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Sample records for higher drug concentrations

  1. Drug addiction, love, and the higher power.

    Science.gov (United States)

    Sussman, Steve; Reynaud, Michel; Aubin, Henri-Jean; Leventhal, Adam M

    2011-09-01

    This discussion piece suggests that reliance on a Higher Power in drug abuse recovery programs is entertained among some addicts for its psychobiological effects. Prayer, meditation, early romantic love, and drug abuse may have in common activation of mesolimbic dopaminergic pathways of the brain and the generation of intense emotional states. In this sense, reliance on a Higher Power may operate as a substitute addiction, which replaces the psychobiological functions formerly served by drug use. Implications of this perspective are discussed.

  2. Cast Stone Formulation At Higher Sodium Concentrations

    International Nuclear Information System (INIS)

    Fox, K. M.; Edwards, T. A.; Roberts, K. B.

    2013-01-01

    concentration in the salt solution reduced the time to peak heat flow, and reducing the amount of slag in the premix increased the time to peak heat flow. These observations may help to describe some of the cured properties of the samples, in particular the differences in compressive strength observed after 28 and 90 days of curing. Samples were cured for at least 28 days at ambient temperature in the laboratory prior to cured properties analyses. The low activity waste form for disposal at the Hanford Site is required to have a compressive strength of at least 500 psi. After 28 days of curing, several of the test mixes had mean compressive strengths that were below the 500 psi requirement. Higher sodium concentrations and higher water to premix ratios led to reduced compressive strength. Higher fly ash concentrations decreased the compressive strength after 28 days of curing. This may be explained in that the cementitious phases matured more quickly in the mixes with higher concentrations of slag, as evidenced by the data for the time to peak heat generation. All of the test mixes exhibited higher mean compressive strengths after 90 days of curing, with only one composition having a mean compressive strength of less than 500 psi. Leach indices were determined for the test mixes for contaminants of interest. The leaching performance of the mixes evaluated in this study was not particularly sensitive to the factors used in the experimental design. This may be beneficial in demonstrating that the performance of the waste form is robust with respect to changes in the mix composition. The results of this study demonstrate the potential to achieve significantly higher waste loadings in Cast Stone and other low temperature, cementitious waste forms. Additional work is needed to elucidate the hydration mechanisms occurring in Cast Stone formulated with highly concentrated salt solutions since these reactions are responsible for determining the performance of the cured waste form. The

  3. Cast Stone Formulation At Higher Sodium Concentrations

    International Nuclear Information System (INIS)

    Fox, K. M.; Roberts, K. A.; Edwards, T. B.

    2014-01-01

    concentration in the salt solution reduced the time to peak heat flow, and reducing the amount of slag in the premix increased the time to peak heat flow. These observations may help to describe some of the cured properties of the samples, in particular the differences in compressive strength observed after 28 and 90 days of curing. Samples were cured for at least 28 days at ambient temperature in the laboratory prior to cured properties analyses. The low activity waste form for disposal at the Hanford Site is required to have a compressive strength of at least 500 psi. After 28 days of curing, several of the test mixes had mean compressive strengths that were below the 500 psi requirement. Higher sodium concentrations and higher water to premix ratios led to reduced compressive strength. Higher fly ash concentrations decreased the compressive strength after 28 days of curing. This may be explained in that the cementitious phases matured more quickly in the mixes with higher concentrations of slag, as evidenced by the data for the time to peak heat generation. All of the test mixes exhibited higher mean compressive strengths after 90 days of curing, with only one composition having a mean compressive strength of less than 500 psi. Leachability indices were determined for the test mixes for contaminants of interest. The leaching performance of the mixes evaluated in this study was not particularly sensitive to the factors used in the experimental design. This may be beneficial in demonstrating that the performance of the waste form is robust with respect to changes in the mix composition. The results of this study demonstrate the potential to achieve significantly higher waste loadings in Cast Stone and other low temperature, cementitious waste forms. Additional work is needed to elucidate the hydration mechanisms occurring in Cast Stone formulated with highly concentrated salt solutions since these reactions are responsible for determining the performance of the cured waste

  4. Cast Stone Formulation At Higher Sodium Concentrations

    Energy Technology Data Exchange (ETDEWEB)

    Fox, K. M. [Savannah River Site (SRS), Aiken, SC (United States). Savannah River National Lab. (SRNL); Roberts, K. A. [Savannah River Site (SRS), Aiken, SC (United States). Savannah River National Lab. (SRNL); Edwards, T. B. [Savannah River Site (SRS), Aiken, SC (United States). Savannah River National Lab. (SRNL)

    2014-02-28

    concentration in the salt solution reduced the time to peak heat flow, and reducing the amount of slag in the premix increased the time to peak heat flow. These observations may help to describe some of the cured properties of the samples, in particular the differences in compressive strength observed after 28 and 90 days of curing. Samples were cured for at least 28 days at ambient temperature in the laboratory prior to cured properties analyses. The low activity waste form for disposal at the Hanford Site is required to have a compressive strength of at least 500 psi. After 28 days of curing, several of the test mixes had mean compressive strengths that were below the 500 psi requirement. Higher sodium concentrations and higher water to premix ratios led to reduced compressive strength. Higher fly ash concentrations decreased the compressive strength after 28 days of curing. This may be explained in that the cementitious phases matured more quickly in the mixes with higher concentrations of slag, as evidenced by the data for the time to peak heat generation. All of the test mixes exhibited higher mean compressive strengths after 90 days of curing, with only one composition having a mean compressive strength of less than 500 psi. Leachability indices were determined for the test mixes for contaminants of interest. The leaching performance of the mixes evaluated in this study was not particularly sensitive to the factors used in the experimental design. This may be beneficial in demonstrating that the performance of the waste form is robust with respect to changes in the mix composition. The results of this study demonstrate the potential to achieve significantly higher waste loadings in Cast Stone and other low temperature, cementitious waste forms. Additional work is needed to elucidate the hydration mechanisms occurring in Cast Stone formulated with highly concentrated salt solutions since these reactions are responsible for determining the performance of the cured waste

  5. Cast Stone Formulation At Higher Sodium Concentrations

    Energy Technology Data Exchange (ETDEWEB)

    Fox, K. M.; Edwards, T. A.; Roberts, K. B.

    2013-10-02

    concentration in the salt solution reduced the time to peak heat flow, and reducing the amount of slag in the premix increased the time to peak heat flow. These observations may help to describe some of the cured properties of the samples, in particular the differences in compressive strength observed after 28 and 90 days of curing. Samples were cured for at least 28 days at ambient temperature in the laboratory prior to cured properties analyses. The low activity waste form for disposal at the Hanford Site is required to have a compressive strength of at least 500 psi. After 28 days of curing, several of the test mixes had mean compressive strengths that were below the 500 psi requirement. Higher sodium concentrations and higher water to premix ratios led to reduced compressive strength. Higher fly ash concentrations decreased the compressive strength after 28 days of curing. This may be explained in that the cementitious phases matured more quickly in the mixes with higher concentrations of slag, as evidenced by the data for the time to peak heat generation. All of the test mixes exhibited higher mean compressive strengths after 90 days of curing, with only one composition having a mean compressive strength of less than 500 psi. Leach indices were determined for the test mixes for contaminants of interest. The leaching performance of the mixes evaluated in this study was not particularly sensitive to the factors used in the experimental design. This may be beneficial in demonstrating that the performance of the waste form is robust with respect to changes in the mix composition. The results of this study demonstrate the potential to achieve significantly higher waste loadings in Cast Stone and other low temperature, cementitious waste forms. Additional work is needed to elucidate the hydration mechanisms occurring in Cast Stone formulated with highly concentrated salt solutions since these reactions are responsible for determining the performance of the cured waste form. The

  6. Cast Stone Formulation At Higher Sodium Concentrations

    Energy Technology Data Exchange (ETDEWEB)

    Fox, K. M.; Roberts, K. A.; Edwards, T. B.

    2013-09-17

    concentration in the salt solution reduced the time to peak heat flow, and reducing the amount of slag in the premix increased the time to peak heat flow. These observations may help to describe some of the cured properties of the samples, in particular the differences in compressive strength observed after 28 and 90 days of curing. Samples were cured for at least 28 days at ambient temperature in the laboratory prior to cured properties analyses. The low activity waste form for disposal at the Hanford Site is required to have a compressive strength of at least 500 psi. After 28 days of curing, several of the test mixes had mean compressive strengths that were below the 500 psi requirement. Higher sodium concentrations and higher water to premix ratios led to reduced compressive strength. Higher fly ash concentrations decreased the compressive strength after 28 days of curing. This may be explained in that the cementitious phases matured more quickly in the mixes with higher concentrations of slag, as evidenced by the data for the time to peak heat generation. All of the test mixes exhibited higher mean compressive strengths after 90 days of curing, with only one composition having a mean compressive strength of less than 500 psi. Leach indices were determined for the test mixes for contaminants of interest. The leaching performance of the mixes evaluated in this study was not particularly sensitive to the factors used in the experimental design. This may be beneficial in demonstrating that the performance of the waste form is robust with respect to changes in the mix composition. The results of this study demonstrate the potential to achieve significantly higher waste loadings in Cast Stone and other low temperature, cementitious waste forms. Additional work is needed to elucidate the hydration mechanisms occurring in Cast Stone formulated with highly concentrated salt solutions since these reactions are responsible for determining the performance of the cured waste form. The

  7. Academic Performance Enhancement Drugs in Higher Education

    Science.gov (United States)

    Aikins, Ross Douglas

    2012-01-01

    Higher education is a place where students are known to navigate various stages of psychosocial development, and experiment with psychoactive substances. Extant research detailing the relationship between drugs and student development typically frame the impact of substance use as exclusively negative or harmful to student health and the outcomes…

  8. Trace element concentrations in higher fungi

    International Nuclear Information System (INIS)

    Byrne, A.R.; Ravnik, V.; Kosta, L.

    1976-01-01

    The concentrations of ten trace elements, As, Br, Cd, Cu, Hg, I, Mn, Se, Zn and V, have been determined in up to 27 species of higher fungi from several sites in Slovenia, Yugoslavia. Analyses were based on destructive neutron activation techniques. Data are presented and compared with the concentrations found in soils. Previously values were non-existent or scanty for these elements, so that the data represent typical levels for basidiomycetes. In addition to confirming high levels of mercury in many species, the survey also found that cadmium is accumulated to a surprising extent by most fungi, the average value being 5 ppm. Among other accumulations found was bromine by the genus Amanita, and selenium by edible Boletus. Correlation analysis between all pairs of trace elements gave values for r of from 0.75 to 0.43 for 7 pairs (Cu and Hg, 0.75; Se and As, 0.69). As well as these features of biochemical interest, the values found and the pattern of accumulation suggest potential uses of fungi in environmental studies

  9. Using Potentiometric Free Drug Sensors to Determine the Free Concentration of Ionizable Drugs in Colloidal Systems

    DEFF Research Database (Denmark)

    Tran, Thuy; Chakraborty, Anjan; Xi, Xi

    2018-01-01

    The present study investigates the use of free drug sensors (FDS) to measure free ionized drug concentrations in colloidal systems, including micellar solutions, emulsions, and lipid formulations during in vitro lipolysis. Diphenhydramine hydrochloride (DPH) and loperamide hydrochloride (LOP) wer...

  10. Urine Creatinine Concentrations in Drug Monitoring Participants and Hospitalized Patients.

    Science.gov (United States)

    Love, Sara A; Seegmiller, Jesse C; Kloss, Julie; Apple, Fred S

    2016-10-01

    Urine drug testing is commonly performed in both clinical and forensic arenas for screening, monitoring and compliance purposes. We sought to determine if urine creatinine concentrations in monitoring program participants were significantly different from hospital in-patients and out-patients undergoing urine drug testing. We retrospectively reviewed urine creatinine submitted in June through December 2015 for all specimens undergoing urine drug testing. The 20,479 creatinine results were categorized as hospitalized patients (H) and monitoring/compliance groups for pain management (P), legal (L) or recovery (R). Median creatinine concentrations (interquartile range, mg/dL) were significantly different (P creatinine concentrations were significantly lower in the R vs. L group (Pcreatinine concentration and may indicate participants' attempts to tamper with their drug test results through dilution means. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  11. Higher milk fat content is associated with higher 25-hydroxyvitamin D concentration in early childhood.

    Science.gov (United States)

    Vanderhout, Shelley M; Birken, Catherine S; Parkin, Patricia C; Lebovic, Gerald; Chen, Yang; O'Connor, Deborah L; Maguire, Jonathon L

    2016-05-01

    Current guidelines for cow's milk consumption in children older than age 2 years suggest 1% or 2% milk to reduce the risk of obesity. Given that milk is the main dietary source of vitamin D for North American children and that vitamin D is fat soluble, we hypothesized 25-hydroxyvitamin D (25(OH)D) concentration to be positively associated with the fat content of milk. The objective was to determine the relationship between the fat content of milk consumed and the serum 25(OH)D concentration; our secondary objective was to explore the role that the volume of milk consumed played in this relationship. We completed a cross-sectional study of children aged 12-72 months in the TARGetKids! research network. Multivariable linear regression was used to test the association between milk fat content and child 25(OH)D, adjusted for clinically relevant covariates. The interaction between volume of milk and fat content was examined. Two thousand eight hundred fifty-seven children were included in the analysis. The fat content of milk was positively associated with 25(OH)D (p = 0.03), and the interaction between the volume of milk consumed and the milk fat content was statistically significant (p = 0.005). Children who drank 1% milk needed 2.46 cups (95% confidence interval (CI) 2.38-2.54) of milk to have a 25(OH)D concentration similar to that of children who drank 1 cup of homogenized milk (3.25% fat). Children who consumed 1% milk had 2.05 (95% CI 1.73-2.42) times higher odds of having a 25(OH)D concentration <50 nmol/L compared with children who consumed homogenized milk. In conclusion, recommendations for children to drink lower-fat milk (1% or 2%) may compromise serum 25(OH)D levels and may require study to ensure optimal childhood health.

  12. Impact of common cytostatic drugs on pollen fertility in higher plants.

    Science.gov (United States)

    Mišík, Miroslav; Kundi, Michael; Pichler, Clemens; Filipic, Metka; Rainer, Bernhard; Mišíková, Katarina; Nersesyan, Armen; Knasmueller, Siegfried

    2016-08-01

    Cytostatic drugs are among the most toxic chemicals which are produced. Many of them cause damage of the genetic material which may affect the fertility of higher organisms. To study the impact of the widely used anticancer drugs [cisplatin (CisPt), etoposide (Et), and 5-fluorouracil (5-FU)] on the reproduction of higher plants, pollen abortion experiments were conducted with species which belong to major plant families, namely with Tradescantia paludosa (Commelinaceae), Arabidopsis thaliana (Brassicaceae), Chelidonium majus (Papaveraceae), and Alisma plantago-aquatica (Alismataceae). All compounds increased the frequencies of abortive grains. The lowest effective doses were in general in a narrow range (i.e., 1 and 10 mg/kg of dry soil). The effects of the individual drugs were similar in T. paludosa, A. plantago-aquatica, and Ch. majus, while A. thaliana was consistently less sensitive. The highest abortion rate was obtained in most experiments with CisPt, followed by 5-FU and Et. Comparisons of the doses which caused effects in the present experiments in the different species with the predicted environment concentrations and with the levels of the cytostatics which were detected in hospital wastewaters show that the realistic environmental concentrations of the drugs are 4-6 orders of magnitude lower. Therefore, it is unlikely that these drugs affect the fertility of higher plants in aquatic and terrestrial ecosystems.

  13. Influence of drug concentration on the diffusion parameters of caffeine

    Science.gov (United States)

    Mustapha, R.Ben; Lafforgue, C.; Fenina, N.; Marty, J.P.

    2011-01-01

    Background and Objectives: In the fields of the pharmaceutical and cosmetic industries and in toxicology, the study of the skin penetration of molecules is very interesting. Various studies have considered the impact of different physicochemical drug characteristics, skin thickness, and formulations, on the transition from the surface of the skin to the underlying tissues or to the systemic circulation; however, the influence of drug concentration on the permeation flux of molecules has rarely been raised. Our study aims to discover the influence of caffeine concentration in a formulation on the percutaneous penetration from gels, as a result of different dose applications to polysulfate membrane and human skin. Materials and Methods: For this purpose, three identical base gels were used at 1, 3, and 5% of caffeine, to evaluate the effect of the concentration of caffeine on in vitro release through the synthetic membrane and ex vivo permeation through the human skin, using diffusion FranzTM cells. Results: The diffusion through the epidermal tissue was significantly slower than through the synthetic membrane, which recorded an increase of flux with an increase in the concentration of caffeine. The skin permeation study showed that diffusion depended not only on the concentration, but also on the deposited amount of gel. Nevertheless, for the same amount of caffeine applied, the flux was more significant from the less concentrated gel. Conclusion: Among all the different concentrations of caffeine examined, 1% gel of caffeine applied at 5 mg / cm2 showed the highest absorption characteristics across human skin. PMID:21572649

  14. Serum magnesium concentration in drug-addicted patients.

    Science.gov (United States)

    Karakiewicz, Beata; Kozielec, Tadeusz; Brodowski, Jacek; Chlubek, Dariusz; Noceń, Iwona; Starczewski, Andrzej; Brodowska, Agnieszka; Laszczyńska, Maria

    2007-03-01

    Drug addiction is a complex problem which leads to many somatic, psychic and social diseases. It is accompanied by the disturbed metabolism of various macro and micronutrients. The aim of this study was to assess serum magnesium concentration in drug-addicted patients and analyze whether Human Immunodeficiency Virus (HIV) infection and methadone treatment affect the level of serum magnesium in these patients. The examination was conducted in a group of 83 people - patients of Szczecin-Zdroje Psychiatric Hospital (Poland). They were 21 to 49 years old, and the mean age was 32 +/- 7 years. The control group consisted of 81 healthy individuals. Flame atomic-absorption spectrometry method was used to determine the magnesium concentration. The total serum magnesium concentration was calculated for the whole patient group, subgroups of women and men, a subgroup of people infected with HIV, and a subgroup receiving methadone substitution treatment. How magnesium behaves depending on age and addiction period, was checked. The mean concentration of magnesium in blood serum of the patients examined was 0.57 mmol/L, which was significantly lower than in the control group. In the subgroup of men it was 0.57 mmol/L, and in the subgroup of women - 0.55 mmol/L; the differences were not statistically significant. In the patient group nobody had the appropriate magnesium concentration in blood serum. No significant correlation was found between the magnesium concentration, age of the patients and addiction period. In the subgroup of seropositive people the mean concentration of magnesium was 0.55 mmol/L, and in the subgroup of non-infected patients - 0.58 mmol/L; the difference was not statistically significant. The mean concentration of magnesium in the subgroup treated with methadone was 0.59 mmol/L, and in the subgroup not involved in this type of therapy - 0.55 mmol/L; it was not a statistically significant difference.

  15. From Recreational to Functional Drug Use: The Evolution of Drugs in American Higher Education, 1960-2014

    Science.gov (United States)

    Aikins, Ross D.

    2015-01-01

    The increasing prevalence of so-called cognitive-enhancing drugs is well documented in American higher education. There has been little historical analysis, however, specifically exploring the role of postsecondary institutions in this evolving drug narrative. This paper traces substance use and research trends in American higher education over…

  16. Skin test concentrations for systemically administered drugs -- an ENDA/EAACI Drug Allergy Interest Group position paper

    NARCIS (Netherlands)

    Brockow, K.; Garvey, L. H.; Aberer, W.; Atanaskovic-Markovic, M.; Barbaud, A.; Bilo, M. B.; Bircher, A.; Blanca, M.; Bonadonna, B.; Campi, P.; Castro, E.; Cernadas, J. R.; Chiriac, A. M.; Demoly, P.; Grosber, M.; Gooi, J.; Lombardo, C.; Mertes, P. M.; Mosbech, H.; Nasser, S.; Pagani, M.; Ring, J.; Romano, A.; Scherer, K.; Schnyder, B.; Testi, S.; Torres, M.; Trautmann, A.; Terreehorst, I.

    2013-01-01

    Skin tests are of paramount importance for the evaluation of drug hypersensitivity reactions. Drug skin tests are often not carried out because of lack of concise information on specific test concentrations. The diagnosis of drug allergy is often based on history alone, which is an unreliable

  17. The drug target genes show higher evolutionary conservation than non-target genes.

    Science.gov (United States)

    Lv, Wenhua; Xu, Yongdeng; Guo, Yiying; Yu, Ziqi; Feng, Guanglong; Liu, Panpan; Luan, Meiwei; Zhu, Hongjie; Liu, Guiyou; Zhang, Mingming; Lv, Hongchao; Duan, Lian; Shang, Zhenwei; Li, Jin; Jiang, Yongshuai; Zhang, Ruijie

    2016-01-26

    Although evidence indicates that drug target genes share some common evolutionary features, there have been few studies analyzing evolutionary features of drug targets from an overall level. Therefore, we conducted an analysis which aimed to investigate the evolutionary characteristics of drug target genes. We compared the evolutionary conservation between human drug target genes and non-target genes by combining both the evolutionary features and network topological properties in human protein-protein interaction network. The evolution rate, conservation score and the percentage of orthologous genes of 21 species were included in our study. Meanwhile, four topological features including the average shortest path length, betweenness centrality, clustering coefficient and degree were considered for comparison analysis. Then we got four results as following: compared with non-drug target genes, 1) drug target genes had lower evolutionary rates; 2) drug target genes had higher conservation scores; 3) drug target genes had higher percentages of orthologous genes and 4) drug target genes had a tighter network structure including higher degrees, betweenness centrality, clustering coefficients and lower average shortest path lengths. These results demonstrate that drug target genes are more evolutionarily conserved than non-drug target genes. We hope that our study will provide valuable information for other researchers who are interested in evolutionary conservation of drug targets.

  18. Nutrient concentrations in a Littorella uniflora community at higher CO2 concentrations and reduced light intensities

    DEFF Research Database (Denmark)

    Andersen, T.; Pedersen, O.; Andersen, F. Ø.

    2005-01-01

    laboratory experiments with isoetid vegetation (Littorella uniflora) where water column CO2 and light could be manipulated in order to test whether (i) light and CO2 availability affect nutrient concentrations in isoetid vegetation, and (ii) if changes in light and CO2 climate affect fluxes of inorganic...... nitrogen (N) and phosphorus (P) from sediment to water column, which potentially could result in increased growth of epiphytic algae. 3. The results showed that the standing stocks of phosphorus and nitrogen in the L. uniflora vegetation were significantly influenced by CO2 concentration and light...... intensity. Both standing stocks of P and N were significantly higher in the mesocosm treatments with high CO2 concentration than in those at low CO2 concentration. Similarly, standing stocks of P and N enhanced with increasing light intensity. 4. Measurements of nutrient fluxes both in the field...

