahn, Jaegyoon; Yoon, Youngmi

    2014-01-01

    The growing number and variety of genetic network datasets increases the feasibility of understanding how drugs and diseases are associated at the molecular level. Properly selected features of the network representations of existing drug-disease associations can be used to infer novel indications of existing drugs. To find new drug-disease associations, we generated an integrative genetic network using combinations of interactions, including protein-protein interactions and gene regulatory network datasets. Within this network, network adjacencies of drug-drug and disease-disease were quantified using a scored path between target sets of them. Furthermore, the common topological module of drugs or diseases was extracted, and thereby the distance between topological drug-module and disease (or disease-module and drug) was quantified. These quantified scores were used as features for the prediction of novel drug-disease associations. Our classifiers using Random Forest, Multilayer Perceptron and C4.5 showed a high specificity and sensitivity (AUC score of 0.855, 0.828 and 0.797 respectively) in predicting novel drug indications, and displayed a better performance than other methods with limited drug and disease properties. Our predictions and current clinical trials overlap significantly across the different phases of drug development. We also identified and visualized the topological modules of predicted drug indications for certain types of cancers, and for Alzheimer’s disease. Within the network, those modules show potential pathways that illustrate the mechanisms of new drug indications, including propranolol as a potential anticancer agent and telmisartan as treatment for Alzheimer’s disease. PMID:25356910

  17. Parenting quality in drug-addicted mothers in a therapeutic mother-child community: the contribution of attachment and personality assessment.

    PubMed

    De Palo, Francesca; Capra, Nicoletta; Simonelli, Alessandra; Salcuni, Silvia; Di Riso, Daniela

    2014-01-01

    Growing evidence shows that attachment is a key risk factor for the diagnosis and treatment of clinical diseases in Axis I, such as drug addiction. Recent literature regarding attachment, psychiatric pathology, and drug addiction demonstrates that there is a clear prevalence of insecure attachment patterns in clinical and drug addicted subjects. Specifically, some authors emphasize that the anxious-insecure attachment pattern is prevalent among drug-addicted women with double diagnosis (Fonagy et al., 1996). The construct of attachment as a risk factor in clinical samples of drug-addicted mothers needs to be studied more in depth though. The present explorative study focused on the evaluation of parenting quality in a therapeutic mother-child community using attachment and personality assessment tools able to outline drug-addicted mothers' profiles. This study involved 30 drug addicted mothers, inpatients of a therapeutic community (TC). Attachment representations were assessed via the Adult Attachment Interview; personality diagnosis and symptomatic profiles were performed using the Structured Clinical Interview of the DSM-IV (SCID-II) and the Symptom Check List-90-R (SCL-90-R), respectively. Both instruments were administered during the first six months of residence in a TC. Results confirmed the prevalence of insecure attachment representations (90%), with a high presence of U patterns, prevalently scored for dangerous and/or not protective experiences in infanthood. Very high values (>5) were found for some experience scales (i.e., neglect and rejection scales). Data also showed very low values (1-3) in metacognitive monitoring, coherence of transcript and coherence of mind scales. Patients' different profiles (U vs. E vs. Ds) were linked to SCID-II diagnosis, providing insightful indications both for treatment planning and intervention on parenting functions and for deciding if to start foster care or adoption proceedings for children. PMID:25309481

  18. Relationship Between Drug Discrimination and Ratings of Subjective Effects: Implications for Assessing and Understanding the Abuse Potential of d-Amphetamine in Humans

    PubMed Central

    Reynolds, Anna R.; Bolin, B. Levi; Stoops, William W.; Rush, Craig R.

    2014-01-01

    The discriminative and subjective effects of drugs in humans are related, but the full extent of this relationship remains to be determined. To further explore this relationship, a retrospective analysis was conducted on data from six studies completed in our laboratory that used identical procedures. The relationship between the discriminative and subjective effects of a range of doses of d-amphetamine (i.e., 2.5–15 mg) was examined using correlational analyses. Significant correlations with discrimination performance were observed on 15 of 20 items from the Drug-Effect Questionnaire across a range of qualities (e.g., Pay For [a positive effect indicative of abuse potential] and Active [a stimulant-like effect]), but the magnitude of these relationships was modest (r < 0.52). The current findings demonstrate that diverse subjective effects contribute to the discriminative effects of d-amphetamine and indicate that the former are a more practical means to assess abuse potential of drugs. Although these procedures are fundamentally related in that they rely on the presence of an interoceptive drug state, they differ in the dimension(s) of the interoceptive effects that participants must quantify. The simultaneous use of drug discrimination and subjective effects may, therefore, reveal complimentary aspects of drug effects that underlie their potential for abuse. PMID:23851485

  19. Closantel plasma and milk disposition in dairy goats: assessment of drug residues in cheese and ricotta.

    PubMed

    Iezzi, S; Lifschitz, A; Sallovitz, J; Nejamkin, P; Lloberas, M; Manazza, J; Lanusse, C; Imperiale, F

    2014-12-01

    Closantel (CLS) is currently used in programs for the strategic control of gastrointestinal nematodes. CLS is extralabel used in different dairy goat production systems. From available data in dairy cows, it can be concluded that residues of CLS persist in milk. The current work evaluated the concentration profiles of CLS in plasma and milk from lactating orally treated dairy goats to assess the residues pattern in dairy products such as cheese and ricotta. Six (6) female Saanen dairy goats were treated orally with CLS administered at 10 mg/kg. Blood and milk samples were collected between 0 and 36 days post-treatment. The whole milk production was collected at 1, 4, 7, and 10 days post-treatment to produce soft cheese and ricotta. CLS concentrations in plasma, milk, cheese, whey, and ricotta were determined by HPLC. The concentrations of CLS measured in plasma were higher than those measured in milk at all sampling times. However, the calculated withdrawal time for CLS in milk was between 39 and 43 days postadministration to dairy goats. CLS residual concentrations in cheese (between 0.93 and 1.8 ?g/g) were higher than those measured in the milk used for its production. CLS concentrations in ricotta were sixfold higher than those in the milk and 20-fold higher than those in the whey used for its production. The persistent and high residual concentrations of CLS in the milk and in the cheese and ricotta should be seriously considered before issuing any recommendation on the extralabel use of CLS in dairy goat farms. PMID:24903569

  20. Assessment of drug-lipid complex formation by a high-throughput Langmuir-balance and correlation to phospholipidosis.

    PubMed

    Vitovic, Pavol; Alakoskela, Juha-Matti; Kinnunen, Paavo K J

    2008-03-27

    Phospholipidosis, the accumulation of phospholipids in cells, is a relatively frequent side effect of cationic amphiphilic drugs. In response to the industry need, several methods have been recently published for the prediction of the phospholipidosis-inducing potential of drug candidates. We describe here a high-throughput physicochemical approach, which is based on the measurement of drug-phospholipid complex formation observed by their effect on the critical micelle concentration (CMC) of a short-chain acidic phospholipid. The relative change due to the drug, CMC(DL)/CMC(L) provides a direct measure of the energy of the drug-phospholipid association, irrespective of the nature of the interaction. Comparison of results for 53 drugs to human data, animal testing, cell culture assays, and other screening methods reveals very good correlation to their phospholipidosis-inducing potential. The method is well suited for screening already in early phases of drug discovery. PMID:18318464

  1. What Matters Most? Assessing the Influence of Demographic Characteristics, College-Specific Risk Factors, and Poly-Drug Use on Nonmedical Prescription Drug Use

    ERIC Educational Resources Information Center

    Lanier, Christina; Farley, Erin J.

    2011-01-01

    Objective: Although prior recent research has revealed a significant relationship between the nonmedical use of prescription drugs, demographic characteristics, college-specific risk factors, and other substance use among college students, there remains a need to conduct a comparative analysis on the differential impact these factors may have on…

  2. Use of cloned and expressed human liver UDP-glucuronosyltransferases for analysis of drug glucuronide formation and assessment of drug toxicity.

    PubMed Central

    Burchell, B; Ebner, T; Baird, S; Bin Senafi, S; Clarke, D; Brierley, C; Sutherland, L

    1994-01-01

    Five cloned human hepatic UDP-glucuronosyltransferase (UGT) cDNAs were stably expressed in tissue culture cell lines. More than 100 drugs and xenobiotics were used as substrates for glucuronidation catalyzed by the cloned human transferases to determine the chemical structures accepted as substrates. UGT-HP1 exhibited a limited substrate specificity for planar phenolic compounds, whereas UGT-HP4 was more accepting of nonplanar phenols, anthraquinones, flavones, alphatic alcohols, aromatic carboxylic acids, steroids and many drugs of varied structure. UGT-HP3 (bilirubin UGT) catalyzed the glucuronidation of ethinylestradiol. UGT-H6 and UGT-H25 (steroid/bile acid UGTs) also catalyzed the glucuronidation of some xenobiotics. Levels of UGT-HP4 activity towards some substrates were sufficient to allow determination of kinetic parameters for the enzyme reaction. Further, metabolism of drugs could be studied by addition to the recombinant cell lines in culture and extraction of the media allowed analysis of glucuronide formation. The protection afforded against cytotoxic drugs was observed. The data presented here demonstrate the potential of using these recombinant cell lines for investigation of phase II metabolism by human UGTs and subtle differences in protein structure which affect their specificity. PMID:7698078

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

    PubMed Central

    Gottfries, Johan; Melgar, Silvia; Michaëlsson, Erik

    2012-01-01

    Preclinical disease models play an important role in the establishment of new treatment paradigms, identification of biomarkers and assessment of drug efficacy and safety. However, the accuracy of these models in context of the human disease are sometimes questioned, e.g. due to trials failing to confirm efficacy in humans. We suggest that one reason behind this gap in predictability may relate to how the preclinical data is analyzed and interpreted. In the present paper, we introduce a holistic approach to analyze and illustrate data in context of one of the most commonly used colitis models, i.e. the mouse dextran sulphate sodium (DSS) colitis model. Diseased mice were followed over time along disease progression and by use of tool pharmacological compounds activating nuclear hormone receptors, respectively. A new multivariate statistics approach was applied including principal component analysis (PCA) with treatment prediction subsequent to establishing the principal component analysis model. Thus, several studies could be overlaid and compared to each other in a new, comprehensive and holistic way. This method, named mouse colitis global property screening, appears applicable not only to any animal modelling series of studies but also to human clinical studies. The prerequisites for the study set up and calculations are delineated and examples of new learnings from the global property screening will be presented. PMID:22279558

  4. Assessing the Assumptions of Respondent-Driven Sampling in the National HIV Behavioral Surveillance System among Injecting Drug Users

    PubMed Central

    Lansky, Amy; Drake, Amy; Wejnert, Cyprian; Pham, Huong; Cribbin, Melissa; Heckathorn, Douglas D

    2012-01-01

    Several assumptions determine whether respondent-driven sampling (RDS) is an appropriate sampling method to use with a particular group, including the population being recruited must know one another as members of the group (i.e., injection drug users [IDUs] must know each other as IDUs) and be networked and that the sample size is small relative to the overall size of the group. To assess these three assumptions, we analyzed city-specific data collected using RDS through the US National HIV Behavioral Surveillance System among IDUs in 23 cities. Overall, 5% of non-seed participants reported that their recruiter was “a stranger.” 20 cities with multiple field sites had ?1 cross-recruitment, a proxy for linked networks. Sample sizes were small in relation to the IDU population size (median = 2.3%; range: 0.6%- 8.0%). Researchers must evaluate whether these three assumptions were met to justify the basis for using RDS to sample specific populations. PMID:23049656

  5. Simulation of Drug Release from PLGA Particles In Vivo

    PubMed Central

    Sasaki, Kaori; Igarashi, Martha; Hinata, Manami; Komori, Yuna

    2013-01-01

    Specific targeting of tissues and/or cells is essential for any type of drug delivery system because this determines the efficacy and side effects of the drug. Poly lactic-co-glycolic acids (PLGA) have long been used as biomaterials for drug delivery due to their excellent biocompatibility and biodegradability. Direct visualization of PLGA particles is feasible even within tissues, and cell specificity of the drug delivery system is normally assessed by using labeled particles. However, particle labeling alone does not address factors such as the release and distribution of the drug. Thus, it is desirable to set up a simulation system of drug release and distribution in vivo. In the present study, we aimed to establish a method to simulate drug distribution in PLGA drug delivery by using Hoechst 33342 as an imitating drug. Our approach enabled us to identify, isolate, and characterize cells exposed to Hoechst 33342 and to deduce the concentration of this fluorescent dye around both targeted and nontargeted cells. We believe that the method described herein will provide essential information regarding the specificity of cell targeting in any type of PLGA drug delivery system. PMID:24222857

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

    PubMed Central

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

    2013-01-01

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

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

    NASA Astrophysics Data System (ADS)

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

    2015-04-01

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

  8. Assessing the performance, practices and roles of drug sellers/dispensers and mothers'/guardians' behaviour for common childhood conditions in Kibaha district, Tanzania.

    PubMed

    Nsimba, S E D

    2007-10-01

    In most third world countries, self-medication is common and pharmacies, drug stores and drug shops are important providers of health advice and inexpensive medicines. We used exit interviews to assess drug sellers'/dispensers' roles and consumers' behaviour in Kibaha district, Coast region, Tanzania. Exit interviews with mothers/guardians reported the following childhood conditions treated with or without prescriptions at drug shops: respiratory infections (34%), fever (21%), a combination of diarrhoea, acute respiratory infection (ARI) and fever (14%), diarrhoea alone (13%) and other conditions (17%). The majority of drug sellers/dispensers prescribed or dispensed branded drugs (85%) for most mothers/guardians who visited these drug shops. In addition, antibiotics in total were prescribed for 31% of the mothers/guardians. Of the antibiotics dispensed, 38% were not prescribed by clinicians. In total, oral rehydration salts (ORSs) (3%), antimalarials (sulphadoxine/pyrimethamine) (24%) and antipyretics (11%), were prescribed in 20% but were bought by only 9%; multivitamins (6%), cough mixtures (4%) and other drugs (2%) (antihelminthics, benzylbenzoate emulsions, ear and eye drops) were also purchased from these facilities. Of the diarrhoea case histories presented by simulated clients at the drug shops, only 35% of the bloody diarrhoea scenarios were accurately diagnosed for getting antibiotics as compared with 44% for watery diarrhoea for which the use of antibiotics were wrongly advised (P<0.01). Furthermore, drug sellers/dispensers in these drug shops recommended use of ORS less frequently (3%) for a combination of diarrhoea, ARI and fever, and 2% for ARI alone than for watery (29%) and bloody diarrhoea (32%), respectively, for children under five years of age (P<0.001). Antimicrobial agents were advised for ARI (38%), watery diarrhoea (44%) and bloody diarrhoea (35%), respectively, with no significant difference among the three common childhood conditions. Antipyretics were advised in almost all childhood conditions but were least in watery (2%) and bloody diarrhoea (4%). This study demonstrates that antibiotics are overused in both the urban and rural settings of Kibaha district and that this is due to both clinicians'and drug sellers'prescribing practices in public and private facilities. The use of branded drugs was more common than that of generic drugs in private pharmacies, drug stores and ordinary shops. It is hereby proposed that any intervention should focus on training both facilities in the district on selectively prescribing and rational use of antibiotics for ARI and diarrhoea, and also to prescribe and dispense generic drugs so that it costs patients less when they buy drugs in shops. There is a need to increase awareness in recommending the use of ORS for clients to manage watery and bloody diarrhoea, and ARI in children under five years of age. PMID:17988473

  9. Chemomorphic Analysis of Malathion in Skin Layers of the Rat: Implications for the Use of Dermatopharmacokinetic Tape Stripping in Exposure Assessment to Pesticides

    Microsoft Academic Search

    Curtis C. Dary; Jerry N. Blancato; Mahmoud A. Saleh

    2001-01-01

    The dermatopharmacokinetic (DPK) method of dermal tape stripping may prove to be a valuable addition to risk assessment protocols for toxic substances as it has been for the assessment of bioequivalence and bioavailability of topical dermatologic drugs. The measurement of drug penetration into stratum corneum (SC) with respect to time is thought to be comparable with drug distribution in underlying

  10. Assessment of gender distribution in dengue surveillance data, the Lao People's Democratic Republic

    PubMed Central

    Prasith, Nouda; Keosavanh, Onechanh; Phengxay, Manilay; Stone, Sara; Lewis, Hannah C; Tsuyuoka, Reiko; Matsui, Tamano; Phongmanay, Panom; Khamphaphongphane, Bouaphanh

    2013-01-01

    Objective Adolescent and young adult males account for a large proportion of dengue cases reported through national surveillance systems in the Western Pacific Region. To preliminarily assess the validity of these observed distributions, a field investigation was conducted in the Lao People's Democratic Republic’s Savannakhet Province in November 2011. Methods Mixed quantitative and qualitative methods were used. Dengue surveillance data from Savannakhet Province, and aggregate hospital admission data from the Savannakhet Provincial Hospital for outpatients and inpatients were analysed by age and sex. Unstructured informal interviews were conducted with local health care workers, primary and secondary school officials and villagers. Results An excess of males was found among reported dengue cases in Savannakhet Province in the 15–49 year age group. Females in the same age group, however, were found to access health care more than their male counterparts. Qualitative assessments attributed this distribution to young females being more health-conscious and having greater health care-seeking behaviour. Discussion The excess of male dengue cases in the surveillance data appeared to be associated with a truly higher risk of dengue rather than greater health care access or health care-seeking behaviour by young men. This investigation indicated the importance of assessing the reported surveillance data within the context of health care utilization behaviour of the population under surveillance. PMID:24015367

  11. 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.