  19. Skin test concentrations for systemically administered drugs -- an ENDA/EAACI Drug Allergy Interest Group position paper

    DEFF Research Database (Denmark)

    Brockow, K; Garvey, L H; Aberer, W

    2013-01-01

    Skin tests are of paramount importance for the evaluation of drug hypersensitivity reactions. Drug skin tests are often not carried out because of lack of concise information on specific test concentrations. The diagnosis of drug allergy is often based on history alone, which is an unreliable...... indicator of true hypersensitivity.To promote and standardize reproducible skin testing with safe and nonirritant drug concentrations in the clinical practice, the European Network and European Academy of Allergy and Clinical Immunology (EAACI) Interest Group on Drug Allergy has performed a literature...... search on skin test drug concentration in MEDLINE and EMBASE, reviewed and evaluated the literature in five languages using the GRADE system for quality of evidence and strength of recommendation. Where the literature is poor, we have taken into consideration the collective experience of the group...

  20. Differences in energy expenditures and growth dilution explain higher PCB concentrations in male summer flounder

    Science.gov (United States)

    Madenjian, Charles P.; Jensen, Olaf P.; Rediske, Richard R.; O'Keefe, James P.; Vastano, Anthony R.; Pothoven, Steven A.

    2016-01-01

    Comparison of polychlorinated biphenyl (PCB) concentrations between the sexes of mature fish may reveal important behavioral and physiological differences between the sexes. We determined whole-fish PCB concentrations in 23 female summer flounder Paralichthys dentatus and 27 male summer flounder from New Jersey coastal waters. To investigate the potential for differences in diet or habitat utilization between the sexes, carbon and nitrogen stable isotope ratios were also determined. In 5 of the 23 female summer flounder, PCB concentrations in the somatic tissue and ovaries were determined. In addition, we used bioenergetics modeling to assess the contribution of the growth dilution effect to the observed difference in PCB concentrations between the sexes. Whole-fish PCB concentrations for females and males averaged 87 and 124 ng/g, respectively; thus males were 43% higher in PCB concentration compared with females. Carbon and nitrogen stable isotope ratios did not significantly differ between the sexes, suggesting that diet composition and habitat utilization did not vary between the sexes. Based on PCB determinations in the somatic tissue and ovaries, we predicted that PCB concentration of females would increase by 0.6%, on average, immediately after spawning due to release of eggs. Thus, the change in PCB concentration due to release of eggs did not explain the higher PCB concentrations observed in males. Bioenergetics modeling results indicated that the growth dilution effect could account for males being 19% higher in PCB concentration compared with females. Thus, the bulk of the observed difference in PCB concentrations between the sexes was not explained by growth dilution. We concluded that a higher rate of energy expenditure in males, stemming from greater activity and a greater resting metabolic rate, was most likely the primary driver for the observed difference in PCB concentrations between the sexes.

  1. Differences in Energy Expenditures and Growth Dilution Explain Higher PCB Concentrations in Male Summer Flounder.

    Directory of Open Access Journals (Sweden)

    Charles P Madenjian

    Full Text Available Comparison of polychlorinated biphenyl (PCB concentrations between the sexes of mature fish may reveal important behavioral and physiological differences between the sexes. We determined whole-fish PCB concentrations in 23 female summer flounder Paralichthys dentatus and 27 male summer flounder from New Jersey coastal waters. To investigate the potential for differences in diet or habitat utilization between the sexes, carbon and nitrogen stable isotope ratios were also determined. In 5 of the 23 female summer flounder, PCB concentrations in the somatic tissue and ovaries were determined. In addition, we used bioenergetics modeling to assess the contribution of the growth dilution effect to the observed difference in PCB concentrations between the sexes. Whole-fish PCB concentrations for females and males averaged 87 and 124 ng/g, respectively; thus males were 43% higher in PCB concentration compared with females. Carbon and nitrogen stable isotope ratios did not significantly differ between the sexes, suggesting that diet composition and habitat utilization did not vary between the sexes. Based on PCB determinations in the somatic tissue and ovaries, we predicted that PCB concentration of females would increase by 0.6%, on average, immediately after spawning due to release of eggs. Thus, the change in PCB concentration due to release of eggs did not explain the higher PCB concentrations observed in males. Bioenergetics modeling results indicated that the growth dilution effect could account for males being 19% higher in PCB concentration compared with females. Thus, the bulk of the observed difference in PCB concentrations between the sexes was not explained by growth dilution. We concluded that a higher rate of energy expenditure in males, stemming from greater activity and a greater resting metabolic rate, was most likely the primary driver for the observed difference in PCB concentrations between the sexes.

  2. POSSIBLE RAMIFICATIONS OF HIGHER MERCURY CONCENTRATIONS IN FILLET TISSUE OF SKINNIER FISH

    Science.gov (United States)

    Mercury concentrations were found to be statistically higher in the fillet tissue of the skinnier individuals of a fish species (striped bass) that was experiencing starvation when collected from Lake Mead, which is located on the Arizona-Nevada border. This is considered a conse...

  3. Concentration and behavior of radiocesium in higher basidiomycetes in some Kanto and the Koshin districts, Japan

    International Nuclear Information System (INIS)

    Sugiyama, Hideo; Iwashima, Kiyoshi; Shibata, Hisashi.

    1990-01-01

    Concentration of 137 Cs, 134 Cs and potassium were measured in several higher fungi and in substrates, soils, woods and litters in some Kanto and the Koshin districts, Japan, following the Chernobyl accident during October to November 1989. 137 Cs concentrations in fungi were in the range of 0.7-101 Bq kg -1 · fresh. Maximum 137 Cs level in them was observed in Boletopsis leucomelas (Pers.: Fr.) Fayod. Significantly higher levels of concentration ratios of 137 Cs in fungi to substrates (e.g.; 137 Cs concentration · fresh in fungus/ 137 Cs concentration · dry in soil), 10 -1 to 10 x 10 -1 , were found nearly 10 to 1000 times as much as leaf vegetables, root crops and potatoes to substrates. It was confirmed that levels of concentration ratios of potassium were similar to those of 137 Cs. In all fungi, 134 Cs which released from the Chernobyl accident and is not present in nuclear weapons fallout was not detected. (author)

  4. Human In Silico Drug Trials Demonstrate Higher Accuracy than Animal Models in Predicting Clinical Pro-Arrhythmic Cardiotoxicity

    Directory of Open Access Journals (Sweden)

    Elisa Passini

    2017-09-01

    Full Text Available Early prediction of cardiotoxicity is critical for drug development. Current animal models raise ethical and translational questions, and have limited accuracy in clinical risk prediction. Human-based computer models constitute a fast, cheap and potentially effective alternative to experimental assays, also facilitating translation to human. Key challenges include consideration of inter-cellular variability in drug responses and integration of computational and experimental methods in safety pharmacology. Our aim is to evaluate the ability of in silico drug trials in populations of human action potential (AP models to predict clinical risk of drug-induced arrhythmias based on ion channel information, and to compare simulation results against experimental assays commonly used for drug testing. A control population of 1,213 human ventricular AP models in agreement with experimental recordings was constructed. In silico drug trials were performed for 62 reference compounds at multiple concentrations, using pore-block drug models (IC50/Hill coefficient. Drug-induced changes in AP biomarkers were quantified, together with occurrence of repolarization/depolarization abnormalities. Simulation results were used to predict clinical risk based on reports of Torsade de Pointes arrhythmias, and further evaluated in a subset of compounds through comparison with electrocardiograms from rabbit wedge preparations and Ca2+-transient recordings in human induced pluripotent stem cell-derived cardiomyocytes (hiPS-CMs. Drug-induced changes in silico vary in magnitude depending on the specific ionic profile of each model in the population, thus allowing to identify cell sub-populations at higher risk of developing abnormal AP phenotypes. Models with low repolarization reserve (increased Ca2+/late Na+ currents and Na+/Ca2+-exchanger, reduced Na+/K+-pump are highly vulnerable to drug-induced repolarization abnormalities, while those with reduced inward current density

  5. Human In Silico Drug Trials Demonstrate Higher Accuracy than Animal Models in Predicting Clinical Pro-Arrhythmic Cardiotoxicity.

    Science.gov (United States)

    Passini, Elisa; Britton, Oliver J; Lu, Hua Rong; Rohrbacher, Jutta; Hermans, An N; Gallacher, David J; Greig, Robert J H; Bueno-Orovio, Alfonso; Rodriguez, Blanca

    2017-01-01

    Early prediction of cardiotoxicity is critical for drug development. Current animal models raise ethical and translational questions, and have limited accuracy in clinical risk prediction. Human-based computer models constitute a fast, cheap and potentially effective alternative to experimental assays, also facilitating translation to human. Key challenges include consideration of inter-cellular variability in drug responses and integration of computational and experimental methods in safety pharmacology. Our aim is to evaluate the ability of in silico drug trials in populations of human action potential (AP) models to predict clinical risk of drug-induced arrhythmias based on ion channel information, and to compare simulation results against experimental assays commonly used for drug testing. A control population of 1,213 human ventricular AP models in agreement with experimental recordings was constructed. In silico drug trials were performed for 62 reference compounds at multiple concentrations, using pore-block drug models (IC 50 /Hill coefficient). Drug-induced changes in AP biomarkers were quantified, together with occurrence of repolarization/depolarization abnormalities. Simulation results were used to predict clinical risk based on reports of Torsade de Pointes arrhythmias, and further evaluated in a subset of compounds through comparison with electrocardiograms from rabbit wedge preparations and Ca 2+ -transient recordings in human induced pluripotent stem cell-derived cardiomyocytes (hiPS-CMs). Drug-induced changes in silico vary in magnitude depending on the specific ionic profile of each model in the population, thus allowing to identify cell sub-populations at higher risk of developing abnormal AP phenotypes. Models with low repolarization reserve (increased Ca 2+ /late Na + currents and Na + /Ca 2+ -exchanger, reduced Na + /K + -pump) are highly vulnerable to drug-induced repolarization abnormalities, while those with reduced inward current density

  6. Higher Desolvation Energy Reduces Molecular Recognition in Multi-Drug Resistant HIV-1 Protease

    Directory of Open Access Journals (Sweden)

    Ladislau C. Kovari

    2012-05-01

    Full Text Available Designing HIV-1 protease inhibitors that overcome drug-resistance is still a challenging task. In this study, four clinical isolates of multi-drug resistant HIV-1 proteases that exhibit resistance to all the US FDA-approved HIV-1 protease inhibitors and also reduce the substrate recognition ability were examined. A multi-drug resistant HIV-1 protease isolate, MDR 769, was co-crystallized with the p2/NC substrate and the mutated CA/p2 substrate, CA/p2 P1’F. Both substrates display different levels of molecular recognition by the wild-type and multi-drug resistant HIV-1 protease. From the crystal structures, only limited differences can be identified between the wild-type and multi-drug resistant protease. Therefore, a wild-type HIV-1 protease and four multi-drug resistant HIV-1 proteases in complex with the two peptides were modeled based on the crystal structures and examined during a 10 ns-molecular dynamics simulation. The simulation results reveal that the multi-drug resistant HIV-1 proteases require higher desolvation energy to form complexes with the peptides. This result suggests that the desolvation of the HIV-1 protease active site is an important step of protease-ligand complex formation as well as drug resistance. Therefore, desolvation energy could be considered as a parameter in the evaluation of future HIV-1 protease inhibitor candidates.

  7. Flurbiprofen concentration in soft tissues is higher after topical application than after oral administration

    Science.gov (United States)

    Kai, Shuken; Kondo, Eiji; Kawaguchi, Yasuyuki; Kitamura, Nobuto; Yasuda, Kazunori

    2013-01-01

    Aim To compare tissue concentrations of flurbiprofen resulting from topical application and oral administration according to the regulatory approved dosing guidelines. Method Sixteen patients were included in this study. Each patient was randomly assigned to the topical application or oral administration group. In each group, a pair of tapes or a tablet, containing a total of 40 mg flurbiprofen, was administered twice at 16 and 2 h before the surgery. Results The flurbiprofen concentration in the fat, tendon, muscle and periosteum tissues was significantly higher (P flurbiprofen to the human body, particularly to soft tissues near the body surface. PMID:22822928

  8. Cocaine use is associated with a higher prevalence of elevated ST2 concentrations.

    Science.gov (United States)

    van Wijk, Xander M R; Vittinghoff, Eric; Wu, Alan H B; Lynch, Kara L; Riley, Elise D

    2017-09-01

    Cocaine is a well-known risk factor for acute cardiac events, but the effects in users outside of acute events are less clear. We investigated a possible association between cocaine use and the concentration of a novel biomarker for cardiac stress and heart failure, ST2. A case-control study was conducted to compare ST2 concentrations by the presence of cocaine in patients presenting for care, but not cardiac care, at an urban safety net hospital. In samples taken from 100 cocaine-positive and 100 cocaine-negative patients, the presence of cocaine was associated with ST2 concentrations>35ng/mL. Serum concentrations of benzoylecgonine, a major cocaine metabolite, were significantly correlated with ST2 concentrations. Cocaine use is associated with subclinical cardiac stress and damage outside of acute cardiac events. This information could add to better stratification of cocaine users with elevated ST2 concentrations who may be at higher risk for developing heart failure and other cardiac complications. Copyright © 2017 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.

  9. Anticancer drugs in Portuguese surface waters - Estimation of concentrations and identification of potentially priority drugs.

    Science.gov (United States)

    Santos, Mónica S F; Franquet-Griell, Helena; Lacorte, Silvia; Madeira, Luis M; Alves, Arminda

    2017-10-01

    Anticancer drugs, used in chemotherapy, have emerged as new water contaminants due to their increasing consumption trends and poor elimination efficiency in conventional water treatment processes. As a result, anticancer drugs have been reported in surface and even drinking waters, posing the environment and human health at risk. However, the occurrence and distribution of anticancer drugs depend on the area studied and the hydrological dynamics, which determine the risk towards the environment. The main objective of the present study was to evaluate the risk of anticancer drugs in Portugal. This work includes an extensive analysis of the consumption trends of 171 anticancer drugs, sold or dispensed in Portugal between 2007 and 2015. The consumption data was processed aiming at the estimation of predicted environmental loads of anticancer drugs and 11 compounds were identified as potentially priority drugs based on an exposure-based approach (PEC b > 10 ng L -1 and/or PEC c > 1 ng L -1 ). In a national perspective, mycophenolic acid and mycophenolate mofetil are suspected to pose high risk to aquatic biota. Moderate and low risk was also associated to cyclophosphamide and bicalutamide exposition, respectively. Although no evidences of risk exist yet for the other anticancer drugs, concerns may be associated with long term effects. Copyright © 2017 Elsevier Ltd. All rights reserved.

  10. Serum vitamin E concentrations among highly functioning hip fracture patients are higher than in nonfracture controls.

    Science.gov (United States)

    D'Adamo, Christopher R; Shardell, Michelle D; Hicks, Gregory E; Orwig, Denise L; Hochberg, Marc C; Semba, Richard D; Yu-Yahiro, Janet A; Ferrucci, Luigi; Magaziner, Jay S; Miller, Ram R

    2011-03-01

    fracture patients demonstrated higher vitamin E concentrations. Thus, the relatively high degree of function among this cohort of hip fracture patients may explain their higher-than-expected vitamin E concentrations. Copyright © 2011 Elsevier Inc. All rights reserved.

  11. Plasma vs heart tissue concentration in humans - literature data analysis of drugs distribution.

    Science.gov (United States)

    Tylutki, Zofia; Polak, Sebastian

    2015-03-12

    Little is known about the uptake of drugs into the human heart, although it is of great importance nowadays, when science desires to predict tissue level behavior rather than to measure it. Although the drug concentration in cardiac tissue seems a better predictor for physiological and electrophysiological changes than its level in plasma, knowledge of this value is very limited. Tissue to plasma partition coefficients (Kp) come to rescue since they characterize the distribution of a drug among tissues as being one of the input parameters in physiologically based pharmacokinetic (PBPK) models. The article reviews cardiac surgery and forensic medical studies to provide a reference for drug concentrations in human cardiac tissue. Firstly, the focus is on whether a drug penetrates into heart tissue at a therapeutic level; the provided values refer to antibiotics, antifungals and anticancer drugs. Drugs that directly affect cardiomyocyte electrophysiology are another group of interest. Measured levels of amiodarone, digoxin, perhexiline and verapamil in different sites in human cardiac tissue where the compounds might meet ion channels, gives an insight into how these more lipophilic drugs penetrate the heart. Much data are derived from postmortem studies and they provide insight to the cardiac distribution of more than 200 drugs. The analysis depicts potential problems in defining the active concentration location, what may indirectly suggest multiple mechanisms involved in the drug distribution within the heart. Copyright © 2015 John Wiley & Sons, Ltd. Copyright © 2015 John Wiley & Sons, Ltd.

  12. The toxicological significance of post-mortem drug concentrations in bile.

    Science.gov (United States)

    Ferner, Robin E; Aronson, Jeffrey K

    2018-01-01

    Some authors have proposed that post-mortem drug concentrations in bile are useful in estimating concentrations in blood. Both The International Association of Forensic Toxicologists (TIAFT) and the US Federal Aviation Administration recommend that samples of bile should be obtained in some circumstances. Furthermore, standard toxicological texts compare blood and bile concentrations, implying that concentrations in bile are of forensic value. To review the evidence on simultaneous measurements of blood and bile drug concentrations reported in the medical literature. We made a systematic search of EMBASE 1980-2016 using the search terms ("bile/" OR "exp drug bile level/concentration/") AND "drug blood level/concentration/", PubMed 1975-2017 for ("bile[tw]" OR "biliary[tw]") AND ("concentration[tw]" OR "concentrations[tw]" OR "level[tw]" OR "levels[tw]") AND "post-mortem[tw]" and also MEDLINE 1990-2016 for information on drugs whose biliary concentrations were mentioned in standard textbooks. The search was limited to human studies without language restrictions. We also examined recent reviews, indexes of relevant journals and citations in Web of Science and Google Scholar. We calculated the bile:blood concentration ratio. The searches together yielded 1031 titles with abstracts. We scanned titles and abstracts for relevance and retrieved 230, of which 161 were considered further. We excluded 49 papers because: the paper reported only one case (30 references); the data referred only to a metabolite (1); the work was published before 1980 (3); the information concerned only samples taken during life (10); or the paper referred to a toxin or unusual recreational drug (5). The remaining 112 papers provided data for analysis, with at least two observations for each of 58 drugs. Bile:blood concentration ratios: Median bile:blood concentration ratios varied from 0.18 (range 0.058-0.32) for dextromoramide to 520 (range 0.62-43,000) for buprenorphine. Median bile

  13. Suspended particle and drug ingredient concentrations in hospital dispensaries and implications for pharmacists' working environments.

    Science.gov (United States)

    Inaba, Ryoichi; Hioki, Atsushi; Kondo, Yoshihiro; Nakamura, Hiroki; Nakamura, Mitsuhiro

    2016-03-01

    The aim of this study was to assess the present status of working environments for pharmacists, including the concentrations of suspended particles and suspended drug ingredients in dispensaries. We conducted a survey on the work processes and working environment in 15 hospital dispensaries, and measured the concentrations of suspended particles and suspended drug ingredients using digital dust counter and high-performance liquid chromatography tandem mass spectrometry (LC-MS/MS), respectively. Of 25 types of powdered drugs that were frequently handled in the 15 dispensaries surveyed, 11 could be quantitatively determined. The amounts of suspended particles were relatively high, but below the reference value, in three dispensaries without dust collectors. The sedative-hypnotic drug zopiclone was detected in the suspended particles at one dispensary that was not equipped with dust collectors, and the antipyretic and analgesic drug acetaminophen was detected in two dispensaries equipped with dust collectors. There was no correlation between the daily number of prescriptions containing powdered drugs and the concentration of suspended particles in dispensaries. On the basis of the suspended particle concentrations measured, we concluded that dust collectors were effective in these dispensaries. However, suspended drug ingredients were detected also in dispensaries with dust collectors. These results suggest that the drug dust control systems of individual dispensaries should be properly installed and managed.

  14. The frequency of drugs among Danish drivers before and after the introduction of fixed concentration limits

    DEFF Research Database (Denmark)

    Steentoft, Anni; Simonsen, Kirsten Wiese; Linnet, Kristian

    2010-01-01

    Until July 2007, the driving under the influence of drugs (DUID) legislation in Denmark was based on impairment, evaluated on the basis of a clinical investigation and toxicological analyses, but in 2007 fixed concentration limits were introduced into the Danish traffic legislation. The objective...... for this study was to investigate the prevalence of medication and illicit drugs among Danish drivers before and after 2007.......Until July 2007, the driving under the influence of drugs (DUID) legislation in Denmark was based on impairment, evaluated on the basis of a clinical investigation and toxicological analyses, but in 2007 fixed concentration limits were introduced into the Danish traffic legislation. The objective...

  15. Prevalence of alcohol and other drugs and the concentrations in blood of drivers killed in road traffic crashes in Sweden.

    Science.gov (United States)

    Ahlner, Johan; Holmgren, Anita; Jones, Alan Wayne

    2014-03-01

    Drunk or drug-impaired drivers represent a major public health and societal problem worldwide. Because over 95% of drivers killed on the roads in Sweden are autopsied, reliable information is available about the use of alcohol and/or other drug before the crash. This retrospective 4-year study (2008-2011) used a forensic toxicology database (TOXBASE) to evaluate the concentrations of alcohol and other drugs in blood samples from drivers killed in road-traffic crashes. The mean age of all victims (N = 895) was 48 ± 20 years, and the majority were male (86%). In 504 drivers (56%), the results of toxicological analysis were negative and these victims were older; mean age (± SD) 47 ± 20 years, than alcohol positive cases (35 ± 14 years) and illicit drug users (34 ± 15 years). In 21% of fatalities, blood-alcohol concentration (BAC) was above the statutory limit for driving (0.2 g/L), although the median BAC was appreciably higher (1.72 g/L). Illicit drugs (mainly amphetamine and cannabis) were identified in ~7% of victims, either alone (2.5%), together with alcohol (1.8%) or a prescription drug (2%). The psychoactive prescription drugs identified were mainly benzodiazepines, z-hypnotics and tramadol, which were found in the blood of 7.6% of crash victims. The high median BAC in fatally-injured drivers speaks strongly towards alcohol-induced impairment as being responsible for the crash. Compared with alcohol, the prevalence of illicit and psychoactive prescription drugs was fairly low despite a dramatic increase in the number of drug-impaired drivers arrested by the police after a zero-tolerance law was introduced in 1999.

  16. Can fluconazole concentrations in saliva be used for therapeutic drug monitoring?

    NARCIS (Netherlands)

    Koks, C. H.; Crommentuyn, K. M.; Hoetelmans, R. M.; Mathôt, R. A.; Beijnen, J. H.

    2001-01-01

    The saliva/plasma concentration ratio of fluconazole was investigated in 22 HIV-1-infected individuals with an oropharyngeal Candida infection to determine whether saliva fluconazole concentrations could provide useful information for therapeutic drug monitoring in this population. Steady-state

  17. Clinical significance of 2 h plasma concentrations of first-line anti-tuberculosis drugs

    DEFF Research Database (Denmark)

    Prahl, Julie B; Johansen, Isik S; Cohen, Arieh S

    2014-01-01

    OBJECTIVES: To study 2 h plasma concentrations of the first-line tuberculosis drugs isoniazid, rifampicin, ethambutol and pyrazinamide in a cohort of patients with tuberculosis in Denmark and to determine the relationship between the concentrations and the clinical outcome. METHODS: After 6......-207 days of treatment (median 34 days) 2 h blood samples were collected from 32 patients with active tuberculosis and from three patients receiving prophylactic treatment. Plasma concentrations were determined using LC-MS/MS. Normal ranges were obtained from the literature. Clinical charts were reviewed...... failure occurred more frequently when the concentrations of isoniazid and rifampicin were both below the normal ranges (P = 0.013) and even more frequently when they were below the median 2 h drug concentrations obtained in the study (P = 0.005). CONCLUSIONS: At 2 h, plasma concentrations of isoniazid...

  18. Mathematical Model to Predict Skin Concentration after Topical Application of Drugs

    Directory of Open Access Journals (Sweden)

    Hiroaki Todo

    2013-12-01

    Full Text Available Skin permeation experiments have been broadly done since 1970s to 1980s as an evaluation method for transdermal drug delivery systems. In topically applied drug and cosmetic formulations, skin concentration of chemical compounds is more important than their skin permeations, because primary target site of the chemical compounds is skin surface or skin tissues. Furthermore, the direct pharmacological reaction of a metabolically stable drug that binds with specific receptors of known expression levels in an organ can be determined by Hill’s equation. Nevertheless, little investigation was carried out on the test method of skin concentration after topically application of chemical compounds. Recently we investigated an estimating method of skin concentration of the chemical compounds from their skin permeation profiles. In the study, we took care of “3Rs” issues for animal experiments. We have proposed an equation which was capable to estimate animal skin concentration from permeation profile through the artificial membrane (silicone membrane and animal skin. This new approach may allow the skin concentration of a drug to be predicted using Fick’s second law of diffusion. The silicone membrane was found to be useful as an alternative membrane to animal skin for predicting skin concentration of chemical compounds, because an extremely excellent extrapolation to animal skin concentration was attained by calculation using the silicone membrane permeation data. In this chapter, we aimed to establish an accurate and convenient method for predicting the concentration profiles of drugs in the skin based on the skin permeation parameters of topically active drugs derived from steady-state skin permeation experiments.

  19. Higher aluminum concentration in Alzheimer's disease after Box-Cox data transformation.

    Science.gov (United States)

    Rusina, Robert; Matěj, Radoslav; Kašparová, Lucie; Kukal, Jaromír; Urban, Pavel

    2011-11-01

    Evidence regarding the role of mercury and aluminum in the pathogenesis of Alzheimer's disease (AD) remains controversial. The aims of our project were to investigate the content of the selected metals in brain tissue samples and the use of a specific mathematical transform to eliminate the disadvantage of a strong positive skew in the original data distribution. In this study, we used atomic absorption spectrophotometry to determine mercury and aluminum concentrations in the hippocampus and associative visual cortex of 29 neuropathologically confirmed AD and 27 age-matched controls. The Box-Cox data transformation was used for statistical evaluation. AD brains had higher mean aluminum concentrations in the hippocampus than controls (0.357 vs. 0.090 μg/g; P = 0.039) after data transformation. Results for mercury were not significant. Original data regarding microelement concentrations are heavily skewed and do not pass the normality test in general. A Box-Cox transformation can eliminate this disadvantage and allow parametric testing.

  20. An introduction to predictive modelling of drug concentration in anaesthesia monitors.

    Science.gov (United States)

    DeCou, J; Johnson, K

    2017-01-01

    A significant amount of anaesthetists' work involves the prediction of drug effects and interactions to produce a smooth general anaesthetic that minimises drug side effects and promotes rapid emergence. Successfully managing this process requires a basic understanding of drug effects, experience and inevitably some guesswork, since it is difficult (and in some cases impossible) to anticipate all relevant patient and surgical factors. Although data are generally available to allow calculation of plasma drug and effect site concentrations, this is often difficult to apply in complex clinical contexts, particularly when multiple drug types are used. In recent years, manufacturers have developed and incorporated into anaesthetic workstations technologies that use drug pharmacodynamic and pharmacokinetic data to predict drug effects and interactions. Such systems can predict the duration and effects of drugs during anaesthesia and assist the anaesthetist to understand complex drug interactions. With this information available, different drug types, doses and combinations may be tailored in a scientific way to maximise useful effects whilst minimising overdose and side-effects, particularly in high-risk patients. Examples are used to illustrate how such systems can be used in practice, and how drug effects and interactions can be simulated to "rehearse" an anaesthetic before any drugs are actually administered. At present only a small number of anaesthetic workstations use this technology, and as yet they are not able to manage all drugs used in anaesthetic practice. However, such systems have the potential to help anaesthetists manage the complexity of their work, and to provide information on predicted drug effects in a way that is useful and relevant to both experienced anaesthetists and trainees. © 2017 The Association of Anaesthetists of Great Britain and Ireland.

  1. Cure of tuberculosis despite serum concentrations of antituberculosis drugs below published reference ranges.

    Science.gov (United States)

    Meloni, Monica; Corti, Natascia; Müller, Daniel; Henning, Lars; Gutteck, Ursula; von Braun, Amrei; Weber, Rainer; Fehr, Jan

    2015-01-01

    Therapeutic target serum concentrations of first-line antituberculosis drugs have not been well defined in clinical studies in tuberculosis (TB) patients. We retrospectively investigated the estimated maximum serum concentrations (eC max) of antituberculosis drugs and clinical outcome of TB patients with therapeutic drug monitoring performed between 2010-2012 at our institution, and follow-up until March 2014. The eC max was defined as the highest serum concentration during a sampling period (2, 4 and 6 hours after drug ingestion). We compared the results with published eC max values, and categorised them as either "within reference range", "low eC max", or "very low eC max".Low/very low eC max-levels were defined as follows: isoniazid 2-3/max levels were classified as "low" or "very low". The eC max was below the relevant reference range in 80% of isoniazid, 95% of rifampicin, 30% of pyrazinamide, and 30% of ethambutol measurements. All but one patient were cured of tuberculosis. Although many antituberculosis drug serum concentrations were below the widely used reference ranges, 16 of 17 patients were cured of tuberculosis. These results challenge the use of the published reference ranges for therapeutic drug monitoring.

  2. Comparison of Active Drug Concentrations in the Pulmonary Epithelial Lining Fluid and Interstitial Fluid of Calves Injected with Enrofloxacin, Florfenicol, Ceftiofur, or Tulathromycin

    Science.gov (United States)

    Foster, Derek M.; Martin, Luke G.; Papich, Mark G.

    2016-01-01

    Bacterial pneumonia is the most common reason for parenteral antimicrobial administration to beef cattle in the United States. Yet there is little information describing the antimicrobial concentrations at the site of action. The objective of this study was to compare the active drug concentrations in the pulmonary epithelial lining fluid and interstitial fluid of four antimicrobials commonly used in cattle. After injection, plasma, interstitial fluid, and pulmonary epithelial lining fluid concentrations and protein binding were measured to determine the plasma pharmacokinetics of each drug. A cross-over design with six calves per drug was used. Following sample collection and drug analysis, pharmacokinetic calculations were performed. For enrofloxacin and metabolite ciprofloxacin, the interstitial fluid concentration was 52% and 78% of the plasma concentration, while pulmonary fluid concentrations was 24% and 40% of the plasma concentration, respectively. The pulmonary concentrations (enrofloxacin + ciprofloxacin combined) exceeded the MIC90 of 0.06 μg/mL at 48 hours after administration. For florfenicol, the interstitial fluid concentration was almost 98% of the plasma concentration, and the pulmonary concentrations were over 200% of the plasma concentrations, exceeding the breakpoint (≤ 2 μg/mL), and the MIC90 for Mannheimia haemolytica (1.0 μg/mL) for the duration of the study. For ceftiofur, penetration to the interstitial fluid was only 5% of the plasma concentration. Pulmonary epithelial lining fluid concentration represented 40% of the plasma concentration. Airway concentrations exceeded the MIC breakpoint for susceptible respiratory pathogens (≤ 2 μg/mL) for a short time at 48 hours after administration. The plasma and interstitial fluid concentrations of tulathromcyin were lower than the concentrations in pulmonary fluid throughout the study. The bronchial concentrations were higher than the plasma or interstitial concentrations, with over 900

  3. Comparison of Active Drug Concentrations in the Pulmonary Epithelial Lining Fluid and Interstitial Fluid of Calves Injected with Enrofloxacin, Florfenicol, Ceftiofur, or Tulathromycin.

    Directory of Open Access Journals (Sweden)

    Derek M Foster

    Full Text Available Bacterial pneumonia is the most common reason for parenteral antimicrobial administration to beef cattle in the United States. Yet there is little information describing the antimicrobial concentrations at the site of action. The objective of this study was to compare the active drug concentrations in the pulmonary epithelial lining fluid and interstitial fluid of four antimicrobials commonly used in cattle. After injection, plasma, interstitial fluid, and pulmonary epithelial lining fluid concentrations and protein binding were measured to determine the plasma pharmacokinetics of each drug. A cross-over design with six calves per drug was used. Following sample collection and drug analysis, pharmacokinetic calculations were performed. For enrofloxacin and metabolite ciprofloxacin, the interstitial fluid concentration was 52% and 78% of the plasma concentration, while pulmonary fluid concentrations was 24% and 40% of the plasma concentration, respectively. The pulmonary concentrations (enrofloxacin + ciprofloxacin combined exceeded the MIC90 of 0.06 μg/mL at 48 hours after administration. For florfenicol, the interstitial fluid concentration was almost 98% of the plasma concentration, and the pulmonary concentrations were over 200% of the plasma concentrations, exceeding the breakpoint (≤ 2 μg/mL, and the MIC90 for Mannheimia haemolytica (1.0 μg/mL for the duration of the study. For ceftiofur, penetration to the interstitial fluid was only 5% of the plasma concentration. Pulmonary epithelial lining fluid concentration represented 40% of the plasma concentration. Airway concentrations exceeded the MIC breakpoint for susceptible respiratory pathogens (≤ 2 μg/mL for a short time at 48 hours after administration. The plasma and interstitial fluid concentrations of tulathromcyin were lower than the concentrations in pulmonary fluid throughout the study. The bronchial concentrations were higher than the plasma or interstitial concentrations

  4. Hypnosis control based on the minimum concentration of anesthetic drug for maintaining appropriate hypnosis.

    Science.gov (United States)

    Furutani, Eiko; Nishigaki, Yuki; Kanda, Chiaki; Takeda, Toshihiro; Shirakami, Gotaro

    2013-01-01

    This paper proposes a novel hypnosis control method using Auditory Evoked Potential Index (aepEX) as a hypnosis index. In order to avoid side effects of an anesthetic drug, it is desirable to reduce the amount of an anesthetic drug during surgery. For this purpose many studies of hypnosis control systems have been done. Most of them use Bispectral Index (BIS), another hypnosis index, but it has problems of dependence on anesthetic drugs and nonsmooth change near some particular values. On the other hand, aepEX has an ability of clear distinction between patient consciousness and unconsciousness and independence of anesthetic drugs. The control method proposed in this paper consists of two elements: estimating the minimum effect-site concentration for maintaining appropriate hypnosis and adjusting infusion rate of an anesthetic drug, propofol, using model predictive control. The minimum effect-site concentration is estimated utilizing the property of aepEX pharmacodynamics. The infusion rate of propofol is adjusted so that effect-site concentration of propofol may be kept near and always above the minimum effect-site concentration. Simulation results of hypnosis control using the proposed method show that the minimum concentration can be estimated appropriately and that the proposed control method can maintain hypnosis adequately and reduce the total infusion amount of propofol.

  5. Lung Tissue Concentrations of Pyrazinamide among Patients with Drug-Resistant Pulmonary Tuberculosis

    Science.gov (United States)

    Heinrichs, M. Tobias; Nikolaishvili, Ketino; Sabulua, Irina; Bablishvili, Nino; Gogishvili, Shota; Avaliani, Zaza; Tukvadze, Nestani; Little, Brent; Bernheim, Adam; Read, Timothy D.; Guarner, Jeannette; Derendorf, Hartmut; Peloquin, Charles A.; Blumberg, Henry M.; Vashakidze, Sergo

    2017-01-01

    ABSTRACT Improved knowledge regarding the tissue penetration of antituberculosis drugs may help optimize drug management. Patients with drug-resistant pulmonary tuberculosis undergoing adjunctive surgery were enrolled. Serial serum samples were collected, and microdialysis was performed using ex vivo lung tissue to measure pyrazinamide concentrations. Among 10 patients, the median pyrazinamide dose was 24.7 mg/kg of body weight. Imaging revealed predominant lung lesions as cavitary (n = 6 patients), mass-like (n = 3 patients), or consolidative (n = 1 patient). On histopathology examination, all tissue samples had necrosis; eight had a pH of ≤5.5. Tissue samples from two patients were positive for Mycobacterium tuberculosis by culture (pH 5.5 and 7.2). All 10 patients had maximal serum pyrazinamide concentrations within the recommended range of 20 to 60 μg/ml. The median lung tissue free pyrazinamide concentration was 20.96 μg/ml. The median tissue-to-serum pyrazinamide concentration ratio was 0.77 (range, 0.54 to 0.93). There was a significant inverse correlation between tissue pyrazinamide concentrations and the amounts of necrosis (R = −0.66, P = 0.04) and acid-fast bacilli (R = −0.75, P = 0.01) identified by histopathology. We found good penetration of pyrazinamide into lung tissue among patients with pulmonary tuberculosis with a variety of radiological lesion types. Our tissue pH results revealed that most lesions had a pH conducive to pyrazinamide activity. The tissue penetration of pyrazinamide highlights its importance in both drug-susceptible and drug-resistant antituberculosis treatment regimens. PMID:28373198

  6. Lung Tissue Concentrations of Pyrazinamide among Patients with Drug-Resistant Pulmonary Tuberculosis.

    Science.gov (United States)

    Kempker, Russell R; Heinrichs, M Tobias; Nikolaishvili, Ketino; Sabulua, Irina; Bablishvili, Nino; Gogishvili, Shota; Avaliani, Zaza; Tukvadze, Nestani; Little, Brent; Bernheim, Adam; Read, Timothy D; Guarner, Jeannette; Derendorf, Hartmut; Peloquin, Charles A; Blumberg, Henry M; Vashakidze, Sergo

    2017-06-01

    Improved knowledge regarding the tissue penetration of antituberculosis drugs may help optimize drug management. Patients with drug-resistant pulmonary tuberculosis undergoing adjunctive surgery were enrolled. Serial serum samples were collected, and microdialysis was performed using ex vivo lung tissue to measure pyrazinamide concentrations. Among 10 patients, the median pyrazinamide dose was 24.7 mg/kg of body weight. Imaging revealed predominant lung lesions as cavitary ( n = 6 patients), mass-like ( n = 3 patients), or consolidative ( n = 1 patient). On histopathology examination, all tissue samples had necrosis; eight had a pH of ≤5.5. Tissue samples from two patients were positive for Mycobacterium tuberculosis by culture (pH 5.5 and 7.2). All 10 patients had maximal serum pyrazinamide concentrations within the recommended range of 20 to 60 μg/ml. The median lung tissue free pyrazinamide concentration was 20.96 μg/ml. The median tissue-to-serum pyrazinamide concentration ratio was 0.77 (range, 0.54 to 0.93). There was a significant inverse correlation between tissue pyrazinamide concentrations and the amounts of necrosis ( R = -0.66, P = 0.04) and acid-fast bacilli ( R = -0.75, P = 0.01) identified by histopathology. We found good penetration of pyrazinamide into lung tissue among patients with pulmonary tuberculosis with a variety of radiological lesion types. Our tissue pH results revealed that most lesions had a pH conducive to pyrazinamide activity. The tissue penetration of pyrazinamide highlights its importance in both drug-susceptible and drug-resistant antituberculosis treatment regimens. Copyright © 2017 American Society for Microbiology.

  7. Serum concentrations of psychotropic drugs in neonates as a PROgnOstic Factor for admission to the neonatology ward and withdrawal symptoms: PROOF-1.

    Science.gov (United States)

    Sparla, Shirley C A; Coppens, Hans; Evers, Inge M; Stramrood, Claire A I; Pasker-de Jong, Pieternel C M; van der Westerlaken, Monique M L; Hogeman, Paul H G; Malingré, Mirte M

    2017-05-01

    The aim is to determine whether serum drug concentrations obtained from the neonate's umbilical cord can be used as a prognostic factor for admission to the neonatology ward and the occurrence of withdrawal symptoms. A retrospective observational monocenter cohort study was carried out among pregnant women using psychotropic drugs and their baby. Binary logistic regression was used for the multivariate analysis. Of the 186 neonates included, 22.6% (n=42) were admitted to the neonatology ward, 6.5% (n=12) because of withdrawal. Among women with therapeutic concentrations of psychotropic medication, 22.0% (n=5) of the neonates had withdrawal symptoms. When comparing neonates with therapeutic versus undetectable drug concentrations, an odds ratio of 3.1 (95% confidence interval: 1.1-8.6) was found for admission to the neonatology ward and an odds ratio of 20.5 (95% confidence interval: 2.2-186.1) for the occurrence of withdrawal symptoms. Therapeutic concentrations of psychotropic drugs in neonates' umbilical cord blood correspond with higher odds for admission to the neonatology ward and the occurrence of withdrawal symptoms compared with neonates with undetectable drug concentrations. The measurement of drug concentrations in the neonate may contribute toward the general clinical assessment of the physician to predict the necessity of admission to the neonatology ward and the risk of withdrawal symptoms.

  8. Rising atmospheric CO2 concentration may imply higher risk of Fusarium mycotoxin contamination of wheat grains.

    Science.gov (United States)

    Bencze, Szilvia; Puskás, Katalin; Vida, Gyula; Karsai, Ildikó; Balla, Krisztina; Komáromi, Judit; Veisz, Ottó

    2017-08-01

    Increasing atmospheric CO 2 concentration not only has a direct impact on plants but also affects plant-pathogen interactions. Due to economic and health-related problems, special concern was given thus in the present work to the effect of elevated CO 2 (750 μmol mol -1 ) level on the Fusarium culmorum infection and mycotoxin contamination of wheat. Despite the fact that disease severity was found to be not or little affected by elevated CO 2 in most varieties, as the spread of Fusarium increased only in one variety, spike grain number and/or grain weight decreased significantly at elevated CO 2 in all the varieties, indicating that Fusarium infection generally had a more dramatic impact on the grain yield at elevated CO 2 than at the ambient level. Likewise, grain deoxynivalenol (DON) content was usually considerably higher at elevated CO 2 than at the ambient level in the single-floret inoculation treatment, suggesting that the toxin content is not in direct relation to the level of Fusarium infection. In the whole-spike inoculation, DON production did not change, decreased or increased depending on the variety × experiment interaction. Cooler (18 °C) conditions delayed rachis penetration while 20 °C maximum temperature caused striking increases in the mycotoxin contents, resulting in extremely high DON values and also in a dramatic triggering of the grain zearalenone contamination at elevated CO 2 . The results indicate that future environmental conditions, such as rising CO 2 levels, may increase the threat of grain mycotoxin contamination.

  9. Flexing the PECs: Predicting environmental concentrations of veterinary drugs in Canadian agricultural soils.

    Science.gov (United States)

    Kullik, Sigrun A; Belknap, Andrew M

    2017-03-01

    Veterinary drugs administered to food animals primarily enter ecosystems through the application of livestock waste to agricultural land. Although veterinary drugs are essential for protecting animal health, their entry into the environment may pose a risk for nontarget organisms. A means to predict environmental concentrations of new veterinary drug ingredients in soil is required to assess their environmental fate, distribution, and potential effects. The Canadian predicted environmental concentrations in soil (PECsoil) for new veterinary drug ingredients for use in intensively reared animals is based on the approach currently used by the European Medicines Agency for VICH Phase I environmental assessments. The calculation for the European Medicines Agency PECsoil can be adapted to account for regional animal husbandry and land use practices. Canadian agricultural practices for intensively reared cattle, pigs, and poultry differ substantially from those in the European Union. The development of PECsoil default values and livestock categories representative of typical Canadian animal production methods and nutrient management practices culminates several years of research and an extensive survey and analysis of the scientific literature, Canadian agricultural statistics, national and provincial management recommendations, veterinary product databases, and producers. A PECsoil can be used to rapidly identify new veterinary drugs intended for intensive livestock production that should undergo targeted ecotoxicity and fate testing. The Canadian PECsoil model is readily available, transparent, and requires minimal inputs to generate a screening level environmental assessment for veterinary drugs that can be refined if additional data are available. PECsoil values for a hypothetical veterinary drug dosage regimen are presented and discussed in an international context. Integr Environ Assess Manag 2017;13:331-341. © 2016 Her Majesty the Queen in Right of Canada

  10. An inert 3D emulsification device for individual precipitation and concentration of amorphous drug nanoparticles.

    Science.gov (United States)

    Lorenz, T; Bojko, S; Bunjes, H; Dietzel, A

    2018-02-13

    Nanosizing increases the specific surface of drug particles, leading to faster dissolution inside the organism and improving the bioavailability of poorly water-soluble drugs. A novel approach for the preparation of drug nanoparticles in water using chemically inert microfluidic emulsification devices is presented in this paper. A lithographic fabrication sequence was established, allowing fabrication of intersecting and coaxial channels of different depths in glass as is required for 3D flow-focusing. Fenofibrate was used as a model for active pharmaceutical ingredients with very low water solubility in the experiments. It was dissolved in ethyl acetate and emulsified in water, as allowed by the 3D flow-focusing geometry. In the thread formation regime, the drug solution turned into monodisperse droplets of sizes down to below 1 μm. Fast supersaturation occurs individually in each droplet, as the disperse phase solvent progressively diffuses into the surrounding water. Liquid antisolvent precipitation results in highly monodisperse and amorphous nanoparticles of sizes down to 128 nm which can be precisely controlled by the continuous and disperse phase pressure. By comparing optically measured droplet sizes with particle sizes by dynamic light scattering, we could confirm that exactly one particle forms in every droplet. Furthermore, a downstream on-chip concentration allowed withdrawal of major volumes of only the continuous phase fluid which enabled an increase of particle concentration by up to 250 times.

  11. Serum vitamin E concentrations among highly functioning hip fracture patients are higher than in nonfracture controls

    OpenAIRE

    D’Adamo, Christopher R.; Shardell, Michelle D.; Hicks, Gregory E.; Orwig, Denise L.; Hochberg, Marc C.; Semba, Richard D.; Yu-Yahiro, Janet A.; Ferrucci, Luigi; Magaziner, Jay S.; Miller, Ram R.

    2011-01-01

    Malnutrition after hip fracture is common and associated with poor outcomes and protracted recovery. Low concentrations of vitamin E have been associated with incident decline in physical function among older adults and may, therefore, be particularly important to functionally compromised patients hip fracture patients. Serum concentrations of α-tocopherol and γ-tocopherol, the 2 major forms of vitamin E, were assessed in 148 female hip fracture patients 65 years or older from the Baltimore H...