  12. TGI-Simulator: a visual tool to support the preclinical phase of the drug discovery process by assessing in silico the effect of an anticancer drug.

    PubMed

    Terranova, Nadia; Magni, Paolo

    2012-02-01

    This paper presents TGI-Simulator, a software tool designed to show, through a 2-D graphical animation, the simulated time effect of an anticancer drug on a tumor mass by exploiting the well-known Tumor Growth Inhibition (TGI) model published by Simeoni et al. [1]. Simeoni TGI model is a mathematical model routinely used by pharma companies and researchers during the drug development process. The application is based on a Java graphical user interface (GUI) including a self installing differential equation solver implemented in Matlab together with an optimization algorithm that performs model identification via Weighted Least Squares (WLS). However, it can graphically show also the simulation results obtained within other scientific software tools, if they are preventively stored into a suitable ASCII file. The tool would be a valid support also for researchers with no specific skills in scientific calculations and in pharmacokinetic and pharmacodynamic modeling but daily involved in pharma companies drug development processes at different levels. The availability of a movie with a temporal varying 2-D iconographic representation is an original instrument to communicate results and learn Simeoni TGI model and its potential application in preclinical studies. PMID:22005012

  13. THE ACQUISITION AND APPLICATION OF ABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION (ADME) DATA IN AGRICULTURAL CHEMICAL SAFETY ASSESSMENTS

    EPA Science Inventory

    A multi-sector international group of government, academic, and industry scientists has developed a proposal for an improved testing scheme for assessing the safety of crop protection chemicals. Incorporation of pharmacokinetic studies describing the absorption, distribution, me...

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

    NASA Astrophysics Data System (ADS)

    Leuchter, S.; Reinert, F.; Müller, W.

    2014-06-01

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

  15. No-reference hair occlusion assessment for dermoscopy images based on distribution feature.

    PubMed

    Xie, Fengying; Li, Yang; Meng, Rusong; Jiang, Zhiguo

    2015-04-01

    The presence of hair is a common quality problem for dermoscopy images, which may influence the accuracy of lesion analysis. In this paper, a novel no-reference hair occlusion assessment method is proposed according to the distribution feature of hairs in the dermoscopy image. Firstly, the image is adaptively enhanced by simple linear iterative clustering (SLIC) combined with isotropic nonlinear filtering (INF). Then, hairs are extracted from the image by an automatic threshold and meanwhile the postprocessing is used to refine the hair through re-extracting omissive hairs and filtering false hairs. Finally, the degree of hair occlusion is evaluated by an objective metric based on the hair distribution. A series of experiments was carried out on both simulated images and real images. The result shows that the proposed local adaptive hair detection method can work well on both sparse hair and dense hair, and the designed metric can effectively evaluate the degree of hair occlusion. PMID:25701625

  16. Biocides in the Yangtze River of China: spatiotemporal distribution, mass load and risk assessment.

    PubMed

    Liu, Wang-Rong; Zhao, Jian-Liang; Liu, You-Sheng; Chen, Zhi-Feng; Yang, Yuan-Yuan; Zhang, Qian-Qian; Ying, Guang-Guo

    2015-05-01

    Nineteen biocides were investigated in the Yangtze River to understand their spatiotemporal distribution, mass loads and ecological risks. Fourteen biocides were detected, with the highest concentrations up to 166 ng/L for DEET in surface water, and 54.3 ng/g dry weight (dw) for triclocarban in sediment. The dominant biocides were DEET and methylparaben, with their detection frequencies of 100% in both phases. An estimate of 152 t/y of 14 biocides was carried by the Yangtze River to the East China Sea. The distribution of biocides in the aquatic environments was significantly correlated to Gross Domestic Product (GDP), total phosphorus (TP) and total nitrogen (TN), suggesting dominant input sources from domestic wastewater of the cities along the river. Risk assessment showed high ecological risks posed by carbendazim in both phases and by triclosan in sediment. Therefore, proper measures should be taken to reduce the input of biocides into the river systems. PMID:25697474

  17. Prescription Drug Use During and Immediately Before Pregnancy in Hawai‘i — Findings from the Hawai‘i Pregnancy Risk Assessment Monitoring System, 2009–2011

    PubMed Central

    Hurwitz, Eric L

    2014-01-01

    There are relatively few population-based studies on prescription drug use during pregnancy. Hawai‘i Pregnancy Risk Assessment Monitoring System (PRAMS) survey data from 4,735 respondents were used to estimate statewide prevalence of overall non-vitamin prescription drug use during and in the month before pregnancy. Data were weighted to be representative of all pregnancies resulting in live births in Hawai‘i in 2009–2011. Of women with recent live births in Hawai‘i, 14.2% (95% CI: 13.0 – 15.5) reported prescription drug use before pregnancy and 17.6% (95% CI: 16.2 – 19.0) reported prescription drug use during pregnancy. Prevalence of prescription drug use both before and during pregnancy was highest among women who had a pre-pregnancy chronic disease, were White, and had a pregnancy-related medical problem. Pain relievers (2.82%; 95% CI: 2.28 – 3.47), psychiatric medications (2.34%; 95% CI: 1.85 – 2.95), and anti-infectives (1.91%; 95% CI: 1.46 – 2.48) were the most common types of medications used before pregnancy. The most commonly-reported prescription medication types taken during pregnancy were anti-infectives (4.00%; 95% CI: 3.34 – 4.79), pain relievers (3.18%; 95% CI: 2.56 – 3.94), and gastrointestinal drugs (3.08%; 95% CI: 2.47 – 3.83). Of women who reported prescription drug use during pregnancy and attended prenatal care, 10.3% (95% CI: 8.0 – 13.2) reported that their healthcare provider had not counseled them during prenatal care on which medicines are safe to use during pregnancy. PMID:25628970

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

    PubMed

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

    2008-05-01

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

  19. The Personality Assessment Inventory Borderline, Drug, and Alcohol Scales as predictors of overall performance in police officers: a series of exploratory analyses

    Microsoft Academic Search

    Peter A. Weiss; John H. Hitchcock; William U. Weiss; Cary Rostow; Robert Davis

    2008-01-01

    Previous studies have established the utility of self-report personality inventories in the pre-employment screening of police officers. The present study therefore sought to explore the relationship between the Personality Assessment Inventory (PAI) Borderline, Drug, and Alcohol Scales and performance as a police officer. The PAI results of 632 police officers who took the test as part of pre-employment screening procedures

  20. Genome-based analysis of the nonhuman primate Macaca fascicularis as a model for drug safety assessment

    PubMed Central

    Ebeling, Martin; Küng, Erich; See, Angela; Broger, Clemens; Steiner, Guido; Berrera, Marco; Heckel, Tobias; Iniguez, Leonardo; Albert, Thomas; Schmucki, Roland; Biller, Hermann; Singer, Thomas; Certa, Ulrich

    2011-01-01

    The long-tailed macaque, also referred to as cynomolgus monkey (Macaca fascicularis), is one of the most important nonhuman primate animal models in basic and applied biomedical research. To improve the predictive power of primate experiments for humans, we determined the genome sequence of a Macaca fascicularis female of Mauritian origin using a whole-genome shotgun sequencing approach. We applied a template switch strategy that uses either the rhesus or the human genome to assemble sequence reads. The sixfold sequence coverage of the draft genome sequence enabled discovery of about 2.1 million potential single-nucleotide polymorphisms based on occurrence of a dimorphic nucleotide at a given position in the genome sequence. Homology-based annotation allowed us to identify 17,387 orthologs of human protein-coding genes in the M. fascicularis draft genome, and the predicted transcripts enabled the design of a M. fascicularis–specific gene expression microarray. Using liver samples from 36 individuals of different geographic origin we identified 718 genes with highly variable expression in liver, whereas the majority of the transcriptome shows relatively stable and comparable expression. Knowledge of the M. fascicularis draft genome is an important contribution to both the use of this animal in disease models and the safety assessment of drugs and their metabolites. In particular, this information allows high-resolution genotyping and microarray-based gene-expression profiling for animal stratification, thereby allowing the use of well-characterized animals for safety testing. Finally, the genome sequence presented here is a significant contribution to the global “3R” animal welfare initiative, which has the goal to reduce, refine, and replace animal experiments. PMID:21862625

  1. Genome-based analysis of the nonhuman primate Macaca fascicularis as a model for drug safety assessment.

    PubMed

    Ebeling, Martin; Küng, Erich; See, Angela; Broger, Clemens; Steiner, Guido; Berrera, Marco; Heckel, Tobias; Iniguez, Leonardo; Albert, Thomas; Schmucki, Roland; Biller, Hermann; Singer, Thomas; Certa, Ulrich

    2011-10-01

    The long-tailed macaque, also referred to as cynomolgus monkey (Macaca fascicularis), is one of the most important nonhuman primate animal models in basic and applied biomedical research. To improve the predictive power of primate experiments for humans, we determined the genome sequence of a Macaca fascicularis female of Mauritian origin using a whole-genome shotgun sequencing approach. We applied a template switch strategy that uses either the rhesus or the human genome to assemble sequence reads. The sixfold sequence coverage of the draft genome sequence enabled discovery of about 2.1 million potential single-nucleotide polymorphisms based on occurrence of a dimorphic nucleotide at a given position in the genome sequence. Homology-based annotation allowed us to identify 17,387 orthologs of human protein-coding genes in the M. fascicularis draft genome, and the predicted transcripts enabled the design of a M. fascicularis-specific gene expression microarray. Using liver samples from 36 individuals of different geographic origin we identified 718 genes with highly variable expression in liver, whereas the majority of the transcriptome shows relatively stable and comparable expression. Knowledge of the M. fascicularis draft genome is an important contribution to both the use of this animal in disease models and the safety assessment of drugs and their metabolites. In particular, this information allows high-resolution genotyping and microarray-based gene-expression profiling for animal stratification, thereby allowing the use of well-characterized animals for safety testing. Finally, the genome sequence presented here is a significant contribution to the global "3R" animal welfare initiative, which has the goal to reduce, refine, and replace animal experiments. PMID:21862625

  2. Atmospheric Ozone 1985. Assessment of our understanding of the processes controlling its present distribution and change, volume 3

    NASA Technical Reports Server (NTRS)

    1985-01-01

    Topics addressed include: assessment models; model predictions of ozone changes; ozone and temperature trends; trace gas effects on climate; kinetics and photchemical data base; spectroscopic data base (infrared to microwave); instrument intercomparisons and assessments; and monthly mean distribution of ozone and temperature.

  3. Drug Testing in Hair

    Microsoft Academic Search

    Pascal Kintz

    Given the limitations of self-reports on drug use, testing for drugs-of-abuse is important for most clinical and forensic\\u000a toxicological situations, both for assessing the reality of the intoxication and for evaluation of the level of drug impairment.\\u000a It is generally accepted that chemical testing of biological fluids is the most objective means of diagnosis of drug use.\\u000a The presence of

  4. PEGylation for drug delivery to ischemic myocardium: pharmacokinetics and cardiac distribution of poly(ethylene glycol)s in mice with normal and ischemic myocardium.

    PubMed

    Sun, GuiLan; Lin, Xiao; Hong, YanLong; Feng, Yi; Ruan, KeFeng; Xu, DeSheng

    2012-08-15

    PEGylation now plays an important role in drug delivery and is considered as the method of choice for improving the pharmacokinetics and stability of parenteral agents. However, its application in treating cardiac diseases is still limited. To guide the design of PEGylation for drug delivery to ischemic myocardium, the effects of the molecular weight of PEG and the myocardial ischemic conditions on PEG levels in plasma and myocardium were studied in this work following intravenous administration of fluorescein isothiocyanate-labeled 20- and 40-kDa mPEGs to mice with normal and ischemic myocardium. The results show that myocardial ischemia caused some consistent changes in pharmacokinetic parameters of mPEGs. Due to the enhanced permeability and retention (EPR) effect caused by ischemia, the distribution of 20- and 40-kDa mPEGs in ischemic hearts was approximately 1.47- and 1.92-fold higher than that in normal hearts, respectively. Under the same heart condition (either normal or ischemic), the cardiac AUC(0.5-24h)s of the two mPEGs were comparable, although their plasma AUCs differed by nearly 4-fold; however, a smoother cardiac level-time profile was achieved by 40-kDa mPEG. This study addressed the relative importance of the EPR effect of ischemic zones and the molecular size of PEG in cardiac drug delivery, which is believed to be helpful for macromolecular drug design. PMID:22525436

  5. A Critical Role for Immune System Response in Mediating Anti-influenza Drug Synergies Assessed by Mechanistic Modeling

    PubMed Central

    Li, Z; Zhou, H; Lu, Y; Colatsky, T

    2014-01-01

    Influenza virus infections represent a serious public health problem worldwide, due to the rapid emergence of drug resistance. One strategy to improve treatment efficacy is to combine drugs that act synergistically. Potentially useful drug combinations are typically identified through empirical testing using in vitro and animal models, but the complexity of the clinical situation warrants the use of more careful analysis and sophisticated approaches. To explore new approaches, we constructed a mechanistic model representing the interaction of antiviral drugs with the viral replication pathway and human immune responses. Simulation of combination therapy using oseltamivir and amantadine predicted significant therapeutic synergy only when immune response was included, in agreement with previous in vitro and in vivo studies using amantadine-resistant strains. Our model can be used to predict the optimal doses for combination therapy, and also raises questions about current drug evaluation methods that do not account for immune system interactions. PMID:25207611

  6. Sensitivity analysis of the tree distribution model PHENOFIT to climatic input characteristics: implications for climate impact assessment

    Microsoft Academic Search

    XA V IER M ORIN; I SABELLE

    2005-01-01

    Species distributions are already affected by climate change. Forecasting their long-term evolution requires models with thoroughly assessed validation. Our aim here is to demonstrate that the sensitivity of such models to climate input characteristics may complicate their validation and introduce uncertainties in their predictions. In this study, we conducted a sensitivity analysis of a process-based tree distribution model PHENOFIT to

  7. Design of the National Water-Quality Assessment Program; occurrence and distribution of water-quality conditions

    USGS Publications Warehouse

    Gilliom, Robert J.; Alley, William M.; Gurtz, Martin E.

    1995-01-01

    The National Water-Quality Assessment Program assesses the status of and trends in the quality of the Nation's ground- and surface-water resources. The occurrence and distribution assessment component characterizes broad-scale water-quality conditions in relation to major contaminant sources and background conditions in each study area. The surface-water design focuses on streams. The ground-water design focuses on major aquifers, with emphasis on recently recharged ground water associated with human activities.

  8. Laser diffraction estimation of particle size distribution of slightly water-soluble drugs coexisting with additives: application to solid dosage forms.

    PubMed

    Nishioka, Y; Ohsawa, T; Kobayashi, M; Noda, K

    1992-06-01

    A simple and quantitative evaluation method for particle size distribution (fx(r)) of slightly water-soluble drugs dispersed in an aqueous medium together with other water-insoluble additives was developed using a laser diffraction method. The particle size distribution function of the powder mixture, (f(r)), was assumed as f(r) = phi x.fx(r) + phi a.fa(r), where phi is the volume fraction of each component dispersed in a measurement medium and fa(r) is the distribution function of another water-insoluble additive "a". In order to calculate fx(r) from f(r), it is necessary to know the density of drug and additive in the measurement medium, d(x) and d(a), but this is difficult to determine since particles usually swell in the medium. Thus, a method was developed to use their relative value, delta a (= da/dx). As a practical application, oxolinic acids (OA) of three sizes (OA-S (about 2 microns), OA-M (about 7 microns) and OA-L (about 24 microns)) were used as model drugs. delta a values were determined for various additives using the mixture of OA-S and each additive. Then, using delta as, fx(r) of OA-M or OA-L in the mixture containing OA-M or OA-L and additives was calculated from the f(r) experimentally determined for the mixture. They agreed well with their original distributions. The method was applied to some dosage forms, and the results obtained had good correlation with those from turbidity, wet sieving or dissolution test. PMID:1394678

  9. Assessment of Uncertainty of Forest Road Hydrology Modeling with the Distributed Hydrology Soil Vegetation Model (DHSVM)

    NASA Astrophysics Data System (ADS)

    Surfleet, C. G.; Skaugset, A. E.; McDonnell, J.