  12. Higher prices at Canadian gas pumps: international crude oil prices or local market concentration? An empirical investigation

    International Nuclear Information System (INIS)

    Anindya Sen

    2003-01-01

    There is little consensus on whether higher retail gasoline prices in Canada are the result of international crude oil price fluctuations or local market power exercised by large vertically-integrated firms. I find that although both increasing local market concentration and higher average monthly wholesale prices are positively and significantly associated with higher retail prices, wholesale prices are more important than local market concentration. Similarly, crude oil prices are more important than the number of local wholesalers in determining wholesale prices. These results suggest that movements in gasoline prices are largely the result of input price fluctuations rather than local market structure. (author)

  13. Treatments that generate higher number of adverse drug reactions and their symptoms

    Directory of Open Access Journals (Sweden)

    Lucía Fernández-López

    2015-12-01

    Full Text Available Objectives: Adverse drug reactions (ADRs are an important cause of morbidity and mortality worldwide and generate high health costs. Therefore, the aims of this study were to determine the treatments which produce more ADRs in general population and the main symptoms they generate. Methods: An observational, cross-sectional study consisting in performing a self-rated questionnaire was carried out. 510 patients were asked about the treatments, illnesses and ADRs, they had suffered from. Results: 26.7% of patients had suffered from some ADR. Classifying patients according to the type of prescribed treatment and studying the number of ADR that they had, we obtained significant differences (p ≤ 0.05 for treatments against arthrosis, anemia and nervous disorders (anxiety, depression, insomnia. Moreover, determining absolute frequencies of these ADRs appearance in each treatment, higher frequencies were again for drugs against arthrosis (22.6% of patients treated for arthrosis suffered some ADR, anemia (14.28%, nerve disorders (13.44% and also asthma (16%. Regarding the symptoms produced by ADRs, the most frequent were gastrointestinal (60% of patients who suffered an ADR, had gastrointestinal symptoms and nervous alterations (dizziness, headache, sleep disturbances etc (24.6%. Conclusion: Therapeutic groups which produce more commonly ADRs are those for arthrosis, anemia, nervous disorders and asthma. In addition, symptoms which are generated more frequently are gastrointestinal and nervous problems. This is in accordance with the usual side effects of mentioned treatments. Health professionals should be informed about it, so that they would be more alert about a possible emergence of an ADR in these treatments. They also could provide enough information to empower patients and thus, they probably could detect ADR events. This would facilitate ADR detection and would avoid serious consequences generated to both patients' health and health economics.

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

    Science.gov (United States)

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

    2013-06-01

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

  15. Considerations for effect site pharmacokinetics to estimate drug exposure: concentrations of antibiotics in the lung.

    Science.gov (United States)

    Rodvold, Keith A; Hope, William W; Boyd, Sara E

    2017-10-01

    Bronchoalveolar lavage (BAL) and microdialysis have become the most reliable and relevant methods for measuring lung concentrations of antibiotics, with the majority of BAL studies involving either healthy adult subjects or patients undergoing diagnostic bronchoscopy. Emphasis on the amount of drug that reaches the site of infection is increasingly recognized as necessary to determine whether a dose selection will translate to good clinical outcomes in the treatment of patients with pneumonia. Observed concentrations and/or parameters of exposure (e.g. area-under-the-curve) need to be incorporated with pharmacokinetic-pharmacodynamic indices so that rational dose selection can be identified for specific pathogens and types of pneumonic infection (community-acquired vs hospital-acquired bacterial pneumonia, including ventilator-associated bacterial pneumonia). Although having measured plasma or lung concentration-time data from critically ill patients to incorporate into pharmacokinetic-pharmacodynamic models is very unlikely during drug development, it is essential that altered distribution, augmented renal clearance, and renal or hepatic dysfunction should be considered. Notably, the number of published studies involving microdialysis and intrapulmonary penetration of antibiotics has been limited and mainly involve beta-lactam agents, levofloxacin, and fosfomycin. Opportunities to measure in high-resolution effect site spatial pharmacokinetics (e.g. with MALDI-MSI or PET imaging) and in vivo continuous drug concentrations (e.g. with aptamer-based probes) now exist. Going forward these studies could be incorporated into antibiotic development programs for pneumonia in order to further increase the probability of candidate success. Copyright © 2017 Elsevier Ltd. All rights reserved.

  16. Targeting higher ferritin concentrations with intravenous iron dextran lowers erythropoietin requirement in hemodialysis patients.

    Science.gov (United States)

    DeVita, M V; Frumkin, D; Mittal, S; Kamran, A; Fishbane, S; Michelis, M F

    2003-11-01

    Although clinical use of recombinant human erythropoietin (rHuEPO) since 1989 has improved anemia in most end-stage renal disease patients, there are still many hemodialysis patients unable to maintain an adequate hematocrit (HCT) without large doses of rHuEPO. This suggests that anemia is not solely a consequence of rHuEPO deficiency, but may be due to other factors including functional iron deficiency. Since the optimal prescription for iron replacement is not yet known, we evaluated the effect of intravenous iron dextran (IVFe) infusion on serum ferritin (SFer) concentration and rHuEPO dose. Our objective was to raise and maintain serum ferritin concentrations to 2 different levels above the National Kidney Foundation Dialysis Outcome Quality Initiative standard of 100 ng/ml to determine whether, and by what degree rHuEPO dose could be lowered. HD patients on i.v. rHuEPO with a SFer concentration > or = 70 ng/ml and an HCT of requirements.

  17. Women Administered Standard Dose Imatinib for Chronic Myeloid Leukemia Have Higher Dose-Adjusted Plasma Imatinib and Norimatinib Concentrations Than Men.

    Science.gov (United States)

    Belsey, Sarah L; Ireland, Robin; Lang, Kathryn; Kizilors, Aytug; Ho, Aloysius; Mufti, Ghulam J; Bisquera, Alessandra; De Lavallade, Hugues; Flanagan, Robert J

    2017-10-01

    The standard dose of imatinib for the treatment of chronic-phase chronic myeloid leukemia (CML) is 400 mg·d. A predose plasma imatinib concentration of >1 mg·L is associated with improved clinical response. This study aimed to assess the plasma imatinib and norimatinib concentrations attained in patients with chronic myeloid leukemia administered standard doses of imatinib adjusted for dose, age, sex, body weight, and response. We evaluated data from a cohort of patients treated between 2008 and 2014 with respect to dose, age, sex, body weight, and response. The study comprised 438 samples from 93 patients (54 male, 39 female). The median imatinib dose was 400 mg·d in men and in women. The plasma imatinib concentration ranged 0.1-5.0 mg·L and was below 1 mg·L in 20% and 16% of samples from men and women, respectively. The mean dose normalized plasma imatinib and norimatinib concentrations were significantly higher in women in comparison with men. This was partially related to body weight. Mixed effects ordinal logistic regression showed no evidence of an association between sex and plasma imatinib (P = 0.13). However, there was evidence of an association between sex and plasma norimatinib, with higher norimatinib concentrations more likely in women than in men (P = 0.02). Imatinib therapeutic drug monitoring only provides information on dosage adequacy and on short-term adherence; longer-term adherence cannot be assessed. However, this analysis revealed that approximately 1 in 5 samples had a plasma imatinib concentration <1 mg·L, which was suggestive of inadequate dosage and/or poor adherence and posed a risk of treatment failure. Higher imatinib exposure in women may be a factor in the increased rate of long-term, stable, deep molecular response (undetectable breakpoint cluster-Abelson (BCR-ABL) transcript levels with a PCR sensitivity of 4.5 log, MR4.5) reported in women.

  18. Adequate plasma drug concentrations suggest that amoxicillin can be administered by continuous infusion using elastomeric pumps.

    Science.gov (United States)

    Arensdorff, Lyne; Boillat-Blanco, Noémie; Decosterd, Laurent; Buclin, Thierry; de Vallière, Serge

    2017-09-01

    Elastomeric pumps can be useful for the administration of antibiotics in the outpatient setting. To determine amoxicillin degradation in elastomeric pumps, as well as the effectiveness of amoxicillin treatment administered by elastomeric pumps. Antibiotic degradation was measured in elastomeric pumps filled with 6 g of amoxicillin in 240 mL of NaCl 0.9% by drawing samples at 12 h intervals when stored in the fridge for 48 h and when worn around the waist for 24 h. Subsequently nine patients were treated with continuous infusions of 8 or 12 g of amoxicillin per day. Plasma amoxicillin concentrations were measured on each visit to the outpatient parenteral antibiotic therapy unit. Clinical outcome was verified 3 months after the end of treatment. Amoxicillin degradation in elastomeric pumps reached 10% after 48 h in the fridge and an additional 30% when worn around the waist for 24 h. Mean plasma drug concentrations achieved with 12 g of amoxicillin per day were 18.5 mg/L (95% CI 13.5-23.5), which is largely above the MIC of amoxicillin-susceptible bacteria. Nine patients treated for various complicated infections were cured and had no unexpected adverse effects. Adequate plasma drug concentrations and favourable clinical outcomes suggest that amoxicillin can be administered by continuous infusion using elastomeric pumps. This treatment modality does not fulfil formal requirements regarding pharmaceutical stability, but the resulting safety impact in patients is probably limited. Therapeutic drug monitoring and a close clinical follow-up are recommended if this route of administration is chosen. © The Author 2017. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  19. Different Levels in Orexin Concentrations and Risk Factors Associated with Higher Orexin Levels: Comparison between Detoxified Opiate and Methamphetamine Addicts in 5 Chinese Cities

    Directory of Open Access Journals (Sweden)

    Haoran Zhang

    2013-01-01

    Full Text Available This study sought to explore the degree of orexin levels in Chinese opiate and methamphetamine addicts and the differences between them. The cross-sectional study was conducted among detoxified drug addicts from Mandatory Detoxification Center (MDC in five Chinese cities. Orexin levels were assayed with radioimmunoassay (RIA. Mann-Whitney U test and Kruskal-Wallis test were used to detect differences across groups, and logistic regression was used to explore the association between orexin levels and characteristics of demographic and drug abuse. Between November 2009 and January 2011, 285 opiates addicts, 112 methamphetamine addicts, and 79 healthy controls were enrolled. At drug withdrawal period, both opiate and methamphetamine addicts had lower median orexin levels than controls, and median orexin levels in opiate addicts were higher than those in methamphetamine addicts (all above P<0.05. Adjusted odds of the above median concentration of orexin were higher for injection than “chasing the dragon” (AOR = 3.1, 95% CI = 1.2–7.9. No significant factors associated with orexin levels of methamphetamine addicts were found. Development of intervention method on orexin system by different administration routes especially for injected opiate addicts at detoxification phase may be significant and was welcome.

  20. Approaches to analysis of data that concentrate near higher-dimensional manifolds

    International Nuclear Information System (INIS)

    Friedman, J.H.; Tukey, J.W.; Tukey, P.A.

    1979-01-01

    The need to explore structure in high-dimensional clouds of data points that may concentrate near (possibly nonlinear) manifolds of lower dimension led to the current development of three new approaches. The first is a computer-graphic system (PRIM'79) that facilitates interactive viewing and manipulation of an ensemble of points. The other two are automatic procedures for separating a cloud into more manageable pieces. One of these (BIDEC) performs successive partitioning of the cloud by use of hyperplanes; the other (Cake Maker) explores expanding sequences of neighborhoods. Both procedures provide facilities for examining the resulting pieces and the relationships among them

  1. Copeptin, a surrogate marker for arginine vasopressin secretion, is associated with higher glucose and insulin concentrations but not higher blood pressure in obese men

    DEFF Research Database (Denmark)

    Asferg, C L; Andersen, Ulrik Bjørn; Linneberg, A

    2014-01-01

    distribution. METHODS: In 103 obese men (mean age ± standard deviation: 49.4 ± 10.2 years) and 27 normal weight control men (mean age: 51.5 ± 8.4 years), taking no medication, we measured 24-h ambulatory blood pressure, fasting blood concentrations of copeptin, lipids, glucose and insulin, and determined body...... blood pressure (r = 0.11, P = 0.29), 24-h diastolic blood pressure (r = 0.11, P = 0.28), BMI (r = 0.09, P = 0.37), total body fatness percentage (r = 0.10, P = 0.33), android fat mass percentage (r = 0.04, P = 0.66) or serum triglyceride concentrations (r = 0.04; P = 0.68). In contrast, plasma copeptin......, and is associated with abnormalities in glucose and insulin metabolism, but not with higher blood pressure or an android fat distribution in obese men....

  2. Plasma drug concentrations and clinical effects of a peripheral alpha-2-adrenoceptor antagonist, MK-467, in horses sedated with detomidine.

    Science.gov (United States)

    Vainionpää, Mari H; Raekallio, Marja R; Pakkanen, Soile A E; Ranta-Panula, Ville; Rinne, Valtteri M; Scheinin, Mika; Vainio, Outi M

    2013-05-01

    To investigate plasma drug concentrations and the effect of MK-467 (L-659'066) on sedation, heart rate and gut motility in horses sedated with intravenous (IV) detomidine. Experimental randomized blinded crossover study. Six healthy horses. Detomidine (10 μg kg(-1) IV) was administered alone (DET) and in combination with MK-467 (250 μg kg(-1) IV; DET + MK). The level of sedation and intestinal sounds were scored. Heart rate (HR) and central venous pressure (CVP) were measured. Blood was collected to determine plasma drug concentrations. Repeated measures anova was used for HR, CVP and intestinal sounds, and the Student's t-test for pairwise comparisons between treatments for the area under the time-sedation curve (AUCsed ) and pharmacokinetic parameters. Significance was set at p Detomidine-induced intestinal hypomotility was prevented by MK-467. AUCsed was significantly higher with DET than DET + MK, but maximal sedations scores did not differ significantly between treatments. MK-467 lowered the AUC of the plasma concentration of detomidine, and increased its volume of distribution and clearance. MK-467 prevented detomidine induced bradycardia and intestinal hypomotility. MK-467 did not affect the clinical quality of detomidine-induced sedation, but the duration of the effect was reduced, which may have been caused by the effects of MK-467 on the plasma concentration of detomidine. MK-467 may be useful clinically in the prevention of certain peripheral side effects of detomidine in horses. © 2013 The Authors. Veterinary Anaesthesia and Analgesia © 2013 Association of Veterinary Anaesthetists and the American College of Veterinary Anesthesia and Analgesia.

  3. Progress and challenges of engineering a biophysical CO2-concentrating mechanism into higher plants.

    Science.gov (United States)

    Rae, Benjamin D; Long, Benedict M; Förster, Britta; Nguyen, Nghiem D; Velanis, Christos N; Atkinson, Nicky; Hee, Wei Yih; Mukherjee, Bratati; Price, G Dean; McCormick, Alistair J

    2017-06-01

    Growth and productivity in important crop plants is limited by the inefficiencies of the C3 photosynthetic pathway. Introducing CO2-concentrating mechanisms (CCMs) into C3 plants could overcome these limitations and lead to increased yields. Many unicellular microautotrophs, such as cyanobacteria and green algae, possess highly efficient biophysical CCMs that increase CO2 concentrations around the primary carboxylase enzyme, Rubisco, to enhance CO2 assimilation rates. Algal and cyanobacterial CCMs utilize distinct molecular components, but share several functional commonalities. Here we outline the recent progress and current challenges of engineering biophysical CCMs into C3 plants. We review the predicted requirements for a functional biophysical CCM based on current knowledge of cyanobacterial and algal CCMs, the molecular engineering tools and research pipelines required to translate our theoretical knowledge into practice, and the current challenges to achieving these goals. © The Author 2017. Published by Oxford University Press on behalf of the Society for Experimental Biology. All rights reserved. For permissions, please email: journals.permissions@oup.com.

  4. Higher Leptin but Not Human Milk Macronutrient Concentration Distinguishes Normal-Weight from Obese Mothers at 1-Month Postpartum.

    Science.gov (United States)

    De Luca, Arnaud; Frasquet-Darrieux, Marine; Gaud, Marie-Agnès; Christin, Patricia; Boquien, Clair-Yves; Millet, Christine; Herviou, Manon; Darmaun, Dominique; Robins, Richard J; Ingrand, Pierre; Hankard, Régis

    2016-01-01

    Exclusively breastfed infants born to obese mothers have previously been shown to gain less weight by 1-month postpartum than infants of normal-weight mothers. Our hypothesis is that human milk composition and volume may differ between obese and normal-weight mothers. To compare human milk leptin, macronutrient concentration, and volume in obese and normal-weight mothers. Mother and infant characteristics were studied as secondary aims. This cross-sectional observational study compared 50 obese mothers matched for age, parity, ethnic origin, and educational level with 50 normal-weight mothers. Leptin, macronutrient human milk concentration, and milk volume were determined at 1 month in exclusively breastfed infants. Mother characteristics and infant growth were recorded. Human milk leptin concentration was higher in obese mothers than normal-weight mothers (4.8±2.7 vs. 2.5±1.5 ng.mL-1, pobese and normal-weight mothers in protein, lipid, carbohydrate content, and volume, nor in infant weight gain. Leptin concentration was higher in the milk of obese mothers than that of normal-weight mothers, but macronutrient concentration was not. It remains to be established whether the higher leptin content impacts on infant growth beyond the 1-month of the study period.

  5. Irritable bowel syndrome is concentrated in people with higher educations in Iran: an inequality analysis

    Science.gov (United States)

    2017-01-01

    OBJECTIVES Like any other health-related disorder, irritable bowel syndrome (IBS) has a differential distribution with respect to socioeconomic factors. This study aimed to estimate and decompose educational inequalities in the prevalence of IBS. METHODS Sampling was performed using a multi-stage random cluster sampling approach. The data of 1,850 residents of Kish Island aged 15 years or older were included, and the determinants of IBS were identified using a generalized estimating equation regression model. The concentration index of educational inequality in cases of IBS was estimated and decomposed as the specific inequality index. RESULTS The prevalence of IBS in this study was 21.57% (95% confidence interval [CI], 19.69 to 23.44%). The concentration index of IBS was 0.20 (95% CI, 0.14 to 0.26). A multivariable regression model revealed that age, sex, level of education, marital status, anxiety, and poor general health were significant determinants of IBS. In the decomposition analysis, level of education (89.91%), age (−11.99%), and marital status (9.11%) were the three main contributors to IBS inequality. Anxiety and poor general health were the next two contributors to IBS inequality, and were responsible for more than 12% of the total observed inequality. CONCLUSIONS The main contributors of IBS inequality were education level, age, and marital status. Given the high percentage of anxious individuals among highly educated, young, single, and divorced people, we can conclude that all contributors to IBS inequality may be partially influenced by psychological factors. Therefore, programs that promote the development of mental health to alleviate the abovementioned inequality in this population are highly warranted. PMID:28171714

  6. Higher concentrations of branched-chain amino acids in breast milk of obese mothers.

    Science.gov (United States)

    De Luca, Arnaud; Hankard, Régis; Alexandre-Gouabau, Marie-Cécile; Ferchaud-Roucher, Véronique; Darmaun, Dominique; Boquien, Clair-Yves

    2016-01-01

    Nutrition during fetal life and early childhood is thought to play a crucial role in the risk for developing metabolic syndrome and cardiovascular diseases in the future adult and branched-chain amino acids (BCAA) intake may play a role in the development of obesity. The aim of this study was to compare the breast milk amino acid profiles of obese and normal weight (control) breast-feeding mothers. Fifty obese and 50 control breast-feeding mothers were enrolled. Age and parity were similar in both groups. Breast milk samples were collected at the end of the first month of lactation. Free amino acid (FAA) concentrations in breast milk were determined by ultra-performance liquid chromatography tandem mass spectrometry. Comparisons between groups were performed using a two-tailed paired t test. We analyzed 45 breast milk samples from each group. Body mass index was 34.3 ± 3.9 kg/m(2) in the obese group and 21.6 ± 1.4 kg/m(2) in the control group (P milk of obese mothers (95.5 ± 38.2 μM versus 79.8 ± 30.9 μM; P = 0.037), as was tyrosine concentration (13.8 ± 7.1 μM versus 10.6 ± 5.2 μM; P = 0.016). The mature breast milk of obese mothers contained 20% more BCAA and 30% more tyrosine than breast milk of control mothers. Whether altered breast milk FAA profile affects metabolic risk in the breast-fed child remains to be explored. Copyright © 2016 Elsevier Inc. All rights reserved.

  7. The Inflammatory Radicular Cysts Have Higher Concentration of TNF-α in Comparison to Odontogenic Keratocysts (Odontogenic Tumour

    Directory of Open Access Journals (Sweden)

    Vladimir Jurisic

    2007-01-01

    Full Text Available TNF-α is a pleiotropic cytokine that is considered as a primary modifier of inflammatory and immune reaction in response to various inflammatory diseases and tumour. We investigated levels of TNF-α in 43 radicular cysts and 15 odontogenic keratocysts, obtained from patients undergoing surgery, under local anaesthesia, and after aspiration of cystic fluid from non-ruptured cysts. TNF-α is elevated in both cysts’ fluid, but higher values were found in radicular cysts in comparison to keratocysts. The significantly higher concentration of TNF-α was associated with smaller radicular cysts, higher protein concentration, higher presence of inflammatory cells in peri cystic tissues, and the degree of vascularisation and cysts wall thickness (Mann-Whitney U-test, p<0.05. No correlation was found based on these parameters in odontogenic keratocyst, but all cysts have detectable concentrations of TNF-α. We here for the first time present that a difference in the concentration of TNF-α exists between these two cystic types.

  8. Concentrations of persistent organochlorine compounds in human milk and placenta are higher in Denmark than in Finland

    DEFF Research Database (Denmark)

    Shen, H.; Main, K.M.; Andersson, A.M.

    2008-01-01

    , oxychlordane (OXC), cis-heptachloroepoxide (c-HE) and 1,1,1-trichloro-2,2-bis(4-chlorophenyl)ethane (p,p'-DDT) were the other main organochlorines detected. Danish samples had significantly higher concentrations of p,p'-DDE, p,p'-DDT, beta-HCH, HCB, dieldrin, c-HE and OXC than did the Finnish samples. Levels...

  9. Higher Plasma Concentration of Food-Specific Antibodies in Persons with Autistic Disorder in Comparison to Their Siblings

    Science.gov (United States)

    Trajkovski, Vladimir; Petlichkovski, Aleksandar; Efinska-Mladenovska, Olivija; Trajkov, Dejan; Arsov, Todor; Strezova, Ana; Ajdinski, Ljubomir; Spiroski, Mirko

    2008-01-01

    Specific IgA, IgG, and IgE antibodies to food antigens in 35 participants with autistic disorder and 21 of their siblings in the Republic of Macedonia were examined. Statistically significant higher plasma concentration of IgA antibodies against alpha-lactalbumin, beta-lactoglobulin, casein, and gliadin were found in the children with autistic…

  10. Citalopram and escitalopram plasma drug and metabolite concentrations: genome-wide associations.

    Science.gov (United States)

    Ji, Yuan; Schaid, Daniel J; Desta, Zeruesenay; Kubo, Michiaki; Batzler, Anthony J; Snyder, Karen; Mushiroda, Taisei; Kamatani, Naoyuki; Ogburn, Evan; Hall-Flavin, Daniel; Flockhart, David; Nakamura, Yusuke; Mrazek, David A; Weinshilboum, Richard M

    2014-08-01

    Citalopram (CT) and escitalopram (S-CT) are among the most widely prescribed selective serotonin reuptake inhibitors used to treat major depressive disorder (MDD). We applied a genome-wide association study to identify genetic factors that contribute to variation in plasma concentrations of CT or S-CT and their metabolites in MDD patients treated with CT or S-CT. Our genome-wide association study was performed using samples from 435 MDD patients. Linear mixed models were used to account for within-subject correlations of longitudinal measures of plasma drug/metabolite concentrations (4 and 8 weeks after the initiation of drug therapy), and single-nucleotide polymorphisms (SNPs) were modelled as additive allelic effects. Genome-wide significant associations were observed for S-CT concentration with SNPs in or near the CYP2C19 gene on chromosome 10 (rs1074145, P = 4.1 × 10(-9) ) and with S-didesmethylcitalopram concentration for SNPs near the CYP2D6 locus on chromosome 22 (rs1065852, P = 2.0 × 10(-16) ), supporting the important role of these cytochrome P450 (CYP) enzymes in biotransformation of citalopram. After adjustment for the effect of CYP2C19 functional alleles, the analyses also identified novel loci that will require future replication and functional validation. In vitro and in vivo studies have suggested that the biotransformation of CT to monodesmethylcitalopram and didesmethylcitalopram is mediated by CYP isozymes. The results of our genome-wide association study performed in MDD patients treated with CT or S-CT have confirmed those observations but also identified novel genomic loci that might play a role in variation in plasma levels of CT or its metabolites during the treatment of MDD patients with these selective serotonin reuptake inhibitors. © 2014 The British Pharmacological Society.