    2007-12-01

    The effects of forest roads on catchment hydrology and sediment production continue to be the focus of concern for impacts to aquatic habitat. However, these processes are complex and difficult to measure at catchment scales. Consequently, the effects of forest roads on watershed hydrology are often studied using distributed hydrologic models. We examined a popular distributed hydrology model used in the Western USA, the Distributive Hydrology Soil Vegetation Model (DHSVM), to predict changes in peak flows, storm run-off volume, and interception of sub-surface flow from forest roads. We apply DHSVM to a 630 hectare watershed in the headwaters of Oak Creek in the McDonald/Dunn Research Forest, managed by the College of Forestry, Oregon State University. The Generalized Likelihood Uncertainty Estimation (GLUE) approach was used to determine the uncertainty of model output for 10,000 model structures. Estimates of road ditchflow and streamflow from the GLUE assessment of DHSVM were compared to observed road ditchflow and streamflow for 2003-2006. Generally DHSVM simulations provided a reasonable fit to the time series for Oak Creek streamflow. The fit of the time series data diminished with spatial scale and for road ditchflow locations. From the GLUE assessment the percentage of DHSVM model structures that exceeded a Nash/Sutcliffe Efficiency of 0.5 were 44% for Oak Creek streamflow but reduced to a range of 0-9% for road locations. The conceptual model for road interception used within DHSVM did not accurately predict road ditchflow throughout the catchment. Given the many uncertainties observed from DHSVM road ditchflow results we question whether cumulative effects analysis of road influences on peak flows and storm volumes with DHSVM is appropriate for catchments with highly variable hillslope responses, such as Oak Creek.

  10. Common Data Models and Efficient Reproducible Workflows for Distributed Ocean Model Skill Assessment

    NASA Astrophysics Data System (ADS)

    Signell, R. P.; Snowden, D. P.; Howlett, E.; Fernandes, F. A.

    2014-12-01

    Model skill assessment requires discovery, access, analysis, and visualization of information from both sensors and models, and traditionally has been possible only by a few experts. The US Integrated Ocean Observing System (US-IOOS) consists of 17 Federal Agencies and 11 Regional Associations that produce data from various sensors and numerical models; exactly the information required for model skill assessment. US-IOOS is seeking to develop documented skill assessment workflows that are standardized, efficient, and reproducible so that a much wider community can participate in the use and assessment of model results. Standardization requires common data models for observational and model data. US-IOOS relies on the CF Conventions for observations and structured grid data, and on the UGRID Conventions for unstructured (e.g. triangular) grid data. This allows applications to obtain only the data they require in a uniform and parsimonious way using web services: OPeNDAP for model output and OGC Sensor Observation Service (SOS) for observed data. Reproducibility is enabled with IPython Notebooks shared on GitHub (http://github.com/ioos). These capture the entire skill assessment workflow, including user input, search, access, analysis, and visualization, ensuring that workflows are self-documenting and reproducible by anyone, using free software. Python packages for common data models are Pyugrid and the British Met Office Iris package. Python packages required to run the workflows (pyugrid, pyoos, and the British Met Office Iris package) are also available on GitHub and on Binstar.org so that users can run scenarios using the free Anaconda Python distribution. Hosted services such as Wakari enable anyone to reproduce these workflows for free, without installing any software locally, using just their web browser. We are also experimenting with Wakari Enterprise, which allows multi-user access from a web browser to an IPython Server running where large quantities of model output reside, increasing the efficiency. The open development and distribution of these workflows, and the software on which they depend, is an educational resource for those new to the field and a center of focus where practitioners can contribute new software and ideas.

  11. Distributed temperature sensing (DTS) as an ecological assessment tool in stream environments

    NASA Astrophysics Data System (ADS)

    Hatch, C. E.; Tyler, S. W.; Boughton, D.; Belica, L.

    2009-12-01

    Temperature has long been used as an indicator of ecosystem health and suitability for aquatic species, particularly in sensitive areas crucial to the survival of declining important fish populations. Typically, temperature surveys are of long duration but very limited in spatial extent. In recent years, considerable attention has been paid to assessing the ecology, and particularly the thermal regimes, of remaining near-pristine headwater catchments. These studies hope to assess habitats for native species restoration and identify key stream reaches where reproduction takes place, as well as seasonal thermal refugia supporting species survival and local thermal heterogeneities in larger stream systems that allow migratory pathways to persist. Raman-spectra distributed temperature sensing (DTS) along fiber-optic cables provides a unique opportunity to measure continuous longitudinal stream temperatures for hundreds of meters, allowing researchers to assess groundwater inflows, thermal refugia, and temperature heterogeneities at an extremely detailed spatial scale. In this compilation of studies, we present data from three semi-arid catchments (Strawberry Creek in the Great Basin, Squaw Creek the Sierra Nevada, and Horse Creek in the coastal range of California) to investigate seasonal and diurnal thermal behavior, the feedback between hydrology, geology and ecosystem function, and most importantly, the identification and spatial variability of thermal refugia.

  12. Assessment of global reporting of adverse drug reactions for anti-malarials, including artemisinin-based combination therapy, to the WHO Programme for International Drug Monitoring

    PubMed Central

    2011-01-01

    Background In spite of enhanced control efforts, malaria remains a major public health problem causing close to a million deaths annually. With support from several donors, large amounts of artemisinin-based combination therapy (ACT) are being deployed in endemic countries raising safety concerns as little is known about the use of ACT in several of the settings where they are deployed. This project was undertaken to profile the provenance of the pharmacovigilance reporting of all anti-malarials, including ACT to the WHO adverse drug reaction (ADR) database (Vigibase™) over the past 40 years. Methods The WHO Programme for International Drug Monitoring, the Uppsala Monitoring Centre (UMC) provided anonymized extracts of Vigibase™ covering the period 1968-2008. All countries in the programme were clustered according to their malaria control phase and income status. The number of individual case safety reports (ICSRs) of anti-malarials was analyzed according to those clusters. Results From 1968 to 2008, 21,312 ICSRs suspecting anti-malarials were received from 64 countries. Low-income countries, that are also malaria-endemic (categorized as priority 1 countries) submitted only 1.2% of the ICSRs. Only 60 out of 21,312 ICSRs were related to ACT, 51 of which were coming from four sub-Saharan African countries. Although very few ICSRs involved artemisinin-based compounds, many of the adverse events reported were potentially serious. Conclusions This paper illustrates the low reporting of ADRs to anti-malarials in general and ACT in particular. Most reports were submitted by non-endemic and/or high-income countries. Given the current mix of large donor funding, the insufficient information on safety of these drugs, increasing availability of ACT and artemisinin-based monotherapies in public and private sector channels, associated potential for inappropriate use and finally a pipeline of more than 10 new novel anti-malarials in various stages of development, the presence of well functioning national pharmacovigilance systems is vital to ensure safe and responsible scale up of ACT deployment. Bringing together the competencies of national pharmacovigilance centres and various types of organizations in the NGO, academic and private sectors with global coordination to create short- and long-term solutions may help address the lag between rapidly growing ACT use and poor ADR reporting. PMID:21388536

  13. Assessing sites contaminated with unexploded ordnance: statistical modeling of ordnance spatial distribution.

    PubMed

    Macdonald, Jacqueline A; Small, Mitchell J

    2006-02-01

    More than 40,000 km2 of former military land in the United States are contaminated with unexploded ordnance (UXO). Cleanup costs are estimated to total as much as 140 billion dollars. The amount of contaminated acreage and total costs are likely to increase as the U.S. Department of Defense (DOD) follows through on recently announced plans to close an additional 22 domestic military bases. The U.S. Environmental Protection Agency(EPA) and DOD disagree on how these sites should be characterized to assess their risks and plan for cleanup. As a result, much potentially valuable land remains idle while remediation decisions are pending. One of the sources of disagreement is how the locations of UXO should be characterized, given that the exact spatial distribution of UXO is unknown in advance of cleanup. In this paper, we propose and test a new model to represent the spatial distribution of UXO. Unlike existing DOD models, the new model accounts for the tendency of UXO to cluster, presumably around targets at which soldiers aimed during training. We fit the cluster model to geographic data on UXO locations at two former military installations and show that it describes key characteristics of the data more accuratelythan the existing DOD model. We discuss how the choice of a UXO spatial distribution model could affect important decisions about cleaning up and reusing UXO-affected property. PMID:16509339

  14. Discussion on the influence of truncation of ground motion residual distribution on probabilistic seismic hazard assessment

    NASA Astrophysics Data System (ADS)

    Wu, Jian; Gao, Mengtan; Chen, Kun; Huang, Bei

    2011-09-01

    Recent studies on assessment of a very low annual probability of exceeding (APE) ground motions, 10-4 or less, have highlighted the importance of the upper bound of ground motions when very low probability results are acquired. The truncation level adopted in probabilistic seismic hazard analysis (PSHA) should be determined by an aleatory uncertainty model (i.e., distribution model) of ground motions and the possible maximum and minimum ground motion values of a specific earthquake. However, at the present time, it is impossible to establish the upper bound model for ground motions based on the source characteristics and/or ground motion propagation. McGuire suggested a truncation level be fixed at a number of ? = 6, or the distribution of residuals be truncated in such a manner that site intensity cannot be greater than the epicenter intensity. This study aims to find a reasonable and feasible truncation level to be used in PSHA when the physical mechanism is not available to find the extreme ground motion. A mathematical analysis of the influence of the truncation level on PSHA, case studies of sites in different seismotectonic settings, and a distribution analysis of ground motion residuals are conducted in this study. It is concluded that ? = 4 is the minimum acceptable value for engineering applications for APEs within 0.002 to 10-4, and for low APEs, such as 10-5 and 10-6, the value of ? should be no less than 5 in most regions of China.

  15. Efficacy and tolerability of the new antiepileptic drugs I: Treatment of new onset epilepsy Report of the Therapeutics and Technology Assessment Subcommittee and Quality Standards Subcommittee of the American Academy of Neurology and the American Epilepsy Society

    Microsoft Academic Search

    J. A. French; A. M. Kanner; J. Bautista; B. Abou-Khalil; T. Browne; C. L. Harden; W. H. Theodore; C. Bazil; J. Stern; S. C. Schachter; D. Bergen; D. Hirtz; G. D. Montouris; M. Nespeca; B. Gidal; W. J. Marks; W. R. Turk; J. H. Fischer; B. Bourgeois; A. Wilner; R. E. Faught; R. C. Sachdeo; A. Beydoun; T. A. Glauser

    2010-01-01

    Objective: To assess the evidence demonstrating efficacy, tolerability, and safety of seven new antiepileptic drugs (AEDs) (gabapentin, lamotrigine, topiramate, tiagabine, oxcarbazepine, levetiracetam, and zonisamide—reviewed in the order in which these agents received approval by the US Food and Drug Administration) in the treatment of children and adults with newly diagnosed partial and generalized epilepsies. Methods: A 23-member committee, including general

  16. Nutrients distribution and trophic status assessment in the northern Beibu Gulf, China

    NASA Astrophysics Data System (ADS)

    Lai, Junxiang; Jiang, Fajun; Ke, Ke; Xu, Mingben; Lei, Fu; Chen, Bo

    2014-09-01

    Using historical and 2010 field data, the distribution of nutrients in the northern Beibu Gulf of China is described. There was a decreasing trend in the concentration of nutrients from the north coast to offshore waters of the northern Beibu Gulf, reflecting the influence of inputs from land-based sources. High concentrations of dissolved inorganic nitrogen (DIN) and phosphate (PO4-P) occurred mainly at Fangchenggang Bay, Qinzhou Bay, and Lianzhou Bay. Four different methods were used to assess eutrophication. The trophic status of the Beibu Gulf was characterized using the single factor, Eutrophication index (EI), Trophic index (TRIX) and Assessment of Estuarine Trophic Status (ASSETS) methods. Based on nutrient concentrations, 73.9% of DIN and 26.7% of PO4-P samples exceeded the fourth grade Seawater Quality Standard of China. Eutrophication index values varied widely, but higher levels of eutrophication were generally found in bays and estuaries. TRIX values ranged from 2.61 to 7.27, with an average of 4.98, indicating a mesotrophic and moderately productive system. A positive correlation between TRIX and harmful algal species richness and abundance was observed. The ASSETS model evaluates eutrophication status based on a Pressure-State-Response approach, including three main indices: influencing factors, overall eutrophic condition, and future outlook. The Beibu Gulf was graded as moderate using ASSETS. The single factor and Chinese nutrient index methods were considered inadequate for the assessment of trophic status. TRIX can be used as an indicator of trophic state and ASSETS showed good potential to assess eutrophication. The results of TRIX and ASSETS depend on threshold values. To establish these values, further research is required within the northern Beibu Gulf.

  17. Assessing the structural conservation of protein pockets to study functional and allosteric sites: implications for drug discovery

    Microsoft Academic Search

    Alejandro Panjkovich; Xavier Daura

    2010-01-01

    BACKGROUND: With the classical, active-site oriented drug-development approach reaching its limits, protein ligand-binding sites in general and allosteric sites in particular are increasingly attracting the interest of medicinal chemists in the search for new types of targets and strategies to drug development. Given that allostery represents one of the most common and powerful means to regulate protein function, the traditional

  18. In vitro assessment of drug delivery through an endotracheal tube using a dry powder inhaler delivery system.

    PubMed Central

    Everard, M. L.; Devadason, S. G.; Le Souëf, P. N.

    1996-01-01

    BACKGROUND: Jet nubulisers and metered dose inhalers are widely used to deliver aerosolised drugs to the lungs of intubated patients in adult intensive care units. Drug delivery using these systems has been shown to be inefficient and both forms of delivery have the potential to induce paradoxical bronchoconstriction in patients with reactive airways disease. METHODS: Experiments were carried out to determine whether it was possible to deliver drug from a dry powder delivery system through an endotracheal tube. A 200 micrograms budesonide Turbohaler was enclosed in a chamber which allowed it to be inserted into a ventilator circuit. Experiments were performed with a multistage liquid impinger in which drug was drawn through the Turbohaler and endotracheal tube at 60 l/min providing an index of the maximum drug delivery achievable via this route. A second series of experiments was performed in which the Turbohaler was placed in a ventilator circuit using a Servo 900C volume cycled ventilator. Drug delivered from the Turbohaler during the inspiratory phase was collected on a filter placed between the end of a 9 mm endotracheal tube and a model lung. A tidal volume of 500 ml and inspiratory time of 0.5 seconds was used. Budesonide was assayed using an ultraviolet spectrophotometric assay. RESULTS: Thirty percent of the nominal dose passed through the endotracheal tube and was collected in the multistage liquid impinger. Mean drug delivery to the filter in the ventilator circuit was 20%. CONCLUSIONS: This in vitro study indicates that drugs from dry powder inhalers (in this case the Turbohaler) can be satisfactorily delivered through endotracheal tubes and that clinical evaluation of this technique is now indicated. Images PMID:8658374

  19. Impedance-based cell culture platform to assess light-induced stress changes with antagonist drugs using retinal cells.

    PubMed

    Bennet, Devasier; Kim, Sanghyo

    2013-05-21

    This Article describes an unprecedented, simple, and real-time in vitro analytical tool to measure the luminous effect on the time responses function of retinal ganglion cells (RGC-5) by electric cell substrate impedance sensing (ECIS) system. The ECIS system was used for the continuous measurement of different color light-induced effects on the response of cells that exposed to protective drugs. The measurement suggests that the association of photo-oxidative stress was mediated by reactive oxygen species (ROS), which plays a critical role that leads to cell stress, damages, and retinopathy, resulting in eye degenerative diseases. Continuous light radiation caused time-dependent decline of RGC-5 response and resulted in photodamage within 10 h due to adenosine 5'-triphosphate depletion and increased ROS level, which is similar to in vivo photodamage. The ECIS results were correlated with standard cell viability assay. ECIS is very helpful to determine the protective effects of analyzed drugs such as ?-carotene, quercetin, agmatine, and glutathione in RGC-5 cells, and the maximum drug activity of nontoxic safer drug concentrations was found to be 0.25, 0.25, 0.25, and 1.0 mM, respectively. All drugs show protection against light radiation toxicity in a dose-dependent manner; the most effective drug was found to be glutathione. The proposed system identifies the phototoxic effects in RGC-5 and provides high throughput drug screening for photo-oxidative stress during early stages of drug discovery. This study is convenient and potential enough for the direct measurements of the photoprotective effect in vitro and would be of broad interest in the field of therapeutics. PMID:23596983

  20. Uncertainty assessment of spatially distributed nitrate reduction potential in groundwater using multiple geological realizations

    NASA Astrophysics Data System (ADS)

    Hansen, A. L.; Gunderman, D.; He, X.; Refsgaard, J. C.

    2014-11-01

    Spatially distributed nitrate reduction potential in groundwater was estimated for the clay till dominated Norsminde fjord catchment in Denmark using the distributed hydrological model MIKE SHE. The nitrate transport was simulated using particle tracking and nitrate was assumed to be instantaneously reduced at the redox interface. Spatially distributed depths of the redox interface were estimated based on the spatial patterns in groundwater recharge and sediment redox capacity. Uncertainty of the estimated nitrate reduction due to geological uncertainty was assessed using multiple geological realizations. The geological realizations were generated using the geostatistical software TProGS and either conditioned based on borehole data only or soft conditioned based on both borehole data and geophysical data. Finally an upscaling of the predicted nitrate reduction was done in order to evaluate the change in uncertainty with increasing scale. The study showed that the uncertainty (one standard deviation) of the estimated nitrate reduction potential (in percentage of nitrate input) on the original 100 m model scale was 25% if only using borehole data and 19% if combining the borehole data with geophysical data. The uncertainty on the model predictions decreased with increasing aggregation scale. The decrease in uncertainty was most apparent the first 500 m, where after the uncertainty started to level off. This scale corresponded well to the mean length of the sand units within the clay till. It is concluded that using geophysical data in combination with borehole data in generation of geological realizations can help decrease uncertainty on the estimated nitrate reduction and that the predictive capability of distributed models is constrained by the spatial resolution of key data such as geology.

  1. Assessment of Thiopurine–based drugs according to Thiopurine S-methyltransferase genotype in patients with Acute Lymphoblastic Leukemia

    PubMed Central

    Azimi, F; Jafariyan, M; Khatami, S; Mortazavi, Y; Azad, M

    2014-01-01

    For the past half century, thiopurines have earned themselves a reputation as effective anti-cancer and immunosuppressive drugs. Thiopurine S-methyltransferase (TPMT) is involved in the metabolism of all thiopurines and is one of the main enzymes that inactivates mercaptopurine. 6-MP is now used as a combination therapies for maintenance therapy of children with acute lymphocytic leukemia (ALL). In all patients receiving mercaptopurine, there is a risk of bone marrow suppression. TPMT activity is inherited as a monogenic, co-dominant trait. More than 25 variants are known. Genetic testing is available for several TPMT variant alleles. Most commonly TPMT*2, *3A, and *3C are tested for, which account for >90% of inactivating alleles. Differences in DNA that alter the expression or function of proteins that are targeted by drugs can contribute significantly to variation in the responses of individuals.Genotyping may become part of routine investigations to help clinicians tailor drug treatment effectively. This success is mainly due to the development of combination therapies and stratification of patients according to risk of treatment failure and relapse, rather than the discovery of new drugs. The aim of this study was to investigate the effect of genotype or methyltransferase enzyme activity before starting therapy in children with ALL. This can prevent the side effect of thiopurine drugs. In fact, the common polymorphism of this enzyme in population could be a prognostic factor in relation to drug use and treatment of patients with ALL. PMID:24734162

  2. In Vitro Determination of Drug Transfer from Drug-Coated Balloons

    PubMed Central

    Seidlitz, Anne; Kotzan, Nadine; Nagel, Stefan; Reske, Thomas; Grabow, Niels; Harder, Claus; Petersen, Svea; Sternberg, Katrin; Weitschies, Werner

    2013-01-01

    Drug-coated balloons are medical devices designed to locally deliver drug to diseased segments of the vessel wall. For these dosage forms, drug transfer to the vessel wall needs to be examined in detail, since drug released into the blood is cleared from the site. In order to examine drug transfer, a new in vitro setup was developed combining the estimation of drug loss during advancement to the site of application in a model coronary artery pathway with a hydrogel compartment representing, as a very simplified model, the vessel wall. The transfer of fluorescent model substances as well as the drug paclitaxel from coated balloons to the simulated vessel wall was evaluated using this method. The model was suitable to quantify the fractions transferred to the hydrogel and also to qualitatively assess distribution patterns in the hydrogel film. In the case of fluorescein sodium, rhodamin b and paclitaxel, vast amounts of the coated substance were lost during the simulated passage and only very small fractions of about 1% of the total load were transferred to the gel. This must be attributed to good water solubility of the fluorescent substances and the mechanical instability of the paclitaxel coating. Transfer of the hydrophobic model substance triamterene was however nearly unaffected by the preliminary tracking procedure with transferred fractions ranging from 8% to 14%. Analysis of model substance distribution yielded inhomogeneous distributions indicating that the coating was not evenly distributed on the balloon surface and that a great fraction of the coating liquid did not penetrate the folds of the balloon. This finding is contradictory to the generally accepted assumption of a drug depot inside the folds and emphasizes the necessity to thoroughly characterize in vitro performance of drug-coated balloons to support the very promising clinical data. PMID:24391863

  3. A Novel Method for the Investigation of Liquid\\/Liquid Distribution Coefficients and Interface Permeabilities Applied to the Water-Octanol-Drug System

    Microsoft Academic Search

    Paul C. Stein; Massimiliano di Cagno; Annette Bauer-Brandl

    Purpose  In this work a new, accurate and convenient technique for the measurement of distribution coefficients and membrane permeabilities\\u000a based on nuclear magnetic resonance (NMR) is described.\\u000a \\u000a \\u000a \\u000a \\u000a Methods  This method is a novel implementation of localized NMR spectroscopy and enables the simultaneous analysis of the drug content\\u000a in the octanol and in the water phase without separation. For validation of the method,

  4. Assessment of the aerosol distribution over Indian subcontinent in CMIP5 models

    NASA Astrophysics Data System (ADS)

    Sanap, S. D.; Ayantika, D. C.; Pandithurai, G.; Niranjan, K.

    2014-04-01

    This paper examines the aerosol distribution over Indian subcontinent as represented in 21 models from Coupled Model Inter-comparison Project Phase 5 (CMIP5) simulations, wherein model simulated aerosol optical depth (AOD) is compared with Moderate Resolution Imaging Spectro-radiometer (MODIS) satellite observations. The objective of the study is to provide an assessment of the capability of various global models, participating in CMIP5 project, in capturing the realistic spatial and temporal distribution of aerosol species over the Indian subcontinent. Results from our analysis show that majority of the CMIP5 models (excepting HADGEM2-ES, HADGEM2-CC) seriously underestimates the spatio-temporal variability of aerosol species over the Indian subcontinent, in particular over Indo-Gangetic Plains (IGP). Since IGP region is dominated by anthropogenic activities, high population density, and wind driven transport of dust and other aerosol species, MODIS observations reveal high AOD values over this region. Though the representation of black carbon (BC) loading in many models is fairly good, the dust loading is observed to be significantly low in majority of the models. The presence of pronounced dust activity over northern India and dust being one of the major constituent of aerosol species, the biases in dust loading has a great impact on the AOD of that region. We found that considerable biases in simulating the 850 hPa wind field (which plays important role in transport of dust from adjacent deserts) would be the possible reason for poor representation of dust AOD and in turn total AOD over Indian region in CMIP5 models. In addition, aerosol radiative forcing (ARF) underestimated/overestimated in most of the models. However, spatial distribution of ARF in multi-model ensemble mean is comparable reasonably well with observations with bias in magnitudes. This analysis emphasizes the fundamental need to improve the representation of aerosol species in current state of the art climate models. As reported in Intergovernmental Panel on Climate Change (IPCC) fourth assessment report (AR4), the level of scientific understanding (LOSU) of climatic impact of aerosols is medium-low. For better understanding of short and long term implications of changing concentrations of aerosol species on climate, it is imperative to have a realistic representation of aerosol distribution over regions with high aerosol loading.

  5. Assessment of the Aerosol Distribution Over Indian Subcontinent in CMIP5 Models

    NASA Astrophysics Data System (ADS)

    Sanap, S. D.; Pandithurai, G.

    2014-12-01

    This paper examines the aerosol distribution over Indian subcontinent as represented in 21 models from Coupled Model Inter-comparison Project Phase 5 (CMIP5) simulations, wherein model simulated aerosol optical depth (AOD) is compared with Moderate Resolution Imaging Spectro-radiometer (MODIS) satellite observations. The objective of the study is to provide an assessment of the capability of various global models, participating in CMIP5 project, in capturing the realistic spatial and temporal distribution of aerosol species over the Indian subcontinent. Results from our analysis show that majority of the CMIP5 models seriously underestimates the spatio-temporal variability of aerosol species over the Indian subcontinent, in particular over Indo-Gangetic Plains(IGP). Though the representation of black carbon (BC) loading in many models is fairly good, the dust loading is observed to be significantly low in majority of the models. The presence of pronounced dust activity over northern India and dust being one of the major constituent of aerosol species, the biases in dust loading has a great impact on the AOD of that region. We found that considerable biases in simulating the 850 hPa wind field (which plays important role in transport of dust from adjacent deserts) would be the possible reason for poor representation of dust AOD and in turn total AOD over Indian region in CMIP5 models. In addition, aerosol radiative forcing (ARF) underestimated/overestimated in most of the models. However, spatial distribution of ARF in multi-model ensemble mean is comparable reasonably well with observations with bias in magnitudes. This analysis emphasizes the fundamental need to improve the representation of aerosol species in current state of the art climate models. As reported in Intergovernmental Panel on Climate Change (IPCC) fourth assessment report (AR4), the level of scientific understanding (LOSU) of climatic impact of aerosols is medium-low. For better understanding of short and long term implications of changing concentrations of aerosol species on climate, it is imperative to have a realistic representation of aerosol distribution over regions with high aerosol loading.

  6. Distribution and assessment of marine debris in the deep Tyrrhenian Sea (NW Mediterranean Sea, Italy).

    PubMed

    Angiolillo, Michela; di Lorenzo, Bianca; Farcomeni, Alessio; Bo, Marzia; Bavestrello, Giorgio; Santangelo, Giovanni; Cau, Angelo; Mastascusa, Vincenza; Cau, Alessandro; Sacco, Flavio; Canese, Simonepietro

    2015-03-15

    Marine debris is a recognized global ecological concern. Little is known about the extent of the problem in the Mediterranean Sea regarding litter distribution and its influence on deep rocky habitats. A quantitative assessment of debris present in the deep seafloor (30-300 m depth) was carried out in 26 areas off the coast of three Italian regions in the Tyrrhenian Sea, using a Remotely Operated Vehicle (ROV). The dominant type of debris (89%) was represented by fishing gears, mainly lines, while plastic objects were recorded only occasionally. Abundant quantities of gears were found on rocky banks in Sicily and Campania (0.09-0.12 debris m(-2)), proving intense fishing activity. Fifty-four percent of the recorded debris directly impacted benthic organisms, primarily gorgonians, followed by black corals and sponges. This work provides a first insight on the impact of marine debris in Mediterranean deep ecosystems and a valuable baseline for future comparisons. PMID:25604749

  7. A study on social economic statistic data spatial distribution in land sustainable use assessment

    NASA Astrophysics Data System (ADS)

    Zhong, Kaiwen; Li, Jingliang; Zhang, Xiaodong

    2006-10-01

    A study on Spatialization of Social Economic Statistic Data has a high scientific value for the establishment of land sustainable use assessment model. After summarizing the existent methods of social economic statistic data spatialization and analyzing the GDP spatialization, the author proposes a new spatialization method for GDP. With remote sensing and GIS technique supported, such method is based on the land use types, integrated with spatial method of GDP data with area weightiness and counter-distance weighted method. Finally, based on the spatialization method for GDP mentioned above, the GDP data of Shaoguan city (Guangdong Province, China) was spatialized, and a good effect was obtained. The method presented in this paper can reflect the situation of economic distribution very well. This method of spatialization of social economic statistic data has an important practically meaning.

  8. Assessing the occurrence and distribution of pyrethroids in water and suspended sediments

    USGS Publications Warehouse

    Hladik, M.L.; Kuivila, K.M.

    2009-01-01

    The distribution of pyrethroid insecticides in the environment was assessed by separately measuring concentrations in the dissolved and suspended sediment phases of surface water samples. Filtered water was extracted by HLB solid-phase extraction cartridges, while the sediment on the filter was sonicated and cleaned up using carbon and aluminum cartridges. Detection limits for the 13 pyrethroids analyzed by gas chromatography-tandem mass spectrometry were 0.5 to 1 ng L-1 for water and 2 to 6 ng g for the suspended sediments. Seven pyrethroids were detected in six water samples collected from either urban or agricultural creeks, with bifenthrin detected the most frequently and at the highest concentrations. In spiked water samples and field samples, the majority of the pyrethroids were associated with the suspended sediments.

  9. Assessing T cell clonal size distribution: a non-parametric approach.

    PubMed

    Bolkhovskaya, Olesya V; Zorin, Daniil Yu; Ivanchenko, Mikhail V

    2014-01-01

    Clonal structure of the human peripheral T-cell repertoire is shaped by a number of homeostatic mechanisms, including antigen presentation, cytokine and cell regulation. Its accurate tuning leads to a remarkable ability to combat pathogens in all their variety, while systemic failures may lead to severe consequences like autoimmune diseases. Here we develop and make use of a non-parametric statistical approach to assess T cell clonal size distributions from recent next generation sequencing data. For 41 healthy individuals and a patient with ankylosing spondylitis, who undergone treatment, we invariably find power law scaling over several decades and for the first time calculate quantitatively meaningful values of decay exponent. It has proved to be much the same among healthy donors, significantly different for an autoimmune patient before the therapy, and converging towards a typical value afterwards. We discuss implications of the findings for theoretical understanding and mathematical modeling of adaptive immunity. PMID:25275470

  10. Assessment of herbicide transport and distribution in subsurface environments of an orange field.

    PubMed

    Wu, Lei; Ma, Xiao-Yi; Liu, Xia

    2014-08-01

    The demand for assessing both the variability of risk areas and the intensity of pollutant load rates on pesticide transferring to waters in China has been increasingly vigorous in recent decades. Therefore, to explore the transport of linuron with rainfall and irrigation in canopy-soil systems, an integrated pesticide transport modeling system has been selected and verified for simulating the three-phase linuron environmental fate in an orange field of the Three Gorges Reservoir (TGR) area. Results demonstrate that spatio-temporal distributions of linuron in surface soil primarily depend on its properties, rainfall, irrigation, and its applications; the peak levels of linuron in subsurface and deep soil are closely related to the cumulative and delayed effects. The findings may be used for policy supporting of soil-water-crop-pesticide management in an agricultural field of the TGR area. PMID:25306788

  11. Assessment of the aerosols distribution in the Bucharest metropolitan area in relation with health effects

    NASA Astrophysics Data System (ADS)

    Zoran, M. A.; Dida, M. R.

    2013-06-01

    MODIS Terra/Aqua time-series satellite images and in- situ monitoring of particle matter PM2.5 and PM10 have been used in an effort to qualitatively assess distribution of aerosols in the greater Bucharest area during 2010-2011 period. It was found that PM2.5 and PM10 aerosols exhibit their highest concentration mostly in the central part mainly due to road traffic as well as in the industrialized parts outside of city's centre. An epidemiological study examining the relationships between adverse health outcomes and exposure to air pollutants in metropolitan agglomeration of Bucharest used ambient air pollution measurements like as PM10 and PM2.5 levels as a proxy for personal exposure levels. The measurements of environmental concentrations of particulate matter air pollutants have been correlated with health effects on respiratory health status of school children in urban/periurban areas of Bucharest.

  12. Monitoring of national drug policies--regional comparison between Bulgaria, Romania, Macedonia, Bosnia Herzegovina.

    PubMed

    Petrova, G I

    2001-11-01

    After the profound economic and political changes most of the East European countries started market-oriented reforms. During the last 10 years rapid development of the private pharmaceutical sector and a slow privatisation process was observed. The balance between the private and public sector became very important for achieving NDP goals. The goal of this study is to evaluate the availability and development of the NDP structures in East European countries--Bulgaria (BG). Romania (Rom), Macedonia (Mac), Bosnia Herzegovina (BiH). For the assessment of the availability of NDP structures a questionnaire focused on seven main NDP components was used. These components are: legislation and regulations; essential drug selection and drug registration; drug allocation in the health budget/public sector financing policy; public sector procurement procedures; public sector distribution and logistics; price policy; information and continuing education on drug use. According to the survey the most developed NDP structures are drug legislation and regulations (incl. quality control), drug registration and drug distribution. We can assume that the people have access to different drugs of appropriate quality and in time. The systems for public drug financing, procurement and price policy are under developing or not efficient enough. The financial availability of drugs is difficult. There is a lack of objective drug information and postgraduate education is not oriented on the ED. It means that there is no guarantee for rational drug prescription and usage of drugs on the markets. PMID:11787250

  13. A theoretical and empirical investigation into the willingness-to-pay function for new innovative drugs by Germany's health technology assessment agency (IQWiG).