  11. Serum concentration of alpha-1 antitrypsin is significantly higher in colorectal cancer patients than in healthy controls

    International Nuclear Information System (INIS)

    Pérez-Holanda, Sergio; Blanco, Ignacio; Menéndez, Manuel; Rodrigo, Luis

    2014-01-01

    The association between alpha-1 antitrypsin (AAT) deficiency and colorectal cancer (CRC) is currently controversial. The present study compares AAT serum concentrations and gene frequencies between a group of CRC patients and a control group of healthy unrelated people (HUP). 267 CRC subjects (63% males, 72 ± 10 years old) were enlisted from a Hospital Clinic setting in Asturias, Spain. The HUP group comprised 327 subjects (67% males, mean age 70 ± 7.5 years old) from the same geographical region. Outcome measures were AAT serum concentrations measured by nephelometry, and AAT phenotyping characterization by isoelectric focusing. Significantly higher serum concentrations were found among CRC (208 ± 60) than in HUP individuals (144 ± 20.5) (p = 0.0001). No differences were found in the phenotypic distribution of the Pi*S and Pi*Z allelic frequencies (p = 0.639), although the frequency of Pi*Z was higher in CRC (21%) than in HUP subjects (15%). The only statistically significant finding in this study was the markedly higher AAT serum concentrations found in CRC subjects compared with HUP controls, irrespective of whether their Pi* phenotype was normal (Pi*MM) or deficient (Pi*MS, Pi*MZ and Pi*SZ). Although there was a trend towards the more deficient Pi* phenotype the more advanced the tumor, the results were inconclusive due to the small sample size. Consequently, more powerful studies are needed to reach firmer conclusions on this matter

  12. A Generic Multi-Compartmental CNS Distribution Model Structure for 9 Drugs Allows Prediction of Human Brain Target Site Concentrations

    NARCIS (Netherlands)

    Yamamoto, Yumi; Valitalo, Pyry A.; van den Berg, Dirk-Jan; Hartman, Robin; van den Brink, Willem; Wong, Yin Cheong; Huntjens, Dymphy R.; Proost, Johannes H.; Vermeulen, An; Krauwinkel, Walter; Bakshi, Suruchi; Aranzana-Climent, Vincent; Marchand, Sandrine; Dahyot-Fizelier, Claire; Couet, William; Danhof, Meindert; van Hasselt, Johan G. C.; de lange, Elizabeth C. M.

    Purpose Predicting target site drug concentration in the brain is of key importance for the successful development of drugs acting on the central nervous system. We propose a generic mathematical model to describe the pharmacokinetics in brain compartments, and apply this model to predict human

  13. Plasma Drug Concentrations of Orally Administered Rosuvastatin in Hispaniolan Amazon Parrots (Amazona ventralis).

    Science.gov (United States)

    Beaufrère, Hugues; Papich, Mark G; Brandão, João; Nevarez, Javier; Tully, Thomas N

    2015-03-01

    Atherosclerotic diseases are common in pet psittacine birds, in particular Amazon parrots. While hypercholesterolemia and dyslipidemia have not definitely been associated with increased susceptibility to atherosclerosis in parrots, these are important and well-known risk factors in humans. Therefore statin drugs such as rosuvastatin constitute the mainstay of human treatment of dyslipidemia and the prevention of atherosclerosis. No pharmacologic studies have been performed in psittacine birds despite the high prevalence of atherosclerosis in captivity. Thirteen Hispaniolan Amazon parrots were used to test a single oral dose of 10 mg/kg of rosuvastatin with blood sampling performed according to a balanced incomplete block design over 36 hours. Because low plasma concentrations were produced in the first study, a subsequent pilot study using a dose of 25 mg/kg in 2 Amazon parrots was performed. Most plasma samples for the 10 mg/kg dose and all samples for the 25 mg/kg dose had rosuvastatin concentration below the limits of quantitation. For the 10 mg/kg study, the median peak plasma concentration and time to peak plasma concentration were 0.032 μg/mL and 2 hours, respectively. Our results indicate that rosuvastatin does not appear suitable in Amazon parrots as compounded and used at the dose in this study. Pharmacodynamic studies investigating lipid-lowering effects of statins rather than pharmacokinetic studies may be more practical and cost effective in future studies to screen for a statin with more ideal properties for potential use in psittacine dyslipidemia and atherosclerotic diseases.

  14. Pairwise and higher-order correlations among drug-resistance mutations in HIV-1 subtype B protease

    Directory of Open Access Journals (Sweden)

    Morozov Alexandre V

    2009-08-01

    Full Text Available Abstract Background The reaction of HIV protease to inhibitor therapy is characterized by the emergence of complex mutational patterns which confer drug resistance. The response of HIV protease to drugs often involves both primary mutations that directly inhibit the action of the drug, and a host of accessory resistance mutations that may occur far from the active site but may contribute to restoring the fitness or stability of the enzyme. Here we develop a probabilistic approach based on connected information that allows us to study residue, pair level and higher-order correlations within the same framework. Results We apply our methodology to a database of approximately 13,000 sequences which have been annotated by the treatment history of the patients from which the samples were obtained. We show that including pair interactions is essential for agreement with the mutational data, since neglect of these interactions results in order-of-magnitude errors in the probabilities of the simultaneous occurence of many mutations. The magnitude of these pair correlations changes dramatically between sequences obtained from patients that were or were not exposed to drugs. Higher-order effects make a contribution of as much as 10% for residues taken three at a time, but increase to more than twice that for 10 to 15-residue groups. The sequence data is insufficient to determine the higher-order effects for larger groups. We find that higher-order interactions have a significant effect on the predicted frequencies of sequences with large numbers of mutations. While relatively rare, such sequences are more prevalent after multi-drug therapy. The relative importance of these higher-order interactions increases with the number of drugs the patient had been exposed to. Conclusion Correlations are critical for the understanding of mutation patterns in HIV protease. Pair interactions have substantial qualitative effects, while higher-order interactions are

  15. The Impact of Serum Drug Concentration on the Efficacy of Imipramine, Pregabalin and their Combination in Painful Polyneuropathy

    DEFF Research Database (Denmark)

    Sindrup, Søren Hein; Holbech, Jakob Vormstrup; Bach, Flemming W

    2017-01-01

    OBJECTIVE: The serum concentration-effect relation was explored for first line drugs in neuropathic pain and aimed to determine if efficacy could be increased. METHODS: Data from a randomized, placebo-controlled, cross-over trial on imipramine, pregabalin and their combination in painful...... polyneuropathy were used. Treatment periods were of 4 weeks' duration, outcome was the weekly median of daily pain rated by a 0-10 numeric scale, and drug concentrations were determined by high-performance liquid chromatography. RESULTS: In 47 patients pain was reduced -1.0 (95% CI -1.5:-0.6) by imipramine, -0.......178). There was no correlation between drug concentration and pain reduction for imipramine (r= 0.17, P=0.247), whereas there was a marginally, positive correlation for pregabalin (r=0.28, P=0.057). There was no interaction between treatment and concentration classes (imipramine

  16. Tacrolimus concentration/dose ratio as a therapeutic drug monitoring strategy: The influence of gender and comedication

    Directory of Open Access Journals (Sweden)

    Rančić Nemanja

    2015-01-01

    Full Text Available Background/Aim. A combination of tacrolimus and other drugs such as corticosteroids has been commonly used immunosuppresive regimens. On the other hand, there is a growing body of evidence that male and female may differ in their response to the equal drug treatment. The aim of the study was to estimated the use of tacrolimus concentration/dose (C/D ratio for the assessment of the influence of gender differences and comedication on tacrolimus exposure in renal transplant recipients. Methods. This prospective case series study included 54 patients, in which the unit of monitoring was outpatient examination (1,872 of the renal transplant patients. The patients were monitored in the period 2010-2014, starting one month after the transplantation. Tacrolimus trough concentrations (TTC were measured by chemiluminescence microparticles immunoassay. Results. TTC and the tacrolimus C/D ratio were significantly lower in the females comparing with the males. Contrary to the males, in the females a significant increase of the tacrolimus daily dose (TDD per body weight and TTC, along with the corticosteroid dose increase, was not accompanied by any significant changes in the tacrolimus C/D ratio; in different corticosteroid doses faster elimination of tacrolimus was found with the exception of the doses > 0.25 mg/kg. In the patients treated with proton pump inhibitors, mainly with pantoprazole TDD per body weight and TTC were significantly higher, while the tacrolimus C/D ratio was significantly lower compared to the patients without this treatment. In the patients treated with calcium channel blockers, TDD per body weight was significantly lower (particularly with amlodipine while the tacrolimus C/D ratio was higher compared to the patients who were not treated by them. Conclusion. A lower tacrolimus exposure was detected in females in comparison to males. When gender differences were considered in the context of different corticosteroid doses, faster

  17. Trace metal concentrations are higher in cartilage than in bones of scaup and pochard wintering in Poland

    International Nuclear Information System (INIS)

    Kalisinska, Elzbieta; Salicki, Wieslaw; Kavetska, Katarzyna M.; Ligocki, Marek

    2007-01-01

    Bones and cartilage of two species of diving ducks: the scaup Aythya marila (n = 24) and the pochard A. ferina (n = 24) were studied. Scaup is protected in Poland where it spends only the winter, while pochard is a game bird, abundant and breeding in Poland. In winter, the two species form large flocks off the southern coast of the Baltic, particularly in the Szczecin Lagoon where they were collected for this study. The bones and cartilage (trachea) were assayed for concentrations (dry weight-based) of three essential metals: iron (Fe), copper (Cu), and zinc (Zn); concentrations of the two toxic metals: lead (Pb) and cadmium (Cd) were assayed as well. These hard tissues of the two species showed the following order of metal concentrations Zn > Fe > Pb > Cu > Cd. In scaup and pochard bones, the respective geometric mean concentrations of Zn, Fe, Pb, Cu, and Cd were 94.4 and 102.0; 20.2 and 24.7; 6.2 and 9.6; 0.19 and 0.26; 0.114 and 0.162 mg/kg. The levels of all the metals in cartilage (Zn 149.1 and 165.8; Fe 58.4 and 116.3; Pb 10.6 and 14.9; Cu 1.41 and 3.31; Cd 0.144 and 0.175 mg/kg, respectively) were higher than in the bones of A. marila and A. ferina. However, statistically significant differences were found in respect to the essential metals only (Zn, Fe, Cu). The inter-species comparisons showed the two species to differ in their cartilage concentrations of Fe, Cu, Zn, and Cd and in their bone concentrations of Pb and Cd. In each case, the pochard exhibited higher concentrations of metals. This study showed distinct differences between trace element accumulation by two heavily mineralised avian body parts: leg bones (tarsometatarsus) and cartilage (trachea). The results are in agreement with data reported by other workers who analysed trace metals in cartilaginous and bone components of the femoral head in homoiotherm vertebrates, including humans. Therefore it is important that intra- and inter-species comparisons of hard biological components be based on

  18. Higher serum concentrations of vimentin and DAKP1 are associated with aggressive breast tumour phenotypes in Ghanaian women.

    Science.gov (United States)

    Arko-Boham, Benjamin; Lomotey, Justice Tanihu; Tetteh, Emmanuel Nomo; Tagoe, Emmanuel Ayitey; Aryee, Nii Ayite; Owusu, Ewurama Ampadu; Okai, Isaac; Blay, Richard Michael; Clegg-Lamptey, Joe-Nat

    2017-01-01

    Breast cancer, the most commonly diagnosed cancer among women and leading cause of cancer-related deaths worldwide, exhibits aggressive behavior in indigenous African women evidenced by high histologic grade tumours with low hormone receptor positivity. Aggressive breast cancers grow quickly, easily metastasize and recur and often have unfavourable outcomes. The current study investigated candidate genes that may regulate tumour aggression in Ghanaian women. We hypothesize that increased expression and function of certain genes other than the widely-held view attributing breast cancer aggression in African populations to their younger population age may be responsible for the aggressive nature of tumours. Employing ELISA, we assayed for vimentin and death-associated protein kinase 1 (DAPK1) from thawed archived (stored at -80 °C) serum samples obtained from 40 clinically confirmed Ghanaian breast cancer patients and 40 apparently healthy controls. Patients' clinical records and tumour parameters matching the samples were retrieved from the database of the hospital. ANOVA was used to compare means of serum protein concentration among groups while Chi-square analysis was used for the categorical data sets with p -value ≤0.05 considered significant. Multiple logistic regression analysis was conducted to determine the association between protein concentration and tumour parameters. Of the 80 samples, 27 (33.8%) and 53 (66.2%) were from young (<35 years) and old (≥35 years), respectively. Vimentin and DAPK1 concentration were higher in patients than controls with higher levels in "young" age group than "old" age group. Vimentin concentration was highest in grade 3 tumours followed by grade 2 and 1 but that for DAPK1 was not significant. For vimentin, tumour area strongly correlated with tumour grade ( r  = 0.696, p  < 0.05) but weakly correlated with tumour stage ( r  = 0.420, p  < 0.05). Patient's age correlated with DAPK1 concentration ( r  = 0

  19. Comparison of direct sampling and brochoalveolar lavage for determining active drug concentrations in the pulmonary epithelial lining fluid of calves injected with enrofloxacin or tilmicosin.

    Science.gov (United States)

    Foster, D M; Sylvester, H J; Papich, M G

    2017-12-01

    Antibiotic distribution to interstitial fluid (ISF) and pulmonary epithelial fluid (PELF) was measured and compared to plasma drug concentrations in eight healthy calves. Enrofloxacin (Baytril ® 100) was administered at a dose of 12.5 mg/kg subcutaneously (SC), and tilmicosin (Micotil ® 300) was administered at a dose of 20 mg/kg SC. PELF, sampled by two different methods-bronchoalveolar lavage (BAL) and direct sampling (DS)-plasma, and ISF were collected from each calf and measured for tilmicosin, enrofloxacin and its metabolite ciprofloxacin by HPLC. Pharmacokinetic analysis was performed on the concentrations in each fluid, for each drug. The enrofloxacin/ciprofloxacin concentration as measured by AUC in DS samples was 137 ± 72% higher than in plasma, but in BAL samples, this value was 535 ± 403% (p enrofloxacin/ciprofloxacin concentrations collected by DS were significantly different than those collected by BAL, but the tilmicosin concentrations were not significantly different between the two methods. Concentrations of enrofloxacin/ciprofloxacin exceeded the MIC values for bovine respiratory disease pathogens but tilmicosin did not reach MIC levels for these pathogens in any fluids. © 2017 John Wiley & Sons Ltd.

  20. Drug Concentration Thresholds Predictive of Therapy Failure and Death in Children With Tuberculosis: Bread Crumb Trails in Random Forests.

    Science.gov (United States)

    Swaminathan, Soumya; Pasipanodya, Jotam G; Ramachandran, Geetha; Hemanth Kumar, A K; Srivastava, Shashikant; Deshpande, Devyani; Nuermberger, Eric; Gumbo, Tawanda

    2016-11-01

     The role of drug concentrations in clinical outcomes in children with tuberculosis is unclear. Target concentrations for dose optimization are unknown.  Plasma drug concentrations measured in Indian children with tuberculosis were modeled using compartmental pharmacokinetic analyses. The children were followed until end of therapy to ascertain therapy failure or death. An ensemble of artificial intelligence algorithms, including random forests, was used to identify predictors of clinical outcome from among 30 clinical, laboratory, and pharmacokinetic variables.  Among the 143 children with known outcomes, there was high between-child variability of isoniazid, rifampin, and pyrazinamide concentrations: 110 (77%) completed therapy, 24 (17%) failed therapy, and 9 (6%) died. The main predictors of therapy failure or death were a pyrazinamide peak concentration <38.10 mg/L and rifampin peak concentration <3.01 mg/L. The relative risk of these poor outcomes below these peak concentration thresholds was 3.64 (95% confidence interval [CI], 2.28-5.83). Isoniazid had concentration-dependent antagonism with rifampin and pyrazinamide, with an adjusted odds ratio for therapy failure of 3.00 (95% CI, 2.08-4.33) in antagonism concentration range. In regard to death alone as an outcome, the same drug concentrations, plus z scores (indicators of malnutrition), and age <3 years, were highly ranked predictors. In children <3 years old, isoniazid 0- to 24-hour area under the concentration-time curve <11.95 mg/L × hour and/or rifampin peak <3.10 mg/L were the best predictors of therapy failure, with relative risk of 3.43 (95% CI, .99-11.82).  We have identified new antibiotic target concentrations, which are potential biomarkers associated with treatment failure and death in children with tuberculosis. © The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America.

  1. Five year results of an international proficiency testing programme for measurement of antifungal drug concentrations

    NARCIS (Netherlands)

    Lempers, V.J.C.; Alffenaar, J.W.C.; Touw, D.J.; Burger, D.M.; Uges, D.R.A.; Aarnoutse, R.E.; Brüggemann, R.J.M.

    2014-01-01

    OBJECTIVES: Since 2007 the Dutch Association for Quality Assessment in Therapeutic Drug Monitoring (KKGT) has organized an international interlaboratory proficiency testing (PT) programme for measurement of antifungal drugs in plasma. We describe the 5 year results of the laboratories' performance.

  2. Effects of the summer holiday season on UV filter and illicit drug concentrations in the Korean wastewater system and aquatic environment.

    Science.gov (United States)

    Kim, Ki Yong; Ekpeghere, Kalu Ibe; Jeong, Hee-Jin; Oh, Jeong-Eun

    2017-08-01

    Seasonal variations in the concentrations of eight ultraviolet (UV) filters and 22 illicit drugs including their metabolites in the Korean aquatic environment were investigated. Seawater samples from three beaches, water samples from two rivers, and influents and effluents from three wastewater treatment plants were analyzed. The UV filter concentrations in the seawater, river water, and effluent samples were 39.4-296, 35.4-117, and 6.84-51.1 ng L -1 , respectively. The total UV filter concentrations in the seawater samples were 1.9-4.4 times higher at the peak of the holiday season than outside the peak holiday season. An environmental risk assessment showed that ethylhexyl methoxy cinnamate (EHMC) could cause adverse effects on aquatic organisms in the seawater at the three beaches during the holiday period. Seven of the 22 target illicit drugs including their metabolites were detected in the wastewater influent samples, and the total illicit drug concentrations in the influent samples were 0.08-65.4 ng L -1 . The estimated daily consumption rates for cis-tramadol (Cis-TRM), methamphetamine (MTP), meperidine (MEP), and codeine (COD) were 25.7-118.4, 13.8-36.1, 1.36-12.6, and 1.75-8.64 mg d -1 (1000 people) -1 , respectively. In popular vacation area, the illicit drug consumption rates (Cis-TRM, MTP and MEP) were 1.6-2.6 times higher at the peak of the summer holiday season than at the beginning of the summer. Copyright © 2017 Elsevier Ltd. All rights reserved.

  3. Higher Magnitude Cash Payments Improve Research Follow-up Rates Without Increasing Drug Use or Perceived Coercion

    Science.gov (United States)

    Festinger, David S.; Marlowe, Douglas B.; Dugosh, Karen L.; Croft, Jason R.; Arabia, Patricia L.

    2008-01-01

    In a prior study (Festinger et al., 2005) we found that neither the mode (cash vs. gift card) nor magnitude ($10, $40, or $70) of research follow-up payments increased rates of new drug use or perceptions of coercion. However, higher payments and payments in cash were associated with better follow-up attendance, reduced tracking efforts, and improved participant satisfaction with the study. The present study extended those findings to higher payment magnitudes. Participants from an urban outpatient substance abuse treatment program were randomly assigned to receive $70, $100, $130, or $160 in either cash or a gift card for completing a follow-up assessment at 6 months post-admission (n ≅ 50 per cell). Apart from the payment incentives, all participants received a standardized, minimal platform of follow-up efforts. Findings revealed that neither the magnitude nor mode of payment had a significant effect on new drug use or perceived coercion. Consistent with our previous findings, higher payments and cash payments resulted in significantly higher follow-up rates and fewer tracking calls. In addition participants receiving cash vs. gift cards were more likely to use their payments for essential, non-luxury purchases. Follow-up rates for participants receiving cash payments of $100, $130, and $160 approached or exceeded the FDA required minimum of 70% for studies to be considered in evaluations of new medications. This suggests that the use of higher magnitude payments and cash payments may be effective strategies for obtaining more representative follow-up samples without increasing new drug use or perceptions of coercion. PMID:18395365

  4. Linezolid Trough Concentrations Correlate with Mitochondrial Toxicity-Related Adverse Events in the Treatment of Chronic Extensively Drug-Resistant Tuberculosis.

    Science.gov (United States)

    Song, Taeksun; Lee, Myungsun; Jeon, Han-Seung; Park, Yumi; Dodd, Lori E; Dartois, Véronique; Follman, Dean; Wang, Jing; Cai, Ying; Goldfeder, Lisa C; Olivier, Kenneth N; Xie, Yingda; Via, Laura E; Cho, Sang Nae; Barry, Clifton E; Chen, Ray Y

    2015-11-01

    Long-term linezolid use is limited by mitochondrial toxicity-associated adverse events (AEs). Within a prospective, randomized controlled trial of linezolid to treat chronic extensively drug-resistant tuberculosis, we serially monitored the translational competence of mitochondria isolated from peripheral blood of participants by determining the cytochrome c oxidase/citrate synthase activity ratio. We compared this ratio with AEs associated with mitochondrial dysfunction. Linezolid trough concentrations were determined for 38 participants at both 600 mg and 300 mg doses. Those on 600 mg had a significantly higher risk of AE than those on 300 mg (HR 3·10, 95% CI 1·23-7 · 86). Mean mitochondrial function levels were significantly higher in patients before starting linezolid compared to their concentrations on 300 mg (P = 0·004) or 600 mg (P linezolid trough concentrations were associated with lower mitochondrial function levels (Spearman's ρ = - 0.48; P = 0.005). Mitochondrial toxicity risk increased with increasing linezolid trough concentrations, with all patients with mean linezolid trough > 2 μg/ml developing an AE related to mitochondrial toxicity, whether on 300 mg or 600 mg. Therapeutic drug monitoring may be useful to prevent the development of mitochondrial toxicity associated with long-term linezolid use.