    PubMed

    Gandjour, Afschin

    2013-11-01

    Under the recently enacted pharmaceutical price and reimbursement regulation in Germany, new drugs are subject to a rapid assessment to determine whether there is sufficient evidence of added clinical benefits compared with the existing standard of treatment. If such added benefits are confirmed, manufacturers and representatives of the Statutory Health Insurance (SHI) are expected to negotiate an appropriate reimbursement price. If parties fail to reach an agreement, a final decision on the reimbursement price will be made by an arbitration body. If one of the parties involved wishes so, then the Institute for Quality and Efficiency in Health Care (Institut für Qualität und Wirtschaftlichkeit im Gesundheitswesen, IQWiG) will be commissioned with a formal evaluation of costs and benefits of the product in question. IQWiG will make a recommendation for a reimbursement price based on the 'efficiency frontier' in a therapeutic area. The purpose of the assessments is to provide support for decision-making bodies that act on behalf of the SHI insurants. To determine the willingness to pay for new drugs, IQWiG uses the following decision rule: the incremental cost-effectiveness ratio of a new drug compared with the next effective intervention should not be higher than that of the next effective intervention compared with its comparator. The purpose of this paper was to investigate the theoretical and empirical relationship between the willingness to pay for drugs and their health benefits. The analysis shows that across disease areas IQWiG has a curvilinear relationship between willingness to pay and health benefits. Future research may address the validity of the willingness-to-pay function from the viewpoint of the individual SHI insurants. PMID:25595007

  14. Drug-binding energetics of human ?-1-acid glycoprotein assessed by isothermal titration calorimetry and molecular docking simulations

    PubMed Central

    Huang, Johnny X.; Cooper, Matthew A.; Baker, Mark A.; Azad, Mohammad A.K.; Nation, Roger L.; Li, Jian; Velkov, Tony

    2012-01-01

    This study utilizes sensitive, modern isothermal titration calorimetric (ITC) methods to characterize the microscopic thermodynamic parameters that drive the binding of basic drugs to ?-1-acid glycoprotein (AGP) and thereby rationalize the thermodynamic data in relation to docking models and crystallographic structures of the drug-AGP complexes. The binding of basic compounds from the tricyclic antidepressant series, together with miaserine, chlorpromazine, disopyramide and cimetidine all displayed an exothermically driven binding interaction with AGP. The impact of protonation/deprotonation events, ionic strength, temperature and the individual selectivity of the A and F1*S AGP variants on drug-binding thermodynamics were characterized. A correlation plot of the thermodynamic parameters for all of the test compounds revealed enthalpy-entropy compensation is in effect. The exothermic binding energetics of the test compounds were driven by a combination of favorable (negative) enthalpic (?H°) and favorable (positive) entropic (?S°) contributions to the Gibbs free energy (?G°). Collectively, the data imply that the free energies that drive drug binding to AGP and its relationship to drug-serum residency evolve from the complex interplay of enthalpic and entropic forces from interactions with explicit combinations of hydrophobic and polar side-chain sub-domains within the multi-lobed AGP ligand binding cavity. PMID:23192962

  15. Distributed cable sensors with memory feature for post-disaster damage assessment

    NASA Astrophysics Data System (ADS)

    Chen, Genda; McDaniel, Ryan D.; Pommerenke, David J.; Sun, Shishuang

    2005-05-01

    A new design of distributed crack sensors is presented for the condition assessment of reinforced concrete (RC) structures during and immediately after an earthquake event. This study is mainly focused on the performance of cable sensors under dynamic loading, particularly their ability to memorize the crack history of an RC member. This unique memory feature enables the post-earthquake condition assessment of structural members such as RC columns, in which the earthquake-induced cracks are closed immediately after an earthquake event due to gravity loads and they are visually undetectable. Factors affecting the onset of the memory feature were investigated experimentally with small-scale RC beams under cyclic loading. Test results indicated that both crack width and the number of loading cycles were instrumental in the onset of the memory feature of cable sensors. Practical issues related to dynamic acquisition with the sensors were discussed. The sensors were proven to be fatigue resistant from the shake table tests of RC columns. They continued to show useful signal after the columns can no longer support additional loads.

  16. Optimal sampling theory and population modelling - Application to determination of the influence of the microgravity environment on drug distribution and elimination

    NASA Technical Reports Server (NTRS)

    Drusano, George L.

    1991-01-01

    The optimal sampling theory is evaluated in applications to studies related to the distribution and elimination of several drugs (including ceftazidime, piperacillin, and ciprofloxacin), using the SAMPLE module of the ADAPT II package of programs developed by D'Argenio and Schumitzky (1979, 1988) and comparing the pharmacokinetic parameter values with results obtained by traditional ten-sample design. The impact of the use of optimal sampling was demonstrated in conjunction with NONMEM (Sheiner et al., 1977) approach, in which the population is taken as the unit of analysis, allowing even fragmentary patient data sets to contribute to population parameter estimates. It is shown that this technique is applicable in both the single-dose and the multiple-dose environments. The ability to study real patients made it possible to show that there was a bimodal distribution in ciprofloxacin nonrenal clearance.

  17. ‘Oorja’ in India: Assessing a large-scale commercial distribution of advanced biomass stoves to households

    PubMed Central

    Thurber, Mark C.; Phadke, Himani; Nagavarapu, Sriniketh; Shrimali, Gireesh; Zerriffi, Hisham

    2015-01-01

    Replacing traditional stoves with advanced alternatives that burn more cleanly has the potential to ameliorate major health problems associated with indoor air pollution in developing countries. With a few exceptions, large government and charitable programs to distribute advanced stoves have not had the desired impact. Commercially-based distributions that seek cost recovery and even profits might plausibly do better, both because they encourage distributors to supply and promote products that people want and because they are based around properly-incentivized supply chains that could more be scalable, sustainable, and replicable. The sale in India of over 400,000 “Oorja” stoves to households from 2006 onwards represents the largest commercially-based distribution of a gasification-type advanced biomass stove. BP's Emerging Consumer Markets (ECM) division and then successor company First Energy sold this stove and the pelletized biomass fuel on which it operates. We assess the success of this effort and the role its commercial aspect played in outcomes using a survey of 998 households in areas of Maharashtra and Karnataka where the stove was sold as well as detailed interviews with BP and First Energy staff. Statistical models based on this data indicate that Oorja purchase rates were significantly influenced by the intensity of Oorja marketing in a region as well as by pre-existing stove mix among households. The highest rate of adoption came from LPG-using households for which Oorja's pelletized biomass fuel reduced costs. Smoke- and health-related messages from Oorja marketing did not significantly influence the purchase decision, although they did appear to affect household perceptions about smoke. By the time of our survey, only 9% of households that purchased Oorja were still using the stove, the result in large part of difficulties First Energy encountered in developing a viable supply chain around low-cost procurement of “agricultural waste” to make pellets. The business orientation of First Energy allowed the company to pivot rapidly to commercial customers when the household market encountered difficulties. The business background of managers also facilitated the initial marketing and distribution efforts that allowed the stove distribution to reach scale. PMID:25814822

  18. Survey and assessment of the effects of nonconventional gases on gas distribution equipment

    SciTech Connect

    Jasionowski, W.J.; Scott, M.I.; Gracey, W.C.

    1982-10-01

    A literature search and a survey of the gas industry were conducted to assess potential problems in the distribution of nonconventional gases. Available literature did not uncover data that would describe potential problems or substantiate the presence of harmful trace elements in final gas compositions produced from various SNG processes. Information from the survey indicates that some companies have encountered problems with nonconventional gases and extraneous additives such as landfill gas, refinery off-gases, oil gas, carbureted water gas, coke-oven gas, propane-air, and compressor lubricant oils. These nonconventional gases and compressor oils may 1) cause pipeline corrosion, 2) degrade some elastomeric materials and greases and affect the integrity of seals, gaskets, O-rings, and meter and regulator diaphragms, and 3) cause operational and safety problems. The survey indicated that 62% of the responding companies plan to use supplemental gas, with most planning on more than one type. Distribution companies intend to significantly increase their use of polyethylene piping from 11.6% in 1980 to 22.4% in 2000 for gas mains and from 33.4% to 50.3% in 2000 for gas service lines.

  19. Aromatic amine contents, component distributions and risk assessment in sludge from 10 textile-dyeing plants.

    PubMed

    Ning, Xun-An; Liang, Jie-Ying; Li, Rui-Jing; Hong, Zhen; Wang, Yu-Jie; Chang, Ken-Lin; Zhang, Ya-Ping; Yang, Zuo-Yi

    2015-09-01

    Aromatic amines (AAs), which are components of synthetic dyes, are recalcitrant to the wastewater treatment process and can accumulate in sludge produced by textile-dyeing, which may pose a threat to the environment. A comprehensive investigation of 10 textile-dyeing plants was undertaken in Guangdong Province in China. The contents and component distributions of AAs were evaluated in this study, and a risk assessment was performed. The total concentrations of 14 AAs (?14 AAs) varied from 11?gg(-1)dw to 82.5?gg(-1)dw, with a mean value of 25?gg(-1)dw. The component distributions of AAs were characterized by monocyclic anilines, of which 2-methoxy-5-methylaniline and 5-nitro-o-toluidine were the most dominant components. The risk quotient (RQ) value was used to numerically evaluate the ecological risk of 14 AAs in the environment. The result showed that the 14 AAs contents in textile-dyeing sludge may pose a high risk to the soil ecosystem after being discarded on soil or in a landfill. PMID:25973862

  20. An inexpensive active optical remote sensing instrument for assessing aerosol distributions.

    PubMed

    Barnes, John E; Sharma, Nimmi C P

    2012-02-01

    Air quality studies on a broad variety of topics from health impacts to source/sink analyses, require information on the distributions of atmospheric aerosols over both altitude and time. An inexpensive, simple to implement, ground-based optical remote sensing technique has been developed to assess aerosol distributions. The technique, called CLidar (Charge Coupled Device Camera Light Detection and Ranging), provides aerosol altitude profiles over time. In the CLidar technique a relatively low-power laser transmits light vertically into the atmosphere. The transmitted laser light scatters off of air molecules, clouds, and aerosols. The entire beam from ground to zenith is imaged using a CCD camera and wide-angle (100 degree) optics which are a few hundred meters from the laser. The CLidar technique is optimized for low altitude (boundary layer and lower troposphere) measurements where most aerosols are found and where many other profiling techniques face difficulties. Currently the technique is limited to nighttime measurements. Using the CLidar technique aerosols may be mapped over both altitude and time. The instrumentation required is portable and can easily be moved to locations of interest (e.g. downwind from factories or power plants, near highways). This paper describes the CLidar technique, implementation and data analysis and offers specifics for users wishing to apply the technique for aerosol profiles. PMID:22442935

  1. Distribution patterns of small-molecule ligands in the protein universe and implications for origin of life and drug discovery

    PubMed Central

    Ji, Hong-Fang; Kong, De-Xin; Shen, Liang; Chen, Ling-Ling; Ma, Bin-Guang; Zhang, Hong-Yu

    2007-01-01

    Background Extant life depends greatly on the binding of small molecules (such as ligands) with macromolecules (such as proteins), and one ligand can bind multiple proteins. However, little is known about the global patterns of ligand-protein mapping. Results By examining 2,186 well-defined small-molecule ligands and thousands of protein domains derived from a database of druggable binding sites, we show that a few ligands bind tens of protein domains or folds, whereas most ligands bind only one, which indicates that ligand-protein mapping follows a power law. Through assigning the protein-binding orders (early or late) for bio-ligands, we demonstrate that the preferential attachment principle still holds for the power-law relation between ligands and proteins. We also found that polar molecular surface area, H-bond acceptor counts, H-bond donor counts and partition coefficient are potential factors to discriminate ligands from ordinary molecules and to differentiate super ligands (shared by three or more folds) from others. Conclusion These findings have significant implications for evolution and drug discovery. First, the chronology of ligand-protein binding can be inferred by the power-law feature of ligand-protein mapping. Some nucleotide-containing ligands, such as ATP, ADP, GDP, NAD, FAD, dihydro-nicotinamide-adenine-dinucleotide phosphate (NDP), nicotinamide-adenine-dinucleotide phosphate (NAP), flavin mononucleotide (FMN) and AMP, are found to be the earliest cofactors bound to proteins, agreeing with the current understanding of evolutionary history. Second, the finding that about 30% of ligands are shared by two or more domains will help with drug discovery, such as in finding new functions from old drugs, developing promiscuous drugs and depending more on natural products. PMID:17727706

  2. Distribution of phthalates, pesticides and drug residues in the dissolved, particulate and sedimentary phases from transboundary rivers (France-Belgium).

    PubMed

    Net, Sopheak; Rabodonirina, Suzanah; Sghaier, Rafika Ben; Dumoulin, David; Chbib, Chaza; Tlili, Ines; Ouddane, Baghdad

    2015-07-15

    Various drug residues, pesticides and phthalates are ubiquitous in the environment. Their presence in the environment has attracted considerable attention due to their potential impacts on ecosystem functioning and on public health. In this work, 14 drug residues, 24 pesticides and 6 phthalates have been quantified in three matrices (in the dissolved phase, associated to suspended solid matter (SSM), and in sediment) collected from fifteen watercourses and rivers located in a highly industrialized zone at the cross-border area of Northern France and Belgium. The extractions have been carried out using accelerated solvent extraction (ASE) for solid matrices (SSM and sediment) and using solid phase extraction (SPE) for liquid matrix. The final extract was analyzed using GC-MS technique. Among the three classes of compounds, phthalates have been found at highest level compared to pesticides and drug residues. The ?6PAE concentrations were ranging from 17.2±2.58 to 179.1±26.9?gL(-1) in dissolved phase, from 2.9±0.4 to 21.1±3.2?gL(-1) in SSM and from 1.1±0.2 to 11.9±1.8?gg(-1)dw in sediment. The ?14drug residue concentrations were lower than 1.3?gL(-1) in the dissolved phases, lower than 30ngL(-1) associated to SSM and from nondetectable levels to 60.7±9.1ngg(-1)dw in sediment. For pesticides, all compounds were below the LOQ values in dissolved phase and in sediment, and only EPTC could be quantified in SSM. PMID:25829293

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

    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. Each level of hardware was evaluated and analyzed for possible failure modes and effects. Criticality was assigned based upon the severity of the effect for each failure mode. Of the 1671 failure modes analyzed, 9 single failures were determined to result in loss of crew or vehicle. Three single failures unique to intact abort were determined to result in possible loss of the crew or vehicle. A possible loss of mission could result if any of 136 single failures occurred. Six of the criticality 1/1 failures are in two rotary and two pushbutton switches that control External Tank and Solid Rocket Booster separation. The other 6 criticality 1/1 failures are fuses, one each per Aft Power Control Assembly (APCA) 4, 5, and 6 and one each per Forward Power Control Assembly (FPCA) 1, 2, and 3, that supply power to certain Main Propulsion System (MPS) valves and Forward Reaction Control System (RCS) circuits.

  4. Assessment of unsuspected exposure to drugs of abuse in children from a Mediterranean city by hair testing.

    PubMed

    Pichini, Simona; Garcia-Algar, Oscar; Alvarez, Airam; Gottardi, Massimo; Marchei, Emilia; Svaizer, Fiorenza; Pellegrini, Manuela; Rotolo, Maria Concetta; Pacifici, Roberta

    2014-02-01

    Hair testing was used to investigate the prevalence of unsuspected exposure to drugs of abuse in a group of children presenting to an urban paediatric emergency department without suggestive signs or symptoms. Hair samples were obtained from 114 children between 24 months and 10 years of age attending the emergency room of Hospital del Mar in Barcelona, Spain. Hair samples from the accompanying parent were also collected. The samples were analyzed for the presence of opiates, cocaine, amphetamines, and cannabinoids by ultra-performance liquid chromatography-tandem mass spectrometry. Parental sociodemographics and possible drug of abuse history were recorded. Hair samples from twenty-three children (20.1%) were positive for cocaine (concentration range 0.15-3.81 ng/mg hair), those of thirteen children (11.4%) to cannabinoids (D9-THC concentration range 0.05-0.54 ng/mg hair), with four samples positive to codeine (0.1-0.25 ng/mg hair), one positive for 2.09 ng methadone per mg hair and one to 6-MAM (0.42 ng/mg hair) and morphine (0. 15 ng/mg hair) . In 69.5 and 69.2% of the positive cocaine and cannabinoids cases respectively, drugs was also found in the hair of accompanying parent. Parental sociodemographics were not associated with children exposure to drugs of abuse. However, the behavioural patterns with potential harmful effects for the child's health (e.g., tobacco smoking, cannabis, benzodiazepines and/or antidepressants use) were significantly higher in the parents of exposed children. In the light of the obtained results (28% overall children exposure to drugs of abuse) and in agreement with 2009 unsuspected 23% cocaine exposure in pre-school children from the same hospital, we support general hair screening to disclose exposure to drugs of abuse in children from risky environments to provide the basis for specific social and health interventions. PMID:24566054

  5. Distribution, Detection of Enterotoxigenic Strains and Antimicrobial Drug Susceptibility Patterns of Bacteroides Fragilis Group in Diarrheic and Non-Diarrheic Feces from Brazilian Infants

    PubMed Central

    Ferreira, Débora Paula; Silva, Vânia Lúcia; Guimarães, Danielle Aparecida; Coelho, Cíntia Marques; Zauli, Danielle Alves Gomes; Farias, Luiz Macêdo; Carvalho, Maria Auxiliadora Roque; Diniz, Claudio Galuppo

    2010-01-01

    Despite the importance of gastrointestinal diseases and their global distribution, affecting millions of individuals around the world, the role and antimicrobial susceptibility patterns of anaerobic bacteria such as those in the Bacteroides fragilis group (BFG) are still unclear in young children. This study investigated the occurrence and distribution of species in the BFG and enterotoxigenic strains in the fecal microbiota of children and their antimicrobial susceptibility patterns. Diarrheic (n=110) and non-diarrheic (n=65) fecal samples from children aged 0–5 years old were evaluated. BFG strains were isolated and identified by conventional biochemical, physiological and molecular approaches. Alternatively, bacteria and enterotoxigenic strains were detected directly from feces by molecular biology. Antimicrobial drug susceptibility patterns were determined by the agar dilution method according to the guidelines for isolated bacteria. BFG was detected in 64.3% of the fecal samples (55% diarrheic and 80.4% non-diarrheic), and 4.6% were enterotoxigenic. Antimicrobial resistance was observed against ampicillin, ampicillin/sulbactam, piperacillin/tazobactam, meropenem, ceftriaxone, clindamycin and chloramphenicol. The data show that these bacteria are prevalent in fecal microbiota at higher levels in healthy children. The molecular methodology was more effective in identifying the B. fragilis group when compared to the biochemical and physiological techniques. The observation of high resistance levels stimulates thoughts about the indiscriminate use of antimicrobial drugs in early infancy. Further quantitative studies are needed to gain a better understanding of the role of these bacteria in acute diarrhea in children. PMID:24031535

  6. Time-dependent effects of transcription- and translation-halting drugs on the spatial distributions of the Escherichia coli chromosome and ribosomes.

    PubMed

    Bakshi, Somenath; Choi, Heejun; Mondal, Jagannath; Weisshaar, James C

    2014-11-01

    Previously observed effects of rifampicin and chloramphenicol indicate that transcription and translation activity strongly affect the coarse spatial organization of the bacterial cytoplasm. Single-cell, time-resolved, quantitative imaging of chromosome and ribosome spatial distributions and ribosome diffusion in live Escherichia coli provides insight into the underlying mechanisms. Monte Carlo simulations of model DNA-ribosome mixtures support a novel nucleoid-ribosome mixing hypothesis. In normal conditions, 70S-polysomes and the chromosomal DNA segregate, while 30S and 50S ribosomal subunits are able to penetrate the nucleoids. Growth conditions and drug treatments determine the partitioning of ribosomes into 70S-polysomes versus free 30S and 50S subunits. Entropic and excluded volume effects then dictate the resulting chromosome and ribosome spatial distributions. Direct observation of radial contraction of the nucleoids 0-5?min after treatment with either transcription- or translation-halting drugs supports the hypothesis that simultaneous transcription, translation, and insertion of proteins into the membrane ('transertion') exerts an expanding force on the chromosomal DNA. Breaking of the DNA-RNA polymerase-mRNA-ribosome-membrane chain in either of two ways causes similar nucleoid contraction on a similar timescale. We suggest that chromosomal expansion due to transertion enables co-transcriptional translation throughout the nucleoids. PMID:25250841

  7. Development, Implementation, and Cost-Assessment of an Integrated Computer-Assisted Instruction Course on Drug Interactions.

    ERIC Educational Resources Information Center

    Narducci, Warren A.

    1985-01-01

    A study of the feasibility of using integrated, computer-assisted instruction in a drug interaction course revealed that despite the high initial time and financial investment, the potential educational benefits and high student acceptance of the instruction supports its application in other curriculum areas. (MSE)

  8. Assessment of anti-inflammatory drugs in the rat using subcutaneous implants of polyurethane foam impregnated with dead tubercle bacilli.

    PubMed Central

    Clarke, A K; Vernon-Roberts, B; Currey, H L

    1975-01-01

    The fluid and cellular phases of inflammatory resonse have been measured using a technique employing subcutaneous implantation of polyurethane foam cubes impregnated with heat-killed Mycobacterium tuberculosis. Phenylbutazone, azathioprine, aspirin, cyclophosphamide, and prednisolone suppressed fluid response, whereas sodium aurothiomalate, hydroxychloroquine, and D-penicillamine had no effect. All the drugs used suppressed the infiltration of inflammatory cells into the cubes. Images PMID:811180

  9. Assessing the Validity of Self-Reports by Gang Members: Results from the Arrestee Drug Abuse Monitoring Program

    ERIC Educational Resources Information Center

    Webb, Vincent J.; Katz, Charles M.; Decker, Scott H.

    2006-01-01

    Scholars who study criminal and delinquent behavior rely on the self-report method for measuring crime and delinquency. Gang researchers also rely on the self-report method for determining gang involvement and measuring criminal and delinquent behavior of gang members. This study examines disclosure rates of recent drug use by gang members in…

  10. POLICY ON DRUG-FREE SCHOOLS AND DRUG-FREE WORKPLACE

    E-print Network

    Jackman, Todd

    , distribution, dispensation, sale, possession or use of any drug outside its workplace or off its campusPOLICY ON DRUG-FREE SCHOOLS AND DRUG-FREE WORKPLACE NOVEMBER 2012 #12;VILLANOVA UNIVERSITY POLICY ON DRUG-FREE SCHOOLS AND DRUG-FREE WORKPLACE STANDARDS OF CONDUCT: 1. Drugs The use of narcotics

  11. A quantitative reverse-transcriptase PCR assay for the assessment of drug activities against intracellular Theileria annulata schizonts

    PubMed Central

    Hostettler, Isabel; Müller, Joachim; Stephens, Chad E.; Haynes, Richard; Hemphill, Andrew

    2014-01-01

    Intracellular schizonts of the apicomplexans Theileria annulata and Theileria parva immortalize bovine leucocytes thereby causing fatal immunoproliferative diseases. Buparvaquone, a hydroxynaphthoquinone related to parvaquone, is the only drug available against Theileria. The drug is only effective at the onset of infection and emerging resistance underlines the need for identifying alternative compounds. Current drug assays employ monitoring of proliferation of infected cells, with apoptosis of the infected host cell as a read-out, but it is often unclear whether active compounds directly impair the viability of the parasite or primarily induce host cell death. We here report on the development of a quantitative reverse transcriptase real time PCR method based on two Theileria genes, tasp and tap104, which are both expressed in schizonts. Upon in vitro treatment of T. annulata infected bovine monocytes with buparvaquone, TaSP and Tap104 mRNA expression levels significantly decreased in relation to host cell actin already within 4 h of drug exposure, while significant differences in host cell proliferation were detectable only after 48–72 h. TEM revealed marked alterations of the schizont ultrastructure already after 2 h of buparvaquone treatment, while the host cell remained unaffected. Expression of TaSP and Tap104 proteins showed a marked decrease only after 24 h. Therefore, the analysis of expression levels of mRNA coding for TaSP and Tap104 allows to directly measuring impairment of parasite viability. We subsequently applied this method using a series of compounds affecting different targets in other apicomplexan parasites, and show that monitoring of TaSP- and Tap104 mRNA levels constitutes a suitable tool for anti-theilerial drug development. PMID:25516828

  12. A quantitative reverse-transcriptase PCR assay for the assessment of drug activities against intracellular Theileria annulata schizonts.

    PubMed

    Hostettler, Isabel; Müller, Joachim; Stephens, Chad E; Haynes, Richard; Hemphill, Andrew

    2014-12-01

    Intracellular schizonts of the apicomplexans Theileria annulata and Theileria parva immortalize bovine leucocytes thereby causing fatal immunoproliferative diseases. Buparvaquone, a hydroxynaphthoquinone related to parvaquone, is the only drug available against Theileria. The drug is only effective at the onset of infection and emerging resistance underlines the need for identifying alternative compounds. Current drug assays employ monitoring of proliferation of infected cells, with apoptosis of the infected host cell as a read-out, but it is often unclear whether active compounds directly impair the viability of the parasite or primarily induce host cell death. We here report on the development of a quantitative reverse transcriptase real time PCR method based on two Theileria genes, tasp and tap104, which are both expressed in schizonts. Upon in vitro treatment of T. annulata infected bovine monocytes with buparvaquone, TaSP and Tap104 mRNA expression levels significantly decreased in relation to host cell actin already within 4 h of drug exposure, while significant differences in host cell proliferation were detectable only after 48-72 h. TEM revealed marked alterations of the schizont ultrastructure already after 2 h of buparvaquone treatment, while the host cell remained unaffected. Expression of TaSP and Tap104 proteins showed a marked decrease only after 24 h. Therefore, the analysis of expression levels of mRNA coding for TaSP and Tap104 allows to directly measuring impairment of parasite viability. We subsequently applied this method using a series of compounds affecting different targets in other apicomplexan parasites, and show that monitoring of TaSP- and Tap104 mRNA levels constitutes a suitable tool for anti-theilerial drug development. PMID:25516828

  13. Drug Safety

    MedlinePLUS

    ... over-the-counter drug. The FDA evaluates the safety of a drug by looking at Side effects ... clinical trials The FDA also monitors a drug's safety after approval. For you, drug safety means buying ...

  14. Drug allergies

    MedlinePLUS

    Allergic reaction - drug (medication); Drug hypersensitivity; Medication hypersensitivity ... Adverse reactions to drugs are common. (adverse means unwanted or unexpected.) Almost any drug can cause an adverse reaction. Reactions range from irritating ...

  15. High Throughput Measurement of Ca2+ Dynamics for Drug Risk Assessment in Human Stem Cell-derived Cardiomyocytes by Kinetic Image Cytometry

    PubMed Central

    Cerignoli, Fabio; Charlot, David; Whittaker, Ross; Ingermanson, Randy; Gehalot, Piyush; Savtchenko, Alex; Gallacher, David J.; Towart, Rob; Price, Jeffrey H.; McDonough, Patrick M.; Mercola, Mark

    2013-01-01

    Current methods to measure physiological properties of cardiomyocytes and predict fatal arrhythmias that can cause sudden death, such as Torsade de Pointes, lack either the automation and throughput needed for early-stage drug discovery and/or have poor predictive value. To increase throughput and predictive power of in vitro assays, we developed kinetic imaging cytometry (KIC) for automated cell-by-cell analyses via intracellular fluorescence Ca2+ indicators. The KIC instrument simultaneously records and analyzes intracellular calcium concentration [Ca2+]i at 30-ms resolution from hundreds of individual cells/well of 96-well plates in seconds, providing kinetic details not previously possible with well averaging technologies such as plate readers. Analyses of human embryonic stem cell and induced pluripotent stem cell-derived cardiomyocytes revealed effects of known cardiotoxic and arrhythmogenic drugs on kinetic parameters of Ca2+ dynamics, suggesting that KIC will aid in the assessment of cardiotoxic risk and in the elucidation of pathogenic mechanisms of heart disease associated with drugs treatment and/or genetic background. PMID:22926323

  16. Polar organic chemical integrative sampling and liquid chromatography- electrospray/ion-trap mass spectrometry for assessing selected prescription and illicit drugs in treated sewage effluents

    USGS Publications Warehouse

    Jones-Lepp, T. L.; Alvarez, D.A.; Petty, J.D.; Huckins, J.N.

    2004-01-01

    The purpose of the research presented in this paper was twofold: (1) to demonstrate the coupling of two state-of-the-art techniques: a time-weighted polar organic chemical integrative sampler (POCIS) and microliquid chromatography-electrospray/ion-trap mass spectrometry and (2) to assess the ability of these methodologies to detect six drugs (azithromycin, fluoxetine, omeprazole, levothyroxine, methamphetamine, methylenedioxymethamphetamine [MDMA]) in a real-world environment, e.g., waste water effluent. In the effluent from three wastewater treatment plants (WWTPs), azithromycin was detected at concentrations ranging from 15 to 66 ng/L, which is equivalent to a total annual release of 1 to 4 kg into receiving waters. Detected and confirmed in the effluent from two WWTPs were two illicit drugs, methamphetamine and MDMA, at 2 and 0.5 ng/L, respectively. Although the ecotoxicologic significance of drugs in environmental matrices, particularly water, has not been closely examined, it can only be surmised that these substances have the potential to adversely affect biota that are continuously exposed to them even at very low levels. The potential for chronic effects on human health is also unknown but of increasing concern because of the multi-use character of water, particularly in densely populated, arid areas.

  17. Toxicity assessment of molecularly targeted drugs incorporated into multiagent chemotherapy regimens for pediatric acute lymphocytic leukemia (ALL): review from an international consensus conference.

    PubMed

    Horton, Terzah M; Sposto, Richard; Brown, Patrick; Reynolds, C Patrick; Hunger, Stephen P; Winick, Naomi J; Raetz, Elizabeth A; Carroll, William L; Arceci, Robert J; Borowitz, Michael J; Gaynon, Paul S; Gore, Lia; Jeha, Sima; Maurer, Barry J; Siegel, Stuart E; Biondi, Andrea; Kearns, Pamela R; Narendran, Aru; Silverman, Lewis B; Smith, Malcolm A; Zwaan, C Michel; Whitlock, James A

    2010-07-01

    One of the challenges of incorporating molecularly targeted drugs into multi-agent chemotherapy (backbone) regimens is defining dose-limiting toxicities (DLTs) of the targeted agent against the background of toxicities of the backbone regimen. An international panel of 22 pediatric acute lymphocytic leukemia (ALL) experts addressed this issue (www.ALLNA.org). Two major questions surrounding DLT assessment were explored: (1) how toxicities can be best defined, assessed, and attributed; and (2) how effective dosing of new agents incorporated into multi-agent ALL clinical trials can be safely established in the face of disease- and therapy-related systemic toxicities. The consensus DLT definition incorporates tolerance of resolving Grade 3 and some resolving Grade 4 toxicities with stringent safety monitoring. This functional DLT definition is being tested in two Children's Oncology Group (COG) ALL clinical trials. PMID:20127846

  18. Toxicity Assessment of Molecularly Targeted Drugs Incorporated into Multiagent Chemotherapy Regimens for Pediatric Acute Lymphocytic Leukemia (ALL): Review from an International Consensus Conference

    PubMed Central

    Horton, Terzah M.; Sposto, Richard; Brown, Patrick; Reynolds, C. Patrick; Hunger, Stephen P.; Winick, Naomi J.; Raetz, Elizabeth A.; Carroll, William L.; Arceci, Robert J.; Borowitz, Michael J.; Gaynon, Paul S.; Gore, Lia; Jeha, Sima; Maurer, Barry J.; Siegel, Stuart E.; Biondi, Andrea; Kearns, Pamela R.; Narendran, Aru; Silverman, Lewis B.; Smith, Malcolm A.; Zwaan, C. Michel; Whitlock, James A.

    2009-01-01

    One of the challenges of incorporating molecularly targeted drugs into multi-agent chemotherapy (backbone) regimens is defining dose limiting toxicities (DLTs) of the targeted agent against the background of toxicities of the backbone regimen. An international panel of 22 pediatric acute lymphocytic leukemia (ALL) experts addressed this issue (www.ALLNA.org). Two major questions surrounding DLT assessment were explored: 1) how toxicities can be best defined, assessed, and attributed; and 2) how effective dosing of new agents incorporated into multi-agent ALL clinical trials can be safely established in the face of disease- and therapy-related systemic toxicities. The consensus DLT definition incorporates tolerance of resolving Grade 3 and some resolving Grade 4 toxicities with stringent safety monitoring. This functional DLT definition is being tested in two Children’s Oncology Group (COG) ALL clinical trials. PMID:20127846

  19. [Distribution of metals in urban dusts of Hefei and health risk assessment].