  5. [Effect of high magnesium ion concentration on the electron transport rate and proton exchange in thylakoid membranes in higher plants].

    Science.gov (United States)

    Ignat'ev, A R; Khorobrykh, S A; Ivanov, B N

    2001-01-01

    The effects of magnesium ion concentration on the rate of electron transport in isolated pea thylakoids were investigated in the pH range from 4.0 up to 8.0. In the absence of magnesium ions in the medium and in the presence of 5 mM MgCl2 in the experiments not only without added artificial acceptors but also with ferricyanide or methylviologen as an acceptor, this rate had a well-expressed maximum at pH 5.0. It was shown that, after depression to minimal values at pH 5.5-6.5, it gradually rose with increasing pH. An increase in magnesium ion concentration up to 20 mM essentially affected the electron transfer rate: it decreased somewhat at pH 4.0-5.0 but increased at higher pH values. At this magnesium ion concentration, the maximum rate was at pH 6.0-6.5 and the minimum, at pH 7.0. Subsequent rise upon increasing pH to 8.0 was expressed more sharply. The influence of high magnesium ion concentration on the rate of electron transport was not observed in the presence of gramicidin D. It was found that without uncoupler, the changes in the electron transfer rate under the influence of magnesium ions correlated to the changes in the first-order rate constant of the proton efflux from thylakoids. It is supposed that the change in the ability of thylakoids to keep protons by the action of magnesium ions is the result of electrostatic interactions of these ions with the charges on the external surface of membranes. A possible role of regulation of the electron transport rate by magnesium ions in vivo is discussed.

  6. Higher Anti-CMV IgG Concentrations are Associated with Worse Neurocognitive Performance During Suppressive Antiretroviral Therapy.

    Science.gov (United States)

    Letendre, Scott; Bharti, Ajay; Perez-Valero, Ignacio; Hanson, Barbara; Franklin, Donald; Woods, Steven Paul; Gianella, Sara; de Oliveira, Michelli Faria; Heaton, Robert K; Grant, Igor; Landay, Alan L; Lurain, Nell

    2018-03-01

    To determine the association of CMV infection with neurocognitive performance in HIV+ adults. Cross-sectional, observational, exploratory study. Anti-CMV IgG concentrations in blood and CMV DNA copies in blood and cerebrospinal fluid (CSF) were measured in stored specimens of 80 HIV+ adults who were previously assessed with a standardized, comprehensive neurocognitive test battery. Thirty-eight were taking suppressive antiretroviral therapy (ART, HIV RNA ≤ 50 copies/mL) and 42 were not taking ART. A panel of 7 soluble biomarkers were also measured by immunoassay in CSF. Anti-CMV IgG concentrations ranged from 5.2 to 46.1 U/mL. CMV DNA was detected in 7 (8.8%) blood plasma but in none of the CSF specimens. Higher anti-CMV IgG levels were associated with older age (p=0.0017), lower nadir CD4+ T-cell count (pperformance overall (p=0.059). This correlation was present in those taking suppressive ART (p=0.0049) but not in those who were not taking ART (p=0.92). Worse neurocognitive performance remained associated with higher anti-CMV IgG levels after accounting for other covariates in multivariate models (Model p=0.0038). Detectable plasma CMV DNA was associated with AIDS (p=0.05) but not with neurocognitive performance. CMV may influence neurocognitive performance in HIV+ adults taking suppressive ART. Future clinical trials of anti-CMV therapy should help determine whether the observed relationships are causal.

  7. Patients with Posttraumatic Stress Disorder with Comorbid Major Depressive Disorder Require a Higher Dose of Psychotropic Drugs.

    Science.gov (United States)

    Chiba, Hiromi; Oe, Misari; Uchimura, Naohisa

    2016-01-01

    Major depressive disorder (MDD) has been associated with stressful life events and with posttraumatic stress disorder (PTSD). PTSD and MDD comorbidity was also reported to be associated with greater symptom severity and lower levels of functioning. However, the characteristics of pharmacotherapy for PTSD with MDD are not fully understood. To understand this relationship, we conducted a retrospective review using medical charts at the Department of Neuropsychiatry, Kurume University Hospital. Information from 55 patients with PTSD was analyzed. Five cases were excluded after re-evaluation of the PTSD diagnosis. A higher rate of type II trauma was observed in the PTSD with MDD group (50.0%) than in the PTSD-only group [13.6%; χ(2) (1, n =50) = 7.26, p<0.01]. Patients with comorbid MDD were significantly older, had more severe PTSD symptomatology, and a longer duration of treatment. They also received higher doses of psychotropic drugs, regardless of the type (antidepressants, antipsychotics, benzodiazepines), than the PTSD-only group. Our results showed that comorbid MDD is associated with higher doses of psychotropic drugs, suggesting difficulties in treatment.

  8. Heroin and cocaine abusers have higher discount rates for delayed rewards than alcoholics or non-drug-using controls.

    Science.gov (United States)

    Kirby, Kris N; Petry, Nancy M

    2004-04-01

    To test a prediction of the discounting model of impulsiveness that discount rates would be positively associated with addiction. The delay-discount rate refers to the rate of reduction in the present value of a future reward as the delay to that reward increases. We estimated participants' discount rates on the basis of their pattern of choices between smaller immediate rewards ($11-80) and larger, delayed rewards ($25-85; at delays from 1 week to 6 months) in a questionnaire format. Participants had a one-in-six chance of winning a reward that they chose on one randomly selected trial. Heroin (n = 27), cocaine (n = 41) and alcohol (n = 33) abusers and non-drug-using controls (n = 44) were recruited from advertisements. They were tested in a drug abuse research clinic at a medical school. On average, the cocaine and heroin groups had higher rates than controls (both P rates for heroin abusers (P = 0.03), but not for cocaine or alcohol abusers (both P > 0.50). These data suggest that discount rates vary with the preferred drug of abuse, and that high discount rates should be considered in the development of substance abuse prevention and treatment efforts.

  9. Toward the establishment of standardized in vitro tests for lipid-based formulations. 2. The effect of bile salt concentration and drug loading on the performance of type I, II, IIIA, IIIB, and IV formulations during in vitro digestion.

    Science.gov (United States)

    Williams, Hywel D; Anby, Mette U; Sassene, Philip; Kleberg, Karen; Bakala-N'Goma, Jean-Claude; Calderone, Marilyn; Jannin, Vincent; Igonin, Annabel; Partheil, Anette; Marchaud, Delphine; Jule, Eduardo; Vertommen, Jan; Maio, Mario; Blundell, Ross; Benameur, Hassan; Carrière, Frédéric; Müllertz, Anette; Pouton, Colin W; Porter, Christopher J H

    2012-11-05

    The LFCS Consortium was established to develop standardized in vitro tests for lipid-based formulations (LBFs) and to examine the utility of these tests to probe the fundamental mechanisms that underlie LBF performance. In this publication, the impact of bile salt (sodium taurodeoxycholate, NaTDC) concentration and drug loading on the ability of a range of representative LBFs to generate and sustain drug solubilization and supersaturation during in vitro digestion testing has been explored and a common driver of the potential for drug precipitation identified. Danazol was used as a model poorly water-soluble drug throughout. In general, increasing NaTDC concentrations increased the digestion of the most lipophilic LBFs and promoted lipid (and drug) trafficking from poorly dispersed oil phases to the aqueous colloidal phase (AP(DIGEST)). High NaTDC concentrations showed some capacity to reduce drug precipitation, although, at NaTDC concentrations ≥3 mM, NaTDC effects on either digestion or drug solubilization were modest. In contrast, increasing drug load had a marked impact on drug solubilization. For LBFs containing long-chain lipids, drug precipitation was limited even at drug loads approaching saturation in the formulation and concentrations of solubilized drug in AP(DIGEST) increased with increased drug load. For LBFs containing medium-chain lipids, however, significant precipitation was evident, especially at higher drug loads. Across all formulations a remarkably consistent trend emerged such that the likelihood of precipitation was almost entirely dependent on the maximum supersaturation ratio (SR(M)) attained on initiation of digestion. SR(M) defines the supersaturation "pressure" in the system and is calculated from the maximum attainable concentration in the AP(DIGEST) (assuming zero precipitation), divided by the solubility of the drug in the colloidal phases formed post digestion. For LBFs where phase separation of oil phases did not occur, a

  10. Soybean greatly reduces valproic acid plasma concentrations: A food–drug interaction study

    Science.gov (United States)

    Marahatta, Anu; Bhandary, Bidur; Jeong, Seul-Ki; Kim, Hyung-Ryong; Chae, Han-Jung

    2014-01-01

    The aim of this study was to investigate the effects of soy on the pharmacokinetics and pharmacodynamics of valproic acid (VPA). In a preclinical study, rats were pretreated with two different amounts of soy extract for five days (150 mg/kg and 500 mg/kg), which resulted in decreases of 57% and 65% in the Cmax of VPA, respectively. AUC of VPA decreased to 83% and 70% in the soy pretreatment groups. Interestingly, the excretion rate of VPA glucuronide (VPAG) was higher in the soy-fed groups. Levels of UDP-glucuronosyltransferase (UGT) UGT1A3, UGT1A6, UGT2B7 and UGT2B15 were elevated in the soy-treated group, and GABA concentrations were elevated in the brain after VPA administration. However, this was less pronounced in soy extract pretreated group than for the untreated group. This is the first study to report the effects of soy pretreatment on the pharmacokinetics and pharmacodynamics of VPA in rodents. PMID:24618639

  11. Soybean greatly reduces valproic acid plasma concentrations: a food-drug interaction study.

    Science.gov (United States)

    Marahatta, Anu; Bhandary, Bidur; Jeong, Seul-Ki; Kim, Hyung-Ryong; Chae, Han-Jung

    2014-03-12

    The aim of this study was to investigate the effects of soy on the pharmacokinetics and pharmacodynamics of valproic acid (VPA). In a preclinical study, rats were pretreated with two different amounts of soy extract for five days (150 mg/kg and 500 mg/kg), which resulted in decreases of 57% and 65% in the Cmax of VPA, respectively. AUC of VPA decreased to 83% and 70% in the soy pretreatment groups. Interestingly, the excretion rate of VPA glucuronide (VPAG) was higher in the soy-fed groups. Levels of UDP-glucuronosyltransferase (UGT) UGT1A3, UGT1A6, UGT2B7 and UGT2B15 were elevated in the soy-treated group, and GABA concentrations were elevated in the brain after VPA administration. However, this was less pronounced in soy extract pretreated group than for the untreated group. This is the first study to report the effects of soy pretreatment on the pharmacokinetics and pharmacodynamics of VPA in rodents.

  12. Spectrophotometric Method for the Determination of Two Coformulated Drugs with Highly Different Concentrations. Application on Vildagliptin and Metformin Hydrochloride

    Science.gov (United States)

    Zaazaa, H. E.; Elzanfaly, E. S.; Soudi, A. T.; Salem, M. Y.

    2016-03-01

    A new smart simple validated spectrophotometric method was developed for the determination of two drugs one of which is in a very low concentration compared to the other. The method is based on spiking and dilution then simple mathematical manipulation of the absorbance spectra. This method was applied for the determination of a binary mixture of vildagliptin and metformin hydrochloride in the ratio 50:850 in laboratory prepared mixtures containing both drugs in this ratio and in pharmaceutical dosage form with good recoveries. The developed method was validated according to ICH guidelines and can be used for routine quality control testing.

  13. Effects of drugs in subtoxic concentrations on the metabolic fluxes in human hepatoma cell line Hep G2

    International Nuclear Information System (INIS)

    Niklas, Jens; Noor, Fozia; Heinzle, Elmar

    2009-01-01

    Commonly used cytotoxicity assays assess the toxicity of a compound by measuring certain parameters which directly or indirectly correlate to the viability of the cells. However, the effects of a given compound at concentrations considerably below EC 50 values are usually not evaluated. These subtoxic effects are difficult to identify but may eventually cause severe and costly long term problems such as idiosyncratic hepatotoxicity. We determined the toxicity of three hepatotoxic compounds, namely amiodarone, diclofenac and tacrine on the human hepatoma cell line Hep G2 using an online kinetic respiration assay and analysed the effects of subtoxic concentrations of these drugs on the cellular metabolism by using metabolic flux analysis. Several changes in the metabolism could be detected upon exposure to subtoxic concentrations of the test compounds. Upon exposure to diclofenac and tacrine an increase in the TCA-cycle activity was observed which could be a signature of an uncoupling of the oxidative phosphorylation. The results indicate that metabolic flux analysis could serve as an invaluable novel tool for the investigation of the effects of drugs. The described methodology enables tracking the toxicity of compounds dynamically using the respiration assay in a range of concentrations and the metabolic flux analysis permits interesting insights into the changes in the central metabolism of the cell upon exposure to drugs.

  14. Effect of Na2SO3 concentration to drug loading and drug release of ascorbic acid in chitosan edible film as drug delivery system membrane

    Directory of Open Access Journals (Sweden)

    Kistriyani Lilis

    2018-01-01

    Full Text Available Chitosan is a type of carbohydrate compounds produced from waste marine products, in particular the class of shrimp, crabs and clams. Chitosan is often process into edible films and utilized for food packaging also has potential as a membrane for drug delivery system. Drug loading and drug release can be controlled by improve the characteristics of the membrane by adding crosslinker. The purpose of this research is to study the effect of addition of crosslinker to the rate of loading and release of ascorbic acid in the chitosan edible film. Na2SO3 was used as crosslinker. Two grams of chitosan was dissolved into 100 ml of distilled water. Acetic acid and plasticizer were added in the solution then heated at 50°C. Na2SO3 solution with mass various of Na2SO3 dissolved, 01026 0.3; and 0.5 grams were added about 30 mL to make edible film. The analysis include of drug loading, drug release and tensile strength. The result showed that the loading of edible film with crosslinker 0.15 g; 0.3 g; and 0.5 g respectively were 60.98 ppm; 52.53 ppm; and 40.88 ppm, meanwhile for the release with crosslinker 0.15 g; 0.3 g; and 0.5 g respectively were 3.78 ppm; 5.72 ppm; and 5.97 ppm.

  15. Relationship between self-reported adherence, antiretroviral drug concentration measurement and self-reported symptoms in patients treated for HIV-1 infection.

    Science.gov (United States)

    Fabbiani, Massimiliano; Di Giambenedetto, Simona; Cingolani, Antonella; Fanti, Iuri; Colafigli, Manuela; Tamburrini, Enrica; Cauda, Roberto; Navarra, Pierluigi; De Luca, Andrea; Murri, Rita

    2016-01-01

    The aim of the study was to explore relationships between self-reported adherence, antiretroviral drug concentration measurement (TDM) and self-reported symptoms. We systematically administered to human immunodeficiency (HIV)-infected outpatients a questionnaire evaluating measures of self-reported adherence (missing doses during last week, deviations from the prescribed timing of therapy, self-initiated discontinuations for > 24 or 48 h, exhausting drugs and present sense of how patients are taking therapy) and a panel of referred symptoms (a symptom score was built summing self-reported scores for each listed symptom). We selected patients who completed the questionnaire and also had a TDM (mainly reflecting adherence in the past few days or weeks), thus comparing these two tools as measures of adherence. A total of 130 patients (64.6% males, median age 44 years, 76.2% with HIV RNA HIV RNA symptom score was associated with a lower self-reported adherence and with a higher proportion of undetectable drug levels. Self-reported adherence and TDM showed a correlation and seemed to be comparable tools for adherence estimation. Self-reported symptoms were associated with lower adherence and undetectable drug levels.

  16. Comparison of concentrations of drugs between blood samples with and without fluoride additive-important findings for Δ9-tetrahydrocannabinol and amphetamine.

    Science.gov (United States)

    Wiedfeld, Christopher; Krueger, Julia; Skopp, Gisela; Musshoff, Frank

    2018-02-17

    Fluoride is a common stabilizing agent in forensic toxicology to avoid the frequent problem of degradation of drugs in blood samples especially described for cocaine. In cases only samples with addition of fluoride are available, it is a crucial question if also concentrations of common drugs other than cocaine (amphetamines, opiates and cannabinoids) are affected by fluoride. So far, there are only rare literature data available on discrepant results especially for Δ 9 -tetrahydrocannabinol (THC). In this study, comparative analysis of positive tested paired routine plasma/serum samples (n = 375), collected at the same time point (one device with and one without fluoride), was carried out with special focus on cannabinoids. Samples were measured with validated routine liquid chromatography-tandem mass spectrometry methods for THC, 11-hydroxy-THC (THC-OH), 11-nor-9-carboxy-THC (THC-COOH), cocaine, benzoylecgonine, ecgonine methyl ester, morphine, codeine, amphetamine, methamphetamine, 3,4-methylenedioxymethamphetamine, 3,4-methylenedioxyamphetamine, and 3,4-methylenedioxyethylamphetamine, and results were statistically evaluated. Beside the expected stabilization effect on cocaine and the consequently reduced concentration of ecgonine methyl ester in fluoride samples, benzoylecgonine was elevated compared to respective samples without fluoride. Most importantly, new findings were significantly reduced mean concentrations of THC (- 17%), THC-OH (- 17%), and THC-COOH (- 22%) in fluoride samples. Mean amphetamine concentration was significantly higher in samples with the additive (+ 6%). For the other amphetamine type of drugs as well as for morphine and codeine, no significant differences could be seen. Whenever specified thresholds have been set, such as in most European countries, the use of different blood sample systems may result in a motorist being differently charged or prosecuted. The findings will support forensic toxicologists at the

  17. Mass Spectrometry to Determine Intracellular Concentrations of Antiretroviral Drugs: From chemistry to clinical application

    NARCIS (Netherlands)

    J.J.A. van Kampen (Jeroen)

    2009-01-01

    textabstractAround 1995 – 1996, treatment options for patients infected with the human immunodefiency virus (HIV), the causative agent of acquired immunodeficiency syndrome (AIDS) 1, 2, improved dramatically. Therapy with a combination of several classes of antiretroviral drugs resulted in a

  18. Impact of concentration and rate of intraluminal drug delivery on absorption and gut wall metabolism of verapamil in humans.

    Science.gov (United States)

    Glaeser, Hartmut; Drescher, Siegfried; Hofmann, Ute; Heinkele, Georg; Somogyi, Andrew A; Eichelbaum, Michel; Fromm, Martin F

    2004-09-01

    In humans gut wall metabolism can be quantitatively as important as hepatic drug metabolism in limiting the systemic exposure to drugs after oral administration. However, it has been proposed that the role of gut wall metabolism might be overemphasized, because high luminal drug concentrations would lead to a saturation of gut wall metabolism. Therefore we investigated the impact of concentration and rate of intraluminal drug delivery on absorption (F(abs)) and gastrointestinal extraction (E(GI)) of a luminally administered cytochrome P450 (CYP) 3A4 substrate (verapamil) using a multilumen perfusion catheter in combination with a stable isotope technique. Two 20-cm-long, adjacent jejunal segments were isolated with the multilumen perfusion catheter in 7 subjects. In this study 80 mg of unlabeled verapamil (d0-verapamil 15 min) was infused into one segment over a 15-minute period, 80 mg of 3-fold deuterated verapamil (d3-verapamil 240 min) was administered over a 240-minute period into the other segment, and simultaneously, 5 mg of 7-fold deuterated verapamil (d7-verapamil) was injected intravenously over a 15-minute period. The rate of intraluminal drug delivery had only a modest effect on bioavailability of the verapamil isotopes (after correction for F abs ) (F/F abs d3-verapamil 240 min versus d0-verapamil 15 min, 0.24 +/- 0.10 versus 0.20 +/- 0.09; P d3-verapamil 240 min was 0.50 +/- 0.18 compared with 0.59 +/- 0.14 for d0 -verapamil 15 min ( P d0-verapamil 15 min ) correlated strongly with E GI (d3-verapamil 240 min ) (r = 0.94, P d0-verapamil 15 min /d3-verapamil 240 min (r = 0.62, P =.03). Substantial gut wall metabolism of verapamil occurs in humans and can be predicted from ex vivo data by use of shed enterocytes. The different intraluminal concentrations and rates of intraluminal drug delivery did not lead to a pronounced saturation of intestinal drug metabolism.

  19. Cost-effectiveness of routine measuring of serum drug concentrations and anti-drug antibodies in treatment of rheumatoid arthritis patients with TNF-α blockers

    Directory of Open Access Journals (Sweden)

    Laine J

    2016-04-01

    Full Text Available Juha Laine,1 T Sakari Jokiranta,2,3 Kari K Eklund,4,5 Merja Väkeväinen,1 Kari Puolakka6 1Pfizer Oy, Helsinki, 2United Medix Laboratories Ltd, Espoo, 3Research Programs Unit, Immunobiology, 4Department of Rheumatology, University of Helsinki, 5Helsinki University Central Hospital, Helsinki, 6Department of Medicine, South Karelia, Finland Abstract: Monitoring of anti-drug antibodies (ADAbs or serum concentrations of biologicals in treatment of rheumatoid arthritis could provide an explanation for a loss of efficacy and help in the choice of subsequent medication. Current clinical practices do not generally include such monitoring of tumor necrosis factor (TNF-α blockers on a routine basis. The main aims of this study were to estimate the probabilities of optimal and nonoptimal treatment decisions if infliximab or adalimumab drug trough level (DL and ADAbs are tested or not in rheumatoid arthritis, and to model cost-effectiveness of performing such monitoring on a routine basis. Data on DLs and ADAbs concentrations were obtained in Finland from clinically requested monitoring analyses of 486 and 1,137 samples from patients on adalimumab and infliximab, respectively. DL was within the target range in 42% of samples from adalimumab- and 50.4% of infliximab-treated patients. ADAbs were detected in approximately 20% and 13.5% of samples from adalimumab- and infliximab-treated patients, respectively. ADAbs were found in 52.3% and 41.3% of those with low adalimumab or infliximab DLs, respectively. The monitoring data were incorporated into probabilities for making the optimal treatment decision. Economic impact of clinical decision-making was modeled in a short-term (3–6 months scenario with 100 hypothetical patients. In the model, the combined measurement of DLs and ADAbs was cost-saving compared to the nontesting scenario when the monitoring results affected the treatment decision in at least 2–5 of 100 patients, a proportion which is easily

  20. Concentration and drug prices in the retail market for malaria treatment in rural Tanzania.

    Science.gov (United States)

    Goodman, Catherine; Kachur, S Patrick; Abdulla, Salim; Bloland, Peter; Mills, Anne

    2009-06-01

    The impact of market concentration has been little studied in markets for ambulatory care in the developing world, where the retail sector often accounts for a high proportion of treatments. This study begins to address this gap through an analysis of the consumer market for malaria treatment in rural areas of three districts in Tanzania. We developed methods for investigating market definition, sales volumes and concentration, and used these to explore the relationship between antimalarial retail prices and competition.The market was strongly geographically segmented and highly concentrated in terms of antimalarial sales. Antimalarial prices were positively associated with market concentration. High antimalarial prices were likely to be an important factor in the low proportion of care-seekers obtaining appropriate treatment.Retail sector distribution of subsidised antimalarials has been proposed to increase the coverage of effective treatment, but this analysis indicates that local market power may prevent such subsidies from being passed on to rural customers. Policymakers should consider the potential to maintain lower retail prices by decreasing concentration among antimalarial providers and recommending retail price levels. Copyright (c) 2009 John Wiley & Sons, Ltd.

  1. Probe for intracellular concentrations of drugs: delayed fluorescence from acridine orange

    International Nuclear Information System (INIS)

    Wardman, P.; Dennis, M.F.; White, J.

    1989-01-01

    The aim of this work is to develop fluorescent probes that will indicate effective concentrations of therapeutic agents, or endogenous protectors, at important cellular sites. Acridine orange associates with nucleic acids and emits a 'delayed' fluorescence signal. This signal is quenched by oxidants such as oxygen, nitroaryl radiosensitizers, adriamycin and mitomycin-c, and reductants such as thiols, ascorbate and other radioprotectors. The quenching of the acridine orange delayed fluorescence reflects the effective concentration of these therapeutically-important oxidants and reductants near DNA. The relative concentration of basic radiosensitizers such as pimonidazole (Ro 03-8799) near the DNA is greater than that of misonidazole. Thiols quench the delayed fluorescence signal according to the degree of ionization of the thiol function; this may model the reactivity of thiols with guanine radical sites in DNA. Ascorbate and aminopyrine do not quench the delayed fluorescence from cells stained with acridine orange as these compounds are taken up by cells very inefficiently

  2. Determination of safety margins for whole blood concentrations of alcohol and nineteen drugs in driving under the influence cases.

    Science.gov (United States)

    Kristoffersen, Lena; Strand, Dag Helge; Liane, Veronica Horpestad; Vindenes, Vigdis; Tvete, Ingunn Fride; Aldrin, Magne

    2016-02-01

    Legislative limits for driving under the influence of 20 non-alcohol drugs were introduced in Norway in February 2012. Per se limits corresponding to blood alcohol concentrations (BAC) of 0.2g/kg were established for 20 psychoactive drugs, and limits for graded sanctions corresponding to BACs of 0.5 and 1.2g/kg were determined for 13 of these drugs. This new legislation made it possible for the courts to make sentences based on the analytical results, similar to the situation for alcohol. To ensure that the reported concentration is as least as high as the true concentration, with a 99% safety level, safety margins had to be calculated for each of the substances. Diazepam, tetrahydrocannabinol (THC) and alcohol were used as model substances to establish a new model for estimating the safety margins. The model was compared with a previous used model established several years ago, by a similar yet much simpler model, and they were found to be in agreement. The measurement uncertainties depend on the standard batch used, the work list and the measurements' replicate. A Bayesian modelling approach was used to determine the parameters in the model, using a dataset of 4700 diazepam positive specimens and 5400 THC positive specimens. Different safety margins were considered for low and high concentration levels of diazepam (≤2μM (0.6mg/L) and >2μM) and THC (≤0.01μM (0.003mg/L) and >0.01μM). The safety margins were for diazepam 19.5% (≤2μM) and 34% (>2μM), for THC 19.5% (≤0.01μM) and 24.9% (>0.01μM). Concentration dependent safety margins for BAC were based on a dataset of 29500 alcohol positive specimens, and were in the range 10.4% (0.1g/kg) to 4.0% (4.0g/kg) at a 99% safety level. A simplified approach was used to establish safety margins for the compounds amphetamine, MDMA, methamphetamine, alprazolam, phenazepam, flunitrazepam, clonazepam, nitrazepam, oxazepam, buprenorphine, GHB, methadone, ketamine, cocaine, morphine, zolpidem and zopiclone. The

  3. Experimental Determination of Drug Diffusion Coefficients in Unstirred Aqueous Environments by Temporally Resolved Concentration Measurements

    DEFF Research Database (Denmark)

    Di Cagno, Massimiliano Pio; Clarelli, Fabrizio; Vabenø, Jon

    2018-01-01

    or the need for dedicated instrumentation. In this work, a simple but reliable method based on time resolved concentration measurements by UV-visible spectroscopy in an unstirred aqueous environment was developed. This method is based on spectroscopic measurement of the variation of the local concentration...... characteristics (i.e. ionic strength and presence of complexing agents) on the diffusivity. The method can be employed in any research laboratory equipped with a standard UV-visible spectrophotometer, and could become a useful and straightforward tool in order to characterize diffusion coefficients...

  4. Differential mechanism of Escherichia coli Inactivation by (+)-limonene as a function of cell physiological state and drug's concentration.

    Science.gov (United States)

    Chueca, Beatriz; Pagán, Rafael; García-Gonzalo, Diego

    2014-01-01

    (+)-limonene is a lipophilic antimicrobial compound, extracted from citrus fruits' essential oils, that is used as a flavouring agent and organic solvent by the food industry. A recent study has proposed a common and controversial mechanism of cell death for bactericidal antibiotics, in which hydroxyl radicals ultimately inactivated cells. Our objective was to determine whether the mechanism of Escherichia coli MG1655 inactivation by (+)-limonene follows that of bactericidal antibiotics. A treatment with 2,000 μL/L (+)-limonene inactivated 4 log10 cycles of exponentially growing E. coli cells in 3 hours. On one hand, an increase of cell survival in the ΔacnB mutant (deficient in a TCA cycle enzyme), or in the presence of 2,2'-dipyridyl (inhibitor of Fenton reaction by iron chelation), thiourea, or cysteamine (hydroxyl radical scavengers) was observed. Moreover, the ΔrecA mutant (deficient in an enzyme involved in SOS response to DNA damage) was more sensitive to (+)-limonene. Thus, this indirect evidence indicates that the mechanism of exponentially growing E. coli cells inactivation by 2,000 μL/L (+)-limonene is due to the TCA cycle and Fenton-mediated hydroxyl radical formation that caused oxidative DNA damage, as observed for bactericidal drugs. However, several differences have been observed between the proposed mechanism for bactericidal drugs and for (+)-limonene. In this regard, our results demonstrated that E. coli inactivation was influenced by its physiological state and the drug's concentration: experiments with stationary-phase cells or 4,000 μL/L (+)-limonene uncovered a different mechanism of cell death, likely unrelated to hydroxyl radicals. Our research has also shown that drug's concentration is an important factor influencing the mechanism of bacterial inactivation by antibiotics, such as kanamycin. These results might help in improving and spreading the use of (+)-limonene as an antimicrobial compound, and in clarifying the controversy about

  5. Gaseous polycyclic aromatic hydrocarbon concentrations are higher in urban forests than adjacent open areas during summer but not in winter – Exploratory study

    International Nuclear Information System (INIS)

    Viippola, Viljami; Rantalainen, Anna-Lea; Yli-Pelkonen, Vesa; Tervo, Peatta; Setälä, Heikki

    2016-01-01

    While the potential of plants to uptake polycyclic aromatic hydrocarbons (PAHs) is widely acknowledged, empirical evidence of the effects of this process on local atmospheric PAH concentrations and human health is tenuous. We measured gaseous PAH concentrations using passive samplers in urban tree-covered areas and adjacent open, treeless areas in a near-road environment in Finland to gain information on the ability of urban vegetation to improve air quality. The ability of urban, mostly deciduous, vegetation to affect PAHs was season dependent: during summer, concentrations were significantly higher in tree-covered areas, while in the fall, concentrations in open areas exceeded those in tree-covered areas. During winter, concentrations in tree-covered areas were either lower or did not differ from those in open areas. Results of this study imply that the commonly believed notion that trees unequivocally improve air quality does not apply to PAHs studied here. - Highlights: • Urban tree-cover increases gaseous PAH concentrations during summertime. • Elevated PAH concentrations do not clearly correspond with vegetation properties. • Tree-cover attenuates seasonal PAH concentration fluctuation. - Higher ambient gaseous PAH concentrations were detected within urban tree cover as compared to open areas during summertime.

  6. Survey results show that adults are willing to pay higher insurance premiums for generous coverage of specialty drugs.

    Science.gov (United States)

    Romley, John A; Sanchez, Yuri; Penrod, John R; Goldman, Dana P

    2012-04-01

    Generous coverage of specialty drugs for cancer and other diseases may be valuable not only for sick patients currently using these drugs, but also for healthy people who recognize the potential need for them in the future. This study estimated how healthy people value insurance coverage of specialty drugs, defined as high-cost drugs that treat cancer and other serious health conditions like multiple sclerosis, by quantifying willingness to pay via a survey. US adults were estimated to be willing to pay an extra $12.94 on average in insurance premiums per month for generous specialty-drug coverage--in effect, $2.58 for every dollar in out-of-pocket costs that they would expect to pay with a less generous insurance plan. Given the value that people assign to generous coverage of specialty drugs, having high cost sharing on these drugs seemingly runs contrary to what people value in their health insurance.

  7. Higher Serum 25-Hydroxyvitamin D Concentrations Associate with a Faster Recovery of Skeletal Muscle Strength after Muscular Injury

    Directory of Open Access Journals (Sweden)

    Lindell K. Weaver

    2013-04-01

    Full Text Available The primary purpose of this study was to identify if serum 25-hydroxyvitamin D (25(OHD concentrations predict muscular weakness after intense exercise. We hypothesized that pre-exercise serum 25(OHD concentrations inversely predict exercise-induced muscular weakness. Fourteen recreationally active adults participated in this study. Each subject had one leg randomly assigned as a control. The other leg performed an intense exercise protocol. Single-leg peak isometric force and blood 25(OHD, aspartate and alanine aminotransferases, albumin, interferon (IFN-γ, and interleukin-4 were measured prior to and following intense exercise. Following exercise, serum 25(OHD concentrations increased (p < 0.05 immediately, but within minutes, subsequently decreased (p < 0.05. Circulating albumin increases predicted (p < 0.005 serum 25(OHD increases, while IFN-γ increases predicted (p < 0.001 serum 25(OHD decreases. Muscular weakness persisted within the exercise leg (p < 0.05 and compared to the control leg (p < 0.05 after the exercise protocol. Serum 25(OHD concentrations inversely predicted (p < 0.05 muscular weakness (i.e., control leg vs. exercise leg peak isometric force immediately and days (i.e., 48-h and 72-h after exercise, suggesting the attenuation of exercise-induced muscular weakness with increasing serum 25(OHD prior to exercise. Based on these data, we conclude that pre-exercise serum 25(OHD concentrations could influence the recovery of skeletal muscle strength after an acute bout of intense exercise.

  8. Intraoperative radiotherapy in combination with misonidazole. In special reference to the drug concentration in tumors and normal tissues and to the initial effect of the treatment

    Energy Technology Data Exchange (ETDEWEB)

    Takahashi, Masaji; Ono, Kouji; Hamanaka, Daizaburo; Dodo, Yoshihiro; Hiraoka, Masahiro [Kyoto Univ. (Japan). Faculty of Medicine

    1983-03-01

    A hypoxic cell radiosensitizer, misonidazole, was applied to 28 patients with carcinoma who received intraoperative radiotherapy. A single dose of 2-3g/m/sup 2/ of the drug was given orally to each patient three hours prior to the start of general anesthesia. The levels of misonidazole and its metabolite, desmethylmisonidazole, in blood, tumors and normal tissues taken from excised materials were measured by a high performance liquid chromatography. The results showed that the concentration levels of misonidazole and desmethylmisonidazole in blood correlated neither to oral doses of 2-3g/m/sup 2/ nor to the function of time after drug ingestion until eight hours. The mean value of blood levels was 77.1 +- 10.9..mu..g/ml. A wide range of 10-96% of the blood level was found in tumors. High levels were observed in gastric cancer and brain tumor (glioblastoma) but not in colorectal cancer and osteosarcoma. It was, however, likely that the concentrations in tumors depended on tumor sizes and/or necrotic areas rather than histologic types and/or sites of tumors. It was also noted that the concentration in normal tissues ranged widely from 11 to 87% of the blood level. Higher concentrations showing more than 75% were found in the ulnar nerve, the stomach and the skin. However, 3 of 4 materials for the stomach and 2 of 3 materials for the skin showed low levels of less than 30% and less than 22% respectively. In 27 of 28 cases different doses of 28-50 Gy with different energies of electrons were delivered intraoperatively. It is impossible so far to derive conclusive results of this study, really because of the short period of observation following the treatment.

  9. High affinity capture and concentration of quinacrine in polymorphonuclear neutrophils via vacuolar ATPase-mediated ion trapping: Comparison with other peripheral blood leukocytes and implications for the distribution of cationic drugs

    Energy Technology Data Exchange (ETDEWEB)

    Roy, Caroline; Gagné, Valérie; Fernandes, Maria J.G.; Marceau, François, E-mail: francois.marceau@crchul.ulaval.ca

    2013-07-15

    Many cationic drugs are concentrated in acidic cell compartments due to low retro-diffusion of the protonated molecule (ion trapping), with an ensuing vacuolar and autophagic cytopathology. In solid tissues, there is evidence that phagocytic cells, e.g., histiocytes, preferentially concentrate cationic drugs. We hypothesized that peripheral blood leukocytes could differentially take up a fluorescent model cation, quinacrine, depending on their phagocytic competence. Quinacrine transport parameters were determined in purified or total leukocyte suspensions at 37 °C. Purified polymorphonuclear leukocytes (PMNLs, essentially neutrophils) exhibited a quinacrine uptake velocity inferior to that of lymphocytes, but a consistently higher affinity (apparent K{sub M} 1.1 vs. 6.3 μM, respectively). However, the vacuolar (V)-ATPase inhibitor bafilomycin A1 prevented quinacrine transport or initiated its release in either cell type. PMNLs capture most of the quinacrine added at low concentrations to fresh peripheral blood leukocytes compared with lymphocytes and monocytes (cytofluorometry). Accumulation of the autophagy marker LC3-II occurred rapidly and at low drug concentrations in quinacrine-treated PMNLs (significant at ≥ 2.5 μM, ≥ 2 h). Lymphocytes contained more LAMP1 than PMNLs, suggesting that the mass of lysosomes and late endosomes is a determinant of quinacrine uptake V{sub max}. PMNLs, however, exhibited the highest capacity for pinocytosis (uptake of fluorescent dextran into endosomes). The selectivity of quinacrine distribution in peripheral blood leukocytes may be determined by the collaboration of a non-concentrating plasma membrane transport mechanism, tentatively identified as pinocytosis in PMNLs, with V-ATPase-mediated concentration. Intracellular reservoirs of cationic drugs are a potential source of toxicity (e.g., loss of lysosomal function in phagocytes). - Highlights: • Quinacrine is concentrated in acidic organelles via V-ATPase-mediated ion

  10. High affinity capture and concentration of quinacrine in polymorphonuclear neutrophils via vacuolar ATPase-mediated ion trapping: Comparison with other peripheral blood leukocytes and implications for the distribution of cationic drugs

    International Nuclear Information System (INIS)

    Roy, Caroline; Gagné, Valérie; Fernandes, Maria J.G.; Marceau, François

    2013-01-01

    Many cationic drugs are concentrated in acidic cell compartments due to low retro-diffusion of the protonated molecule (ion trapping), with an ensuing vacuolar and autophagic cytopathology. In solid tissues, there is evidence that phagocytic cells, e.g., histiocytes, preferentially concentrate cationic drugs. We hypothesized that peripheral blood leukocytes could differentially take up a fluorescent model cation, quinacrine, depending on their phagocytic competence. Quinacrine transport parameters were determined in purified or total leukocyte suspensions at 37 °C. Purified polymorphonuclear leukocytes (PMNLs, essentially neutrophils) exhibited a quinacrine uptake velocity inferior to that of lymphocytes, but a consistently higher affinity (apparent K M 1.1 vs. 6.3 μM, respectively). However, the vacuolar (V)-ATPase inhibitor bafilomycin A1 prevented quinacrine transport or initiated its release in either cell type. PMNLs capture most of the quinacrine added at low concentrations to fresh peripheral blood leukocytes compared with lymphocytes and monocytes (cytofluorometry). Accumulation of the autophagy marker LC3-II occurred rapidly and at low drug concentrations in quinacrine-treated PMNLs (significant at ≥ 2.5 μM, ≥ 2 h). Lymphocytes contained more LAMP1 than PMNLs, suggesting that the mass of lysosomes and late endosomes is a determinant of quinacrine uptake V max . PMNLs, however, exhibited the highest capacity for pinocytosis (uptake of fluorescent dextran into endosomes). The selectivity of quinacrine distribution in peripheral blood leukocytes may be determined by the collaboration of a non-concentrating plasma membrane transport mechanism, tentatively identified as pinocytosis in PMNLs, with V-ATPase-mediated concentration. Intracellular reservoirs of cationic drugs are a potential source of toxicity (e.g., loss of lysosomal function in phagocytes). - Highlights: • Quinacrine is concentrated in acidic organelles via V-ATPase-mediated ion trapping

  11. Interdependence of initial cell density, drug concentration and exposure time revealed by real-time impedance spectroscopic cytotoxicity assay

    DEFF Research Database (Denmark)

    Caviglia, Claudia; Zor, Kinga; Canepa, Silvia

    2015-01-01

    We investigated the combined effect of the initial cell density (12 500, 35 000, 75 000, and 100 000 cells cm−2) and concentration of the anti-cancer drug doxorubicin on HeLa cells by performing timedependent cytotoxicity assays using real-time electrochemical impedance spectroscopy. A correlation...... between the rate of cell death and the initial cell seeding density was found at 2.5 μM doxorubicin concentration, whereas this was not observed at 5 or 100 μM. By sensing the changes in the cell–substrate interaction using impedance spectroscopy under static conditions, the onset of cytotoxicity...... was observed 5 h earlier than when using a standard colorimetric end-point assay (MTS) which measures changes in the mitochondrial metabolism. Furthermore, with the MTS assay no cytotoxicity was observed after 15 h of incubation with 2.5 μM doxorubicin, whereas the impedance showed at this time point cell...

  12. Green Pharmaceutical Analysis of Drugs Coformulated with Highly Different Concentrations Using Spiking and Manipulation of Their Ratio Spectra.

    Science.gov (United States)

    Ayoub, Bassam M

    2017-07-01

    Introducing green analysis to pharmaceutical products is considered a significant approach to preserving the environment. This method can be an environmentally friendly alternative to the existing methods, accompanied by a validated automated procedure for the analysis of a drug with the lowest possible number of samples. Different simple spectrophotometric methods were developed for the simultaneous determination of empagliflozin (EG) and metformin (MT) by manipulating their ratio spectra in their application on a recently approved pharmaceutical combination, Synjardy tablets. A spiking technique was used to increase the concentration of EG in samples prepared from the tablets to allow for the simultaneous determination of EG with MT without prior separation. Validation parameters according to International Conference on Harmonization guidelines were acceptable over a concentration range of 2-12 μg/mL for both drugs using derivative ratio and ratio subtraction coupled with extended ratio subtraction. The optimized methods were compared using one-way analysis of variance and proved to be suitable as ecofriendly approaches for industrial QC laboratories.

  13. Biodegradation testing of chemicals with high Henry’s constants – separating mass and effective concentration reveals higher rate constants

    DEFF Research Database (Denmark)

    Birch, Heidi; Andersen, Henrik Rasmus; Comber, Mike

    Microextraction (HS-SPME) was applied directly on the test systems to measure substrate depletion by biodegradation relative to abiotic controls. HS-SPME was also applied to determine air to water partitioning ratios. Water phase biodegradation rate constants, kwater, were up to 72 times higher than test system...

  14. Tamsulosin shows a higher unbound drug fraction in human prostate than in plasma: a basis for uroselectivity?

    Science.gov (United States)

    Korstanje, Cees; Krauwinkel, Walter; van Doesum-Wolters, Francisca L C

    2011-01-01

    AIM The aim of this small patient study was to investigate tamsulosin concentrations in prostate and plasma samples in order to identify potential differences in the pharmacokinetics (PK) in plasma and prostate contributing to its pharmacodynamic activity profile in patients. METHODS Forty-one patients with benign prostatic hyperplasia (BPH) scheduled for open prostatectomy were given tamsulosin 0.4 mg for 6–21 days in order to reach steady-state PK. Patients were randomized over four groups to allow collection of plasma and tissue samples at different time points after last dose administration. Samples were collected during surgery and assayed for tamsulosin HCl. The free fraction (fu) of tamsulosin was determined by ultracentrifugation of plasma and prostate tissue spiked with 14C-tamsulosin. RESULTS Cmax in plasma at 4.4 h for total tamsulosin was 15.2 ng ml−1 and AUC(0,24 h) was 282 ng ml−1 h, while for prostate Cmax at 11.4 h post-dose was 5.4 ng ml−1 and AUC(0,24 h) was 120 ng ml−1 h. AUC(0,24 h) for total tamsulosin in prostate was 43% of the plasma AUC(0,24 h). fu was 0.4 % for plasma and 59.1% for prostate. Therefore calculated on unbound tamsulosin, a ratio of 63 resulted for prostate vs. plasma Cmax concentrations. CONCLUSIONS These data indicate that in patients with confirmed BPH the amount of tamsulosin freely available in the target tissue (prostate) is much higher than in plasma. PMID:21745239

  15. Macromolecular bipill of gemcitabine and methotrexate facilitates tumor-specific dual drug therapy with higher benefit-to-risk ratio

    DEFF Research Database (Denmark)

    Das, Manasmita; Jain, Roopal; Agrawal, Ashish Kumar

    2014-01-01

    -PEG-MTX conjugate over all other pharmaceutical preparations including free drugs, physical mixture of GEM and MTX, and PEGylated GEM/MTX. Toxicity studies in tumor bearing rats as well as healthy mice corroborated that dual drug conjugation is an effective means to synergize the therapeutic indices of potential...

  16. Consumption of meat is associated with higher fasting glucose and insulin concentrations regardless of glucose and insulin genetic risk scores: a meta-analysis of 50,345 Caucasians12

    Science.gov (United States)

    Fretts, Amanda M; Follis, Jack L; Nettleton, Jennifer A; Lemaitre, Rozenn N; Ngwa, Julius S; Wojczynski, Mary K; Kalafati, Ioanna Panagiota; Varga, Tibor V; Frazier-Wood, Alexis C; Houston, Denise K; Lahti, Jari; Ericson, Ulrika; van den Hooven, Edith H; Mikkilä, Vera; Kiefte-de Jong, Jessica C; Mozaffarian, Dariush; Rice, Kenneth; Renström, Frida; North, Kari E; McKeown, Nicola M; Feitosa, Mary F; Kanoni, Stavroula; Smith, Caren E; Garcia, Melissa E; Tiainen, Anna-Maija; Sonestedt, Emily; Manichaikul, Ani; van Rooij, Frank JA; Dimitriou, Maria; Raitakari, Olli; Pankow, James S; Djoussé, Luc; Province, Michael A; Hu, Frank B; Lai, Chao-Qiang; Keller, Margaux F; Perälä, Mia-Maria; Rotter, Jerome I; Hofman, Albert; Graff, Misa; Kähönen, Mika; Mukamal, Kenneth; Johansson, Ingegerd; Ordovas, Jose M; Liu, Yongmei; Männistö, Satu; Uitterlinden, André G; Deloukas, Panos; Seppälä, Ilkka; Psaty, Bruce M; Cupples, L Adrienne; Borecki, Ingrid B; Franks, Paul W; Arnett, Donna K; Nalls, Mike A; Eriksson, Johan G; Orho-Melander, Marju; Franco, Oscar H; Lehtimäki, Terho; Dedoussis, George V; Meigs, James B; Siscovick, David S

    2015-01-01

    loci known to influence fasting glucose or insulin resistance. Conclusion: The association of higher fasting glucose and insulin concentrations with meat consumption was not modified by an index of glucose- and insulin-related single-nucleotide polymorphisms. Six of the participating studies are registered at clinicaltrials.gov as NCT0000513 (Atherosclerosis Risk in Communities), NCT00149435 (Cardiovascular Health Study), NCT00005136 (Family Heart Study), NCT00005121 (Framingham Heart Study), NCT00083369 (Genetics of Lipid Lowering Drugs and Diet Network), and NCT00005487 (Multi-Ethnic Study of Atherosclerosis). PMID:26354543

  17. Higher blood harmane (1-methyl-9H-pyrido[3,4-b]indole) concentrations correlate with lower olfactory scores in essential tremor.