    PubMed

    Li, Ru-Zhong; Zhou, Ai-Jia; Tong, Fang; Wu, Ya-Dong; Zhang, Ping; Yu, Jia

    2011-09-01

    This study focused on the characterization and the health risk assessment of heavy metals in the dust of Hefei City, China. Samples were collected from fifty two sampling points covering six land-use types. Most of the sites were impervious ground such as residential, commercial, industrial, educational and traffic areas, as well as public landscapes and city squares. Concentrations of Zn, Pb, Cu, Cd and Cr were measured to investigate their distribution and evaluate their risk to human health. The US EPA Health Risk Assessment Model was employed to evaluate the carcinogenic and non-carcinogenic risks of heavy metals to child and adult, respectively. The results showed that concentrations of Cd and Zn were 46 and 37 times higher than soil background values, respectively. The concentrations of Cu and Pb were 3-5 times, and Cr concentration was 1.5 times higher than the soil background values of Anhui Province. The carcinogenic risk indexes of Cr and Cd were 3.22 x 10(-7) and 2.26 x 10(-9), respectively, which were lower than the soil management standard of the US EPA, i.e. 1.0 x 10(-6). The total non-carcinogenic hazard index of the five metals for adults was only 0.212, but for children it reached to 1.259 and exceeded the safety threshold value (1.0), suggesting that the adverse health impact on children exposure to metals in urban dusts were relatively serious in Hefei. The ingestion of dust particles was the major exposure pathway for health risk. The orders of non-carcinogenic hazard indexes of land-use types and heavy metals were industrial area > public landscapes and city squares > commercial area > educational area > residential area > traffic area, and Pb > Cr > Zn > Cd > Cu, respectively. PMID:22165236

  20. Radionuclide adsorption distribution coefficients measured in Hanford sediments for the low level waste performance assessment project

    SciTech Connect

    Kaplan, D.I.; Serne, R.J.; Owen, A.T. [and others

    1996-08-01

    Preliminary modeling efforts for the Hanford Site`s Low Level Waste-Performance Assessment (LLW PA) identified {sup 129}I, {sup 237}Np, {sup 79}Se, {sup 99}Tc, and {sup 234},{sup 235},{sup 238}U as posing the greatest potential health hazard. It was also determined that the outcome of these simulations was very sensitive to the parameter describing the extent to which radionuclides sorb to the subsurface matrix, i.e., the distribution coefficient (K{sub d}). The distribution coefficient is a ratio of the radionuclide concentration associated with the solid phase to that in the liquid phase. The objectives of this study were to (1) measure iodine, neptunium, technetium, and uranium K{sub d} values using laboratory conditions similar to those expected at the LLW PA disposal site, and (2) evaluate the effect of selected environmental parameters, such as pH, ionic strength, moisture concentration, and radio nuclide concentration, on K{sub d} values of selected radionuclides. It is the intent of these studies to develop technically defensible K{sub d} values for the PA. The approach taken throughout these studies was to measure the key radio nuclide K{sub d} values as a function of several environmental parameters likely to affect their values. Such an approach provides technical defensibility by identifying the mechanisms responsible for trends in K{sub d} values. Additionally, such studies provide valuable guidance regarding the range of K{sub d} values likely to be encountered in the proposed disposal site.

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

    SciTech Connect

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

    2002-01-01

    This report outlines an approach to assess the local potential for deployment of distributed energy resources (DER), small power-generation installations located close to the point where the energy they produce will be consumed. Although local restraints, such as zoning, building codes, and on-site physical barriers are well-known frustrations to DER deployment, no analysis method has been developed to address them within a broad economic analysis framework. The approach developed here combines established economic optimization techniques embedded in the Distributed Energy Resource Customer Adoption Model (DER-CAM) with a geographic information system (GIS) analysis of local land-use constraint. An example case in the San Diego area is developed from a strictly customer perspective, based on the premise that future development of DER may take the form of microgrids ((mu)Grids) under the control of current utility customers. Beginning with assumptions about which customer combinations h ave complementary energy loads, a GIS was used to locate specific neighborhoods in the San Diego area with promising customer combinations. A detailed energy analysis was conducted for the commercial/residential area chosen covering both electrical and heat energy requirements. Under various scenarios, different combinations of natural gas reciprocating engines were chosen by DER-CAM, ranging in size from 25 kW to 500 kW, often with heat recovery or absorption cooling. These generators typically operate throughout the day and are supplemented by purchased electricity during late-night and early-morning hours, when utility time-of-use prices are lowest. Typical (mu)Grid scenarios displaced about 80 percent of their annual gas heat load through CHP. Self-generation together with absorption cooling dramatically reduce electricity purchases, which usually only occur during nighttime hours.

  2. Preliminary assessment of the interaction of introduced biological agents with biofilms in water distribution systems.

    SciTech Connect

    Sinclair, Michael B.; Caldwell, Sara; Jones, Howland D. T.; Altman, Susan Jeanne; Souza, Caroline Ann; McGrath, Lucas K.

    2005-12-01

    Basic research is needed to better understand the potential risk of dangerous biological agents that are unintentionally or intentionally introduced into a water distribution system. We report on our capabilities to conduct such studies and our preliminary investigations. In 2004, the Biofilms Laboratory was initiated for the purpose of conducting applied research related to biofilms with a focus on application, application testing and system-scale research. Capabilities within the laboratory are the ability to grow biofilms formed from known bacteria or biofilms from drinking water. Biofilms can be grown quickly in drip-flow reactors or under conditions more analogous to drinking-water distribution systems in annular reactors. Biofilms can be assessed through standard microbiological techniques (i .e, aerobic plate counts) or with various visualization techniques including epifluorescent and confocal laser scanning microscopy and confocal fluorescence hyperspectral imaging with multivariate analysis. We have demonstrated the ability to grow reproducible Pseudomonas fluorescens biofilms in the annular reactor with plate counts on the order of 10{sup 5} and 10{sup 6} CFU/cm{sup 2}. Stationary phase growth is typically reached 5 to 10 days after inoculation. We have also conducted a series of pathogen-introduction experiments, where we have observed that both polystyrene microspheres and Bacillus cereus (as a surrogate for B. anthracis) stay incorporated in the biofilms for the duration of our experiments, which lasted as long as 36 days. These results indicated that biofilms may act as a safe harbor for bio-pathogens in drinking water systems, making it difficult to decontaminate the systems.

  3. Volcanic Hazard Assessment Through Analysis of Physical Characteristics and Distribution of Volcanic Projectiles

    NASA Astrophysics Data System (ADS)

    Alatorre-Ibarguengoitia, M. A.; Kueppers, U.; Delgado-Granados, H.; Dingwell, D. B.

    2006-12-01

    Dealing with hazards at active volcanoes requires detailed knowledge of eruptive history and a good understanding of pre- and syn-eruptive processes. Despite improvement in monitoring systems, such an understanding cannot be based on direct field observations alone. Experimental and theoretical modelling are two essential components of modern volcanic hazard analysis. Volcanic ballistic projectiles (VBP) are a major hazard related to volcanic explosions. They may affect people, ecology, infrastructure and aircraft. In order to determine the potential areas for VBP fall, it is needed to estimate maximum ranges under different explosive scenarios. Each scenario is defined by the kinetic energy calculated from the impact location and its dimension and the physical characteristics of the projectiles (e.g. density, drag coefficient). The kinetic energy derives from the excess pressure in the expanding volatile phase driving the explosion. The design and development of "fragmentation bomb" technology has provided volcanology with the capability of controlled and systematic analysis of the fragmentation behavior of magma upon rapid decompression. Study of samples from several volcanoes has demonstrated a close relationship between open porosity and overpressure required for complete fragmentation of samples (fragmentation threshold). Analysis of the experimentally generated pyroclasts by fractal analysis shows that grain-size distribution is linearly dependent on open porosity and PEF (potential energy for fragmentation). Combination of these two approaches (kinetic energy from the distribution of VBP and potential energy (PEF) from scaled experiments and investigation of experimental and natural pyroclasts), taken together with seismic monitoring provides the potential for a significantly more refined hazard assessment of active, explosive volcanoes.

  4. The application of a computerized measurement of the content analysis of natural language to the assessment of the effects of psychoactive drugs.

    PubMed

    Gottschalk, L A

    1999-03-01

    This article aims to answer the question whether developing technology is now capable of measuring objectively and accurately the effects of psychoactive pharmacological agents by means of computerized assessments of psychological states and traits through the analysis of content and form of people's speech. At the present time, psychopharmacological researchers involved in clinical trials rely on DSM-IV criteria and standardized self-report measures and observer rating scales to assess psychoactive drug effects. Attention is drawn to the potentially unrecognized measurement errors and relatively low interrater reliability by these methods--for example, all raters are not free of observer bias and every subject administered a drug is not equally and accurately well-informed about the self. The computerized content analysis methods tend to avoid these biases and measurement errors. A review is provided describing the Gottschalk-Gleser method of measuring psychobiological dimensions from the form and content of short (usually five-minute) speech samples of verbal behavior, generally elicited by standardized and purposely ambiguous instructions to talk about any interesting or dramatic personal life experiences. Norms have been obtained by this method of speech elicitation, adjusted for age, sex and educational level. Sections are provided covering cross-cultural and language validation research on the Gottschalk-Gleser content analysis method, the influence of medical or psychiatric illness as well as psychoactive drugs on verbal content analysis-derived scores, and the research carried out for more than 20 years computerizing this content analysis procedure through the development of artificial intelligence software enabling these measurements to be done from typescripts of speech samples on computer diskettes. A brief review deals with the general applications of this method of measurement to basic and clinical psychiatry, psychosomatic medicine, neuropsychology, the diagnostic process in a psychiatry outpatient clinic, children's mental health problems, dream research, and assessment of mental processes during PET scanning of the brain. This is followed by a review of the applications of this method of content analysis of speech to neuropsychopharmacological testing of antianxiety, antidepressive, antipsychotic, and other psychoactive drugs, as well as to pharmacokinetic variables and clinical response. This method is now in the process of being used in clinical trials in psychopharmacology and is recommended for more extensive use in this research area. PMID:10327394

  5. Comparison of non-invasive methods for the assessment of haemodynamic drug effects in healthy male and female volunteers: sex differences in cardiovascular responsiveness.

    PubMed Central

    Wolzt, M; Schmetterer, L; Rheinberger, A; Salomon, A; Unfried, C; Breiteneder, H; Ehringer, H; Eichler, H G; Fercher, A F

    1995-01-01

    1. The study was performed to determine the sensitivity and short-term and day-to-day variability of a novel technique based on laser interferometry of ocular fundus pulsations and of non-invasive methods for the quantification of haemodynamic drug effects. An additional aim was to assess sex differences in haemodynamic responsiveness to cardiovascular drugs in male and female healthy volunteers. 2. Ten males and nine females (age range 20-33 years) were studied in a double-blind, randomized, cross-over trial. Simultaneous measurements from systemic haemodynamics, laser interferometry of ocular fundus pulsations, systolic time intervals from mechanocardiography, a/b ratio from oxymetric fingerplethysmography and Doppler sonography of the radial artery were used to describe the haemodynamic effects of cumulative, stepwise increasing intravenous doses of phenylephrine, isoprenaline, sodium nitroprusside and of placebo. 3. Laser interferometry detected the isoprenaline-effects at the lowest dose level of 0.1 micrograms min-1 with a high signal-to-noise ratio. The reproducibility of measurements under baseline was high, no changes were observed after systemically effective doses of phenylephrine or sodium nitroprusside. Systolic time intervals were sensitive and specific for isoprenaline-induced effects, PEP and QS2c-measurements had high reproducibility. Fingerplethysmography proved a sensitive measurement for the detection of the vasodilating effects of sodium nitroprusside, but was not specific, and showed low reproducibility. Measurements from Doppler sonography had lower reproducibility and sensitivity compared with the other applied methods. 4. There was a significant sex difference for several of the haemodynamic parameters under baseline conditions; however, the responsiveness to the drugs under study was not different, when drug effects were expressed as %-change from the baseline. 5. Laser interferometry is a valuable non-invasive, highly sensitive and specific approach for the detection of pulse pressure changes. A battery of non-invasive tests appears useful for the characterization of cardiovascular drugs. Gender differences may not pose a relevant problem for the study of acute haemodynamic effects of cardiovascular drugs. Images Figure 1 PMID:7640140

  6. DISTRIBUTED GRID-CONNECTED PHOTOVOLTAIC POWER SYSTEM EMISSION OFFSET ASSESSMENT: STATISTICAL TEST OF SIMULATED- AND MEASURED-BASED DATA

    EPA Science Inventory

    This study assessed the pollutant emission offset potential of distributed grid-connected photovoltaic (PV) power systems. Computer-simulated performance results were utilized for 211 PV systems located across the U.S. The PV systems' monthly electrical energy outputs were based ...

  7. Assessing effects of forecasted climate change on the diversity and distribution of European higher plants for 2050

    Microsoft Academic Search

    M. Bakkenes; J. R. M. Alkemade; F. Ihle; R. Leemans; J. B. Latour

    2002-01-01

    The rapidly increasing atmospheric concentrations of greenhouse gases may lead to significant changes in regional and seasonal climate patterns. Such changes can strongly influence the diversity and distribution of species and, therefore, affect ecosystems and biodiversity. To assess these changes we developed a model, called euromove. The model uses climate data from 1990 to 2050 as compiled from the image

  8. Are standard tests sensitive enough to evaluate effects of human pharmaceuticals in aquatic biota? Facing changes in research approaches when performing risk assessment of drugs.

    PubMed

    Aguirre-Martínez, G V; Owuor, M A; Garrido-Pérez, C; Salamanca, M J; Del Valls, T A; Martín-Díaz, M L

    2015-02-01

    Nowadays, the presence of pharmaceutical products in aquatic environments is not only common, but is also of significant concern regarding the adverse effect they may produce to aquatic biota. In order to determine the adverse effects of caffeine (CAF), ibuprofen (IBU), carbamazepine (CBZ) and novobiocin (NOV), at environmental occurring concentrations, standardized endpoints applied in current guidelines were evaluated in four organisms including bioluminescence response in Vibrio fischeri, growth inhibition in Isochrysis galbana (marine water) and Pseudokirchneriella subcapitata (fresh water) and fertilization and embryo-larval development in Paracentrotus lividus. To reach this aim bioassays were implemented by exposing organisms to water spiked with drugs dissolved in DMSO (0.001% v/v). Risk characterization was performed, calculating the environmental impact of drugs by calculating environmental concentration and predicted no effect concentration ratio (MEC/PNEC). Results indicate that acute toxicity was found above environmental concentrations in the order of mg L(-1) for bacteria bioluminescence, microalgae growth inhibition and sea urchin fertilization. However, teratogenicity was observed on sea urchin after exposure to environmental concentrations of drugs at 0.00001 mg L(-1); at this concentration CBZ and IBU were found to reduce significantly the embryo-larval development compared to controls (p<0.01). The risk calculated for selected drugs suggested they are harmless for aquatic environment except when applying the embryo-larval development endpoint. Endpoints applied in this study showed the necessity of using more sensitive responses, when assessing risk of pharmaceuticals in aquatic environments, since endpoints applied in current guidelines may not be suitable. PMID:25000509

  9. Toxicity assessments of nonsteroidal anti-inflammatory drugs in isolated mitochondria, rat hepatocytes, and zebrafish show good concordance across chemical classes

    SciTech Connect

    Nadanaciva, Sashi [Compound Safety Prediction, Worldwide Medicinal Chemistry, Pfizer, Inc., Groton, CT 06340 (United States); Aleo, Michael D. [Drug Safety Research and Development, Pfizer Inc., Groton, CT 06340 (United States); Strock, Christopher J. [Cyprotex US, Watertown, MA 02472 (United States); Stedman, Donald B. [Drug Safety Research and Development, Pfizer Inc., Groton, CT 06340 (United States); Wang, Huijun [Computational Sciences, Pfizer Inc., Groton, CT 06340 (United States); Will, Yvonne, E-mail: yvonne.will@pfizer.com [Compound Safety Prediction, Worldwide Medicinal Chemistry, Pfizer, Inc., Groton, CT 06340 (United States)

    2013-10-15

    To reduce costly late-stage compound attrition, there has been an increased focus on assessing compounds in in vitro assays that predict attributes of human safety liabilities, before preclinical in vivo studies are done. Relevant questions when choosing a panel of assays for predicting toxicity are (a) whether there is general concordance in the data among the assays, and (b) whether, in a retrospective analysis, the rank order of toxicity of compounds in the assays correlates with the known safety profile of the drugs in humans. The aim of our study was to answer these questions using nonsteroidal anti-inflammatory drugs (NSAIDs) as a test set since NSAIDs are generally associated with gastrointestinal injury, hepatotoxicity, and/or cardiovascular risk, with mitochondrial impairment and endoplasmic reticulum stress being possible contributing factors. Eleven NSAIDs, flufenamic acid, tolfenamic acid, mefenamic acid, diclofenac, meloxicam, sudoxicam, piroxicam, diflunisal, acetylsalicylic acid, nimesulide, and sulindac (and its two metabolites, sulindac sulfide and sulindac sulfone), were tested for their effects on (a) the respiration of rat liver mitochondria, (b) a panel of mechanistic endpoints in rat hepatocytes, and (c) the viability and organ morphology of zebrafish. We show good concordance for distinguishing among/between NSAID chemical classes in the observations among the three approaches. Furthermore, the assays were complementary and able to correctly identify “toxic” and “non-toxic” drugs in accordance with their human safety profile, with emphasis on hepatic and gastrointestinal safety. We recommend implementing our multi-assay approach in the drug discovery process to reduce compound attrition. - Highlights: • NSAIDS cause liver and GI toxicity. • Mitochondrial uncoupling contributes to NSAID liver toxicity. • ER stress is a mechanism that contributes to liver toxicity. • Zebrafish and cell based assays are complimentary.

  10. Accuracy of the Kato-Katz method and formalin-ether concentration technique for the diagnosis of Clonorchis sinensis, and implication for assessing drug efficacy

    PubMed Central

    2013-01-01

    Background Clonorchiasis is a chronic neglected disease caused by a liver fluke, Clonorchis sinensis. Chemotherapy is the mainstay of control and treatment efficacy is usually determined by microscopic examination of fecal samples. We assessed the diagnostic accuracy of the Kato-Katz method and the formalin-ether concentration technique (FECT) for C. sinensis diagnosis, and studied the effect of diagnostic approach on drug efficacy evaluation. Methods Overall, 74 individuals aged ?18 years with a parasitological confirmed C. sinensis infection at baseline were re-examined 3 weeks after treatment. Before and after treatment, two stool samples were obtained from each participant and each sample was subjected to triplicate Kato-Katz thick smears and a single FECT examination. Results Thirty-eight individuals were still positive for C. sinensis according to our diagnostic ‘gold’ standard (six Kato-Katz thick smears plus two FECT). Two FECT had a significantly lower sensitivity than six Kato-Katz thick smears (44.7% versus 92.1%; p <0.001). Examination of single Kato-Katz and single FECT considerably overestimated cure rates. Conclusions In settings where molecular diagnostic assays are absent, multiple Kato-Katz thick smears should be examined for an accurate diagnosis of C. sinensis infection and for assessing drug efficacy against this liver fluke infection. PMID:24499644

  11. Development of a spatially distributed model of fish population density for habitat assessment of rivers

    NASA Astrophysics Data System (ADS)

    Sui, Pengzhe; Iwasaki, Akito; Ryo, Masahiro; Saavedra, Oliver; Yoshimura, Chihiro

    2013-04-01

    Flow conditions play an important role in sustaining biodiversity of river ecosystem. However, their relations to freshwater fishes, especially to fish population density, have not been clearly described. This study, therefore, aimed to propose a new methodology to quantitatively link habitat conditions, including flow conditions and other physical conditions, to population density of fish species. We developed a basin-scale fish distribution model by integrating the concept of habitat suitability assessment with a distributed hydrological model (DHM) in order to estimate fish population density with particular attention to flow conditions. Generalized linear model (GLM) was employed to evaluate the relationship between population density of fish species and major environmental factors. The target basin was Sagami River in central Japan, where the river reach was divided into 10 sections by estuary, confluences of tributaries, and river-crossing structures (dams, weirs). The DHM was employed to simulate river discharge from 1998 to 2005, which was used to calculate 10 flow indices including mean discharge, 25th and 75th percentile discharge, duration of low and high flows, number of floods. In addition, 5 water quality parameters and 13 other physical conditions (such as basin area, river width, mean diameter of riverbed material, and number of river-crossing structures upstream and downstream) of each river section were considered as environmental variables. In case of Sagami River, 10 habitat variables among them were then selected based on their correlations to avoid multicollinearity. Finally, the best GLM was developed for each species based on Akaike's information criterion. As results, population densities of 16 fish species in Sagami River were modelled, and correlation coefficients between observed and calculated population densities for 10 species were more than 0.70. The key habitat factors for population density varied among fish species. Minimum discharge (MID) was found to be positively correlated to 9 among 16 fish species. For duration of high and low flows (DHF and DLF), longer DHF/DLF was corresponded to lower population density for 7/6 fish species, respectively, such as Rhinogobius kurodai and Plecoglossus altivelis altivelis. Among physical habitat conditions, sinuosity index (SI, the ratio between actual river section length and straight line length) seems to be the most important parameter for fish population density in Sagami River basin, since it affects 12 out of 16 fish species, followed by mean longitudinal slope (S) and number of downstream dams (NLD). Above results demonstrated the applicability of fish distribution model to provide quantitative information on flow conditions required to maintain fish population, which enabled us to evaluate and project ecological consequences of water resource management policy, such as flood management and water withdrawal.

  12. Assessing Resistance to the Echinocandin Antifungal Drug Caspofungin in Candida albicans by Profiling Mutations in FKS1

    Microsoft Academic Search

    Sergey V. Balashov; Steven Park; David S. Perlin

    2006-01-01

    and is linked to mutations in short conserved regions in the FKS1 gene. The most prominent changes occurred at the serine 645 position in Fks1p with substitutions of proline, tyrosine, and phenylalanine. An allele-specific real-time PCR molecular-beacon assay was developed for rapid identification of drug resistance by targeting FKS1 mutations. Mutations altering serine 645 were reliably identified in both heterozygous

  13. An integrated assessment of the clinical safety of artemether-lumefantrine: a new oral fixed-dose combination antimalarial drug

    Microsoft Academic Search

    R. Bakshi; I. Hermeling-Fritz; I. Gathmann; E. Alteri

    2000-01-01

    Artemether-lumefantrine (A-L), a new fixed-dose oral antimalarial drug, combines the fast onset of action of artemether (an artemisinin derivative) in terms of parasite clearance with the high cure rate of lumefantrine in the treatment of acute uncomplicated Plasmodium falciparum malaria. The extensive clinical trial database of A-L has allowed a comprehensive evaluation of its tolerability and safety in a total

  14. Effect of database profile variation on drug safety assessment: an analysis of spontaneous adverse event reports of Japanese cases

    PubMed Central

    Nomura, Kaori; Takahashi, Kunihiko; Hinomura, Yasushi; Kawaguchi, Genta; Matsushita, Yasuyuki; Marui, Hiroko; Anzai, Tatsuhiko; Hashiguchi, Masayuki; Mochizuki, Mayumi

    2015-01-01

    Background The use of a statistical approach to analyze cumulative adverse event (AE) reports has been encouraged by regulatory authorities. However, data variations affect statistical analyses (eg, signal detection). Further, differences in regulations, social issues, and health care systems can cause variations in AE data. The present study examined similarities and differences between two publicly available databases, ie, the Japanese Adverse Drug Event Report (JADER) database and the US Food and Drug Administration Adverse Event Reporting System (FAERS), and how they affect signal detection. Methods Two AE data sources from 2010 were examined, ie, JADER cases (JP) and Japanese cases extracted from the FAERS (FAERS-JP). Three methods for signals of disproportionate reporting, ie, the reporting odds ratio, Bayesian confidence propagation neural network, and Gamma Poisson Shrinker (GPS), were used on drug-event combinations for three substances frequently recorded in both systems. Results The two databases showed similar elements of AE reports, but no option was provided for a shareable case identifier. The average number of AEs per case was 1.6±1.3 (maximum 37) in the JP and 3.3±3.5 (maximum 62) in the FAERS-JP. Between 5% and 57% of all AEs were signaled by three quantitative methods for etanercept, infliximab, and paroxetine. Signals identified by GPS for the JP and FAERS-JP, as referenced by Japanese labeling, showed higher positive sensitivity than was expected. Conclusion The FAERS-JP was different from the JADER. Signals derived from both datasets identified different results, but shared certain signals. Discrepancies in type of AEs, drugs reported, and average number of AEs per case were potential contributing factors. This study will help those concerned with pharmacovigilance better understand the use and pitfalls of using spontaneous AE data. PMID:26109846

  15. Assessing Vertical Distribution of Trace Species as related to Transport and Emissions

    NASA Astrophysics Data System (ADS)

    Chen, G.; Shook, M.; Scarino, A. J.; Silverman, M. L.; Kleb, M. M.; Crawford, J. H.

    2014-12-01

    The NASA DISCOVER-AQ (Deriving Information on Surface Conditions from COlumn and VERtically Resolved Observations Relevant to Air Quality) field campaign conducted extensive vertical sampling of traces gases and aerosols during four separate deployments: Baltimore, MD (2011); California Central Valley (2013); Houston, TX (2013); and Denver, CO (2014). The campaign's primary objective is to better understand how column measurements can be used to infer surface conditions. In order to achieve this objective, it is necessary to understand the factors that control the vertical distribution of trace species that are highly relevant to air quality issues. Leveraging the over 400 vertical profiles from the Baltimore and Houston deployments, we will contrast the DISCOVER-AQ vertical observations of CO2, CO, O3, NOx, CH2O, and aerosol properties from these coastal regions. After determining airmass origin and atmospheric vertical structure for each of the profiles, the vertical structure of these trace species will be compared to assess the impact and relative importance of vertical transport, advection, and local emissions.

  16. Use of digital multispectral videography to assess seagrass distribution in San Quintin Bay, Baja California, Mexico

    USGS Publications Warehouse

    Ward, D.H.; Tibbitts, T.L.; Morton, Alexandra; Carrera-Gonzalez, Eduardo; Kempka, R.

    2004-01-01

    Apparent threats to the spatial distribution of seagrass in San Quinti??n Bay prompted us to make a detailed assessment of habitats in the bay. Six coastal habitats and three seagrass subclasses were delineated using airborne digital multispectral videography (DMSV), Eelgrass, Zostera marina, was the predominant seagrass and covered 40% (1949 ha) of the areal extent of the bay in 1999. Eelgrass grew over a wide range of tidal depths from about -3.0 in mean lower low water (MLLW) to about 1.0 m MLLW, but greatest spatial extent occurred in intertidal areas -0.6 m to 1.0 m MLLW. Exposed-continuous (i.e., high density) eelgrass was the most abundant habitat in the bay. Widgeongrass, Ruppia maritima, was the only other seagrass present and covered 3% (136 ha) of the areal extent of the entire bay. Widgeongrass grew in single species stands in the upper intertidal (??? 0.4 MLLW) and intermixed with eelgrass at lower tidal depths. Overall accuracy of the six habitat classes and three subclasses in the DMSV map was relatively high at 84%. Our detailed map of San Quintin Bay can be used in future change detection analyses to monitor the health of seagrasses in the bay.

  17. Fraction distribution and risk assessment of heavy metals in sediments of Moshui Lake.

    PubMed

    Liu, Honglei; Li, Liqing; Yin, Chengqing; Shan, Baoqing

    2008-01-01

    To examine the status and risk of heavy metal pollution in urban lakes, in China, the distribution of several heavy metals (e.g., Cr, Cu, Ni, Pb, Zn) in the sediment of Moshui Lake, Hangyang District, Wuhan City, was characterized. The process of rapid urbanization and industrialization of the district was also studied to find out its relationship with the metal accumulation profile in the sediment. It was found that the total concentration of heavy metals in the sediment was higher than the severe effect level (SEL), at all sampling sites, except those in the riparian zone. The Cr and Cu maximum concentrations were 1,780 and 1,250 mg/kg, approximately 16 and 11 times as much as the SEL values, and they appeared as deep as 32 cm in one sample. The carbonate and exchangeable fractions of Zn were more than 50% of the total Zn content, resulting in very high risk according to the Risk Assessment Code (RAC). For Cu and Ni, a medium RAC value was found for carbonate and exchangeable fractions of 11%-20%. As sensitive indicators of contaminants in aquatic systems, heavy metals in the sediment reflect the outcome of regional urbanization, industrialization, and environmental management. With rapid urbanization, sedimentary Pb and Zn concentrations increased. The experimental results showed that high sedimentary heavy metal concentrations had resulted from rapid urbanization and industrialization, which would absolutely lead to substantial aquatic environmental decline in urban lakes. PMID:18575121

  18. Distribution and assessment of surface water contamination by application of chemometric and deterministic models

    NASA Astrophysics Data System (ADS)

    Terrado, Marta; Lavigne, Martin-Pierre; Tremblay, Sebastien; Duchesne, Sophie; Villeneuve, Jean-Pierre; Rousseau, Alain N.; Barceló, Damià; Tauler, Romà

    2009-05-01

    SummaryChemometrics and deterministic modelling is proposed to extract useful information from data sets obtained in environmental monitoring studies. Contamination from organic compounds in the Llobregat River basin (Catalunya, NE Spain) was investigated for the period 2003-2006. From the application of Multivariate Curve Resolution using Alternating Least Squares (MCR-ALS), five different patterns of organic compound contamination are identified, explaining nearly 65% of the total variance of data. While pollution from chlorinated pesticides and alkylphenols shows lower levels in recent years, contamination resulting from PAHs has a rather constant distribution in space as well as in time. On the other hand, diffuse pollution from an agricultural pattern with terbutryn and chlorpyrifos increases in the year 2006 as compared to 2005. Dynamics of the products describing this last agricultural pattern are modeled using the modelling system GIBSI. Existing cultures in the studied area as well as possible pesticide usages and application loads are considered for the simulation of pesticide concentrations in water. In this way, the transfer of pesticides applied on soils to the water system is assessed and compared with other possible scenarios involving alternative practices. A new modelling approach based on considering different contamination patterns instead of using individual variables and chemicals is proposed at the end of this work.

  19. Levels, distribution, and risk assessment of organochlorines in surficial sediments of the Red Sea coast, Egypt.

    PubMed

    El Nemr, Ahmed; Moneer, Abeer A; Khaled, Azza; El-Sikaily, Amany

    2013-06-01

    The analyses of environmentally persistent pollutants like polychlorinated biphenyls (PCBs), hexachlorocyclohexane (HCH) isomers, and dichlorodiphenyltrichloroethane (DDT) and its metabolites in surficial sediment samples collected from 17 locations along with the coast of the Red Sea in Egypt were carried out using gas chromatography-mass spectrometry. Several potential organic contaminants from agricultural (e.g., DDT and its breakdown products, lindane, endrin, dieldrin, and endosulfan) and industrial (PCBs) sources were measured. The levels of 20 organochlorine pesticides (OCPs) and ten PCB congeners in sediment collected from 17 stations along ~1,200 km were investigated. Concentrations of PCBs, HCHs, DDTs, and cyclodienes ranged from 0.40 to 6.17, 0.01 to 0.09, n.d. to 0.46, and 0.08 to 0.90 ppb dry weight. Two statistical programs were applied on the data (principal component analysis, PCA, and cluster analysis, CA), and it was concluded that it is impossible to predict the distribution patterns of the OCPs in a contaminated area. Risk assessment of the organochlorines contaminated in the sediments of the studied area was investigated. PMID:23054273

  20. Spatial distribution and pollution assessment of mercury in sediments of Lake Taihu, China.

    PubMed

    Chen, Chunxiao; Zheng, Binghui; Jiang, Xia; Zhao, Zheng; Zhan, Yuzhu; Yi, Fengjiao; Ren, Jiaying

    2013-02-01

    Spatial distribution patterns of total mercury (THg) in 36 surficial sediment samples representing five regions of Lake Taihu were assessed using the ArcGis geostatistical analyst module. The pollution levels of THg were also evaluated from the same five lake regions. Concentrations of THg were in a ranged of 23-168 ng/g (mean 55 ng/g) in surfical sediments, which was significantly higher than those established baseline levels of the lake. Results of THg indicated that the northern region exhibited notably higher values, the bay regions showed elevated values relative to open areas, and the lakeside regions were higher than those observed in the central area. Lake Taihu suffered moderate to high Hg pollution, and expressed clear Hg enrichment status according to monomial pollution index I(geo) and human activity factors. The concentrations of THg in the surficial sediments of Lake Taihu showed moderate-strong variation (coefficient of variation 52%). Geostatistical analysis indicated a weak spatial self-correlation, suggesting the contamination of Hg in Lake Taihu is primarily the result of anthropogenic activities. PMID:23596952