    Science.gov (United States)

    Louis, Elan D; Rios, Eileen; Pellegrino, Kathryn M; Jiang, Wendy; Factor-Litvak, Pam; Zheng, Wei

    2008-05-01

    Harmane (1-methyl-9H-pyrido[3,4-b]indole), a neurotoxin, may be an environmental risk factor for essential tremor (ET). Harmane and related chemicals are toxic to the cerebellum. Whether it is through this mechanism (cerebellar toxicity) that harmane leads to ET is unknown. Impaired olfaction may be a feature of cerebellar disease. To determine whether blood harmane concentrations correlate with olfactory test scores in patients with ET. Blood harmane concentrations were quantified using high performance liquid chromatography. Odor identification testing was performed with the University of Pennsylvania Smell Identification Test (UPSIT). In 83 ET cases, higher log blood harmane concentration was correlated with lower UPSIT score (rho=-0.46, p<0.001). 25/40 (62.5%) cases with high log blood harmane concentration (based on a median split) had low UPSIT scores (based on a median split) vs. 12/43 (27.9%) ET cases with low log blood harmane concentration (adjusted odd ratios (OR) 4.04, 95% confidence intervals (CI) 1.42-11.50, p=0.009). When compared with the low log blood harmane tertile, the odds of olfactory dysfunction were 2.64 times higher in cases in the middle tertile and 10.95 times higher in cases in the high tertile. In 69 control subjects, higher log blood harmane concentration was not correlated with lower UPSIT score (rho=0.12, p=0.32). Blood harmane concentrations were correlated with UPSIT scores in ET cases but not controls. These analyses set the stage for postmortem studies to further explore the role of harmane as a cerebellar toxin in ET.

  18. [Auxin synthesis by the higher fungus Lentinus edodes (Berk.) Sing in the presence of low concentrations of indole compounds].

    Science.gov (United States)

    Tsivileva, O M; Loshchinina, E A; Makarov, O E; Nikitina, V E

    2012-01-01

    The auxin formation in a submerged culture of the xylotrophic basidiomycete Lentinus edodes (Berk.) Sing (Lentinula edodes (Berk.) Pegler) (shiitake) is studied. Biologically active substances of an indole nature are identified, "the effect of small doses" of which lies in not only the stimulation of growth of the mycelium (indole-3-acetic acid, 2 x 10(-7)-2 x 10(-4) g/l), but also in the induction of tryptophan-independent paths of auxin biosynthesis. The above-mentioned path is realized in the presence of exogenous indole (1 x 10(-3)-1 x 10(-4) g/l), as well as while inducing the biosynthesis of indole-3-acetic acid by its microadditives (1 x 10(-5)-1 x 10(-8) g/l), and is accompanied by the formation of anthranilic acid (up to 1.5 mg/l). Induction of the generative development stage ofshiitake by indole derivatives is revealed. It was found that among the studied compounds only indoleacetamide at a concentration of an order of x 10(-4) g/l in the culture fluid of L. edodes had a pronounced stimulatory effect on the formation of shiitake's brown mycelial film.

  19. Doxorubicin-loaded QuadraSphere microspheres: plasma pharmacokinetics and intratumoral drug concentration in an animal model of liver cancer.

    Science.gov (United States)

    Lee, Kwang-Hun; Liapi, Eleni A; Cornell, Curt; Reb, Philippe; Buijs, Manon; Vossen, Josephina A; Ventura, Veronica Prieto; Geschwind, Jean-Francois H

    2010-06-01

    The purpose of this study was to evaluate, in vitro and in vivo, doxorubicin-loaded poly (vinyl alcohol-sodium acrylate) copolymer microspheres [QuadraSphere microspheres (QSMs)] for transcatheter arterial delivery in an animal model of liver cancer. Doxorubicin loading efficiency and release profile were first tested in vitro. In vivo, 15 rabbits, implanted with a Vx-2 tumor in the liver, were divided into three groups of five rabbits each, based on the time of euthanasia. Twenty-five milligrams of QSMs was diluted in 10 ml of a 10 mg/ml doxorubicin solution and 10 ml of nonionic contrast medium for a total volume of 20 ml. One milliliter of a drug-loaded QSM solution containing 5 mg of doxorubicin was injected into the tumor feeding artery. Plasma doxorubicin and doxorubicinol concentrations, and intratumoral and peritumoral doxorubicin tissue concentrations, were measured. Tumor specimens were pathologically evaluated to record tumor necrosis. As a control, one animal was blandly embolized with plain QSMs in each group. In vitro testing of QSM doxorubicin loadability and release over time showed 82-94% doxorubicin loadability within 2 h and 6% release within the first 6 h after loading, followed by a slow release pattern. In vivo, the doxorubicin plasma concentration declined at 40 min. The peak doxorubicin intratumoral concentration was observed at 3 days and remained detectable till the study's end point (7 days). Mean percentage tumor cell death in the doxorubicin QSM group was 90% at 7 days and 60% in the bland QSM embolization group. In conclusion, QSMs can be efficiently loaded with doxorubicin. Initial experiments with doxorubicin-loaded QSMs show a safe pharmacokinetic profile and effective tumor killing in an animal model of liver cancer.

  20. Doxorubicin-Loaded QuadraSphere Microspheres: Plasma Pharmacokinetics and Intratumoral Drug Concentration in an Animal Model of Liver Cancer

    International Nuclear Information System (INIS)

    Lee, Kwang-Hun; Liapi, Eleni A.; Cornell, Curt; Reb, Philippe; Buijs, Manon; Vossen, Josephina A.; Ventura, Veronica Prieto; Geschwind, Jean-Francois H.

    2010-01-01

    The purpose of this study was to evaluate, in vitro and in vivo, doxorubicin-loaded poly (vinyl alcohol-sodium acrylate) copolymer microspheres [QuadraSphere microspheres (QSMs)] for transcatheter arterial delivery in an animal model of liver cancer. Doxorubicin loading efficiency and release profile were first tested in vitro. In vivo, 15 rabbits, implanted with a Vx-2 tumor in the liver, were divided into three groups of five rabbits each, based on the time of euthanasia. Twenty-five milligrams of QSMs was diluted in 10 ml of a 10 mg/ml doxorubicin solution and 10 ml of nonionic contrast medium for a total volume of 20 ml. One milliliter of a drug-loaded QSM solution containing 5 mg of doxorubicin was injected into the tumor feeding artery. Plasma doxorubicin and doxorubicinol concentrations, and intratumoral and peritumoral doxorubicin tissue concentrations, were measured. Tumor specimens were pathologically evaluated to record tumor necrosis. As a control, one animal was blandly embolized with plain QSMs in each group. In vitro testing of QSM doxorubicin loadability and release over time showed 82-94% doxorubicin loadability within 2 h and 6% release within the first 6 h after loading, followed by a slow release pattern. In vivo, the doxorubicin plasma concentration declined at 40 min. The peak doxorubicin intratumoral concentration was observed at 3 days and remained detectable till the study's end point (7 days). Mean percentage tumor cell death in the doxorubicin QSM group was 90% at 7 days and 60% in the bland QSM embolization group. In conclusion, QSMs can be efficiently loaded with doxorubicin. Initial experiments with doxorubicin-loaded QSMs show a safe pharmacokinetic profile and effective tumor killing in an animal model of liver cancer.

  1. Evaluation of Flexible Tacrolimus Drug Concentration Monitoring Approach in Patients Receiving Extended-Release Once-Daily Tacrolimus Tablets.

    Science.gov (United States)

    Philosophe, Benjamin; Leca, Nicolae; West-Thielke, Patricia M; Horwedel, Timothy; Culkin-Gemmell, Christine; Kistler, Kristin; Stevens, Daniel R

    2018-02-20

    The majority of United States kidney transplant patients are treated with tacrolimus, a drug effective in preventing graft rejection, but with a narrow therapeutic range, necessitating close monitoring to avoid increased risks of transplant rejection or toxicity if the tacrolimus concentration is too low or too high, respectively. The trough drug concentration tests are time sensitive; patients treated on a twice-daily basis have blood draws exactly 12 hours after their previous dose. The schedule's rigidity causes problems for both patients and health care providers. Novel once-daily tacrolimus formulations such as LCPT (an extended-release tablet by Veloxis Pharmaceuticals, Inc., Cary, North Carolina) have allowed for blood draws on a once-daily basis; however, even that schedule can be restrictive. Results from tests taken either before or after that 24-hour target time may be discarded, or worse, may lead to inappropriate dose changes. Data from ASTCOFF, a phase 3B pharmacokinetic clinical trial (NCT02339246), demonstrated that the unique pharmacokinetic curve of LCPT may allow for a therapeutic monitoring window that extends for 3 hours before or after the 24-hour monitoring target. Furthermore, important tools to help clinicians interpret these levels, such as formulas to estimate the 24-hour trough level if an alternative monitoring time is used, were constructed from these data. These study results give treating clinicians access to data that allow them to safely use and monitor LCPT in their patients and expand the body of evidence surrounding differentiation and practical application of the novel LCPT tacrolimus formulation. © 2018, The Authors. The Journal of Clinical Pharmacology published by Wiley Periodicals, Inc. on behalf of American College of Clinical Pharmacology.

  2. Applications of linking PBPK and PD models to predict the impact of genotypic variability, formulation differences, differences in target binding capacity and target site drug concentrations on drug responses and variability.

    Directory of Open Access Journals (Sweden)

    Manoranjenni eChetty

    2014-11-01

    Full Text Available This study aimed to demonstrate the added value of integrating prior in vitro data and knowledge-rich physiologically based pharmacokinetic (PBPK models with pharmacodynamics (PD models. Four distinct applications that were developed and tested are presented here. PBPK models were developed for metoprolol using different CYP2D6 genotypes based on in vitro data. Application of the models for prediction of phenotypic differences in the pharmacokinetics (PK and PD compared favourably with clinical data, demonstrating that these differences can be predicted prior to the availability of such data from clinical trials. In the second case, PK and PD data for an immediate release formulation of nifedipine together with in vitro dissolution data for a controlled release formulation (CR were used to predict the PK and PD of the CR. This approach can be useful to pharmaceutical scientists during formulation development. The operational model of agonism was used in the third application to describe the hypnotic effects of triazolam, and this was successfully extrapolated to zolpidem by changing only the drug related parameters from in vitro experiments. This PBPK modelling approach can be useful to developmental scientists who which to compare several drug candidates in the same therapeutic class. Finally, differences in QTc prolongation due to quinidine in Caucasian and Korean females were successfully predicted by the model using free heart concentrations as an input to the PD models. This PBPK linked PD model was used to demonstrate a higher sensitivity to free heart concentrations of quinidine in Caucasian females, thereby providing a mechanistic understanding of a clinical observation. In general, permutations of certain conditions which potentially change PK and hence PD may not be amenable to the conduct of clinical studies but linking PBPK with PD provides an alternative method of investigating the potential impact of PK changes on PD.

  3. Applications of linking PBPK and PD models to predict the impact of genotypic variability, formulation differences, differences in target binding capacity and target site drug concentrations on drug responses and variability.

    Science.gov (United States)

    Chetty, Manoranjenni; Rose, Rachel H; Abduljalil, Khaled; Patel, Nikunjkumar; Lu, Gaohua; Cain, Theresa; Jamei, Masoud; Rostami-Hodjegan, Amin

    2014-01-01

    This study aimed to demonstrate the added value of integrating prior in vitro data and knowledge-rich physiologically based pharmacokinetic (PBPK) models with pharmacodynamics (PDs) models. Four distinct applications that were developed and tested are presented here. PBPK models were developed for metoprolol using different CYP2D6 genotypes based on in vitro data. Application of the models for prediction of phenotypic differences in the pharmacokinetics (PKs) and PD compared favorably with clinical data, demonstrating that these differences can be predicted prior to the availability of such data from clinical trials. In the second case, PK and PD data for an immediate release formulation of nifedipine together with in vitro dissolution data for a controlled release (CR) formulation were used to predict the PK and PD of the CR. This approach can be useful to pharmaceutical scientists during formulation development. The operational model of agonism was used in the third application to describe the hypnotic effects of triazolam, and this was successfully extrapolated to zolpidem by changing only the drug related parameters from in vitro experiments. This PBPK modeling approach can be useful to developmental scientists who which to compare several drug candidates in the same therapeutic class. Finally, differences in QTc prolongation due to quinidine in Caucasian and Korean females were successfully predicted by the model using free heart concentrations as an input to the PD models. This PBPK linked PD model was used to demonstrate a higher sensitivity to free heart concentrations of quinidine in Caucasian females, thereby providing a mechanistic understanding of a clinical observation. In general, permutations of certain conditions which potentially change PK and hence PD may not be amenable to the conduct of clinical studies but linking PBPK with PD provides an alternative method of investigating the potential impact of PK changes on PD.

  4. Identification of intestinal loss of a drug through physiologically based pharmacokinetic simulation of plasma concentration-time profiles.

    Science.gov (United States)

    Peters, Sheila Annie

    2008-01-01

    Despite recent advances in understanding of the role of the gut as a metabolizing organ, recognition of gut wall metabolism and/or other factors contributing to intestinal loss of a compound has been a challenging task due to the lack of well characterized methods to distinguish it from first-pass hepatic extraction. The implications of identifying intestinal loss of a compound in drug discovery and development can be enormous. Physiologically based pharmacokinetic (PBPK) simulations of pharmacokinetic profiles provide a simple, reliable and cost-effective way to understand the mechanisms underlying pharmacokinetic processes. The purpose of this article is to demonstrate the application of PBPK simulations in bringing to light intestinal loss of orally administered drugs, using two example compounds: verapamil and an in-house compound that is no longer in development (referred to as compound A in this article). A generic PBPK model, built in-house using MATLAB software and incorporating absorption, metabolism, distribution, biliary and renal elimination models, was employed for simulation of concentration-time profiles. Modulation of intrinsic hepatic clearance and tissue distribution parameters in the generic PBPK model was done to achieve a good fit to the observed intravenous pharmacokinetic profiles of the compounds studied. These optimized clearance and distribution parameters are expected to be invariant across different routes of administration, as long as the kinetics are linear, and were therefore employed to simulate the oral profiles of the compounds. For compounds with reasonably good solubility and permeability, an area under the concentration-time curve for the simulated oral profile that far exceeded the observed would indicate some kind of loss in the intestine. PBPK simulations applied to compound A showed substantial loss of the compound in the gastrointestinal tract in humans but not in rats. This accounted for the lower bioavailability of the

  5. Tenofovir alafenamide (TAF) does not deplete mitochondrial DNA in human T-cell lines at intracellular concentrations exceeding clinically relevant drug exposures.

    Science.gov (United States)

    Stray, Kirsten M; Park, Yeojin; Babusis, Darius; Callebaut, Christian; Cihlar, Tomas; Ray, Adrian S; Perron, Michel

    2017-04-01

    HIV-infected patients treated with certain nucleoside reverse transcriptase inhibitors (NRTIs) have experienced adverse effects due to drug-related mitochondrial toxicity. Tenofovir alafenamide (TAF) is a novel prodrug of the NRTI tenofovir (TFV) with an improved safety profile compared to tenofovir disoproxil fumarate (TDF). Prior in vitro studies have demonstrated that the parent nucleotide TFV has no significant effects on mtDNA synthesis. This study investigated whether clinically relevant TAF and TDF exposures affect mtDNA content in human lymphocytes. First, activated or resting peripheral blood mononuclear cells (PBMCs), as well as MT-2 and Jurkat T-cell lines, were continuously treated with ddC for 10 days to establish their susceptibility to mtDNA depletion. PBMCs had low sensitivity to NRTI-mediated mtDNA depletion in vitro. In contrast, ddC treatment of rapidly dividing MT-2 and Jurkat cells resulted in a dose-dependent decrease in mtDNA. Therefore, these two T-cell lines were selected for evaluating TAF and TDF treatment effects. MT-2 and Jurkat cells were pulse-treated with TAF or TDF every 24 h for 10 days to mimic pharmacologically relevant drug exposures. Pulse treatment of cells with 3.3 μM TAF or 1.1 μM TDF for 10 days resulted in 2- to 7-fold greater steady-state intracellular TFV-diphosphate (TFV-DP) levels than those observed clinically in TAF- or TDF-treated patients. At these concentrations, no significant TAF- (106.7% and 84.1% of control; p = 0.77 and 0.12 for MT-2 and Jurkat, respectively) or TDF- (100.6% and 91.0% of control; p = 0.91 and 0.37, respectively) associated reduction in mtDNA content was observed compared with untreated control cells. This study demonstrates that, despite delivering higher intracellular levels of TFV-DP than TDF, TAF does not inhibit mtDNA synthesis in vitro at concentrations exceeding the clinically relevant intracellular drug exposures. Thus, TAF has a low potential for mitochondrial toxicity in

  6. A Western Diet Pattern Is Associated with Higher Concentrations of Blood and Bone Lead among Middle-Aged and Elderly Men.

    Science.gov (United States)

    Wang, Xin; Ding, Ning; Tucker, Katherine L; Weisskopf, Marc G; Sparrow, David; Hu, Howard; Park, Sung Kyun

    2017-07-01

    Background: Little is known about the effects of overall dietary pattern on lead concentration. Objective: We examined the association of overall dietary patterns, derived from a semiquantitative food frequency questionnaire, with bone and blood lead concentrations. Methods: These longitudinal analyses included mostly non-Hispanic white, middle-aged-to-elderly men from the Veterans Affairs Normative Aging Study. Long-term lead exposures were measured as tibia and patella lead concentrations by using K-shell-X-ray fluorescence. Short-term lead exposures were measured as blood lead concentrations by using graphite furnace atomic absorption spectroscopy. Dietary pattern scores were derived by using factor analysis. Linear mixed-effects models were utilized to predict blood lead concentrations among 983 men, aged 44-92 y at baseline, with a total of 3273 observations (during 1987-2008). We constructed linear regression models to determine the relations between dietary patterns and bone lead concentrations among 649 participants with an age range of 49-93 y. Results: Two major dietary patterns were identified: a prudent dietary pattern, characterized by high intakes of fruit, legumes, vegetables, whole grains, poultry, and seafood; and a Western dietary pattern, characterized by high intakes of processed meat, red meat, refined grains, high-fat dairy products, French fries, butter, and eggs. After adjusting for age, smoking status, body mass index, total energy intake, education, occupation, neighborhood-based education and income level, men in the highest tertile of the Western pattern score (compared with the lowest) had 0.91 μg/dL (95% CI: 0.41, 1.42 μg/dL) higher blood lead, 5.96 μg/g (95% CI: 1.76, 10.16 μg/g) higher patella lead, and 3.83 μg/g (95% CI: 0.97, 6.70 μg/g) higher tibia lead. No significant association was detected with the prudent dietary pattern in the adjusted model. Conclusions: These findings suggest that the Western diet is associated with

  7. A lower degree of PBMC L1 methylation is associated with excess body weight and higher HOMA-IR in the presence of lower concentrations of plasma folate.

    Science.gov (United States)

    Piyathilake, Chandrika J; Badiga, Suguna; Alvarez, Ronald D; Partridge, Edward E; Johanning, Gary L

    2013-01-01

    Identification of associations between global DNA methylation and excess body weight (EBW) and related diseases and their modifying factors are an unmet research need that may lead to decreasing DNA methylation-associated disease risks in humans. The purpose of the current study was to evaluate the following; 1) Association between the degree of peripheral blood mononuclear cell (PBMC) L1 methylation and folate, and indicators of EBW, 2) Association between the degree of PBMC L1 methylation and folate, and insulin resistance (IR) as indicated by a higher homeostasis model assessment (HOMA-IR). The study population consisted of 470 child-bearing age women diagnosed with abnormal pap. The degree of PBMC L1 methylation was assessed by pyrosequencing. Logistic regression models specified indicators of EBW (body mass index-BMI, body fat-BF and waist circumference-WC) or HOMA-IR as dependent variables and the degree of PBMC L1 methylation and circulating concentrations of folate as the independent predictor of primary interest. Women with a lower degree of PBMC L1 methylation and lower plasma folate concentrations were significantly more likely to have higher BMI, % BF or WC (OR = 2.49, 95% CI:1.41-4.47, P = 0.002; OR = 2.49, 95% CI:1.40-4.51, P = 0.002 and OR = 1.98, 95% = 1.14-3.48 P = 0.0145, respectively) and higher HOMA-IR (OR = 1.78, 95% CI:1.02-3.13, P = 0.041). Our results demonstrated that a lower degree of PBMC L1 methylation is associated with excess body weight and higher HOMA-IR, especially in the presence of lower concentrations of plasma folate.

  8. Suboptimal Antituberculosis Drug Concentrations and Outcomes in Small and HIV-Coinfected Children in India: Recommendations for Dose Modifications.

    Science.gov (United States)

    Guiastrennec, Benjamin; Ramachandran, Geetha; Karlsson, Mats O; Kumar, A K Hemanth; Bhavani, Perumal Kannabiran; Gangadevi, N Poorana; Swaminathan, Soumya; Gupta, Amita; Dooley, Kelly E; Savic, Radojka M

    2017-12-16

    This work aimed to evaluate the once-daily antituberculosis treatment as recommended by the new Indian pediatric guidelines. Isoniazid, rifampin, and pyrazinamide concentration-time profiles and treatment outcome were obtained from 161 Indian children with drug-sensitive tuberculosis undergoing thrice-weekly dosing as per previous Indian pediatric guidelines. The exposure-response relationships were established using a population pharmacokinetic-pharmacodynamic approach. Rifampin exposure was identified as the unique predictor of treatment outcome. Consequently, children with low body weight (4-7 kg) and/or HIV infection, who displayed the lowest rifampin exposure, were associated with the highest probability of unfavorable treatment (therapy failure, death) outcome (P unfavorable ). Model-based simulation of optimized (P unfavorable ≤ 5%) rifampin once-daily doses were suggested per treatment weight band and HIV coinfection status (33% and 190% dose increase, respectively, from the new Indian guidelines). The established dose-exposure-response relationship could be pivotal in the development of future pediatric tuberculosis treatment guidelines. © 2017, The Authors Clinical Pharmacology & Therapeutics published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.

  9. Postmortem Blood Concentrations of R- and S-Enantiomers of Methadone and EDDP in Drug Users: Influence of Co-Medication and P-glycoprotein Genotype

    DEFF Research Database (Denmark)

    Buchard, Anders; Linnet, Kristian; Johansen, Sys Stybe

    2010-01-01

    We investigated toxicological and pharmacogenetic factors that could influence methadone toxicity using postmortem samples. R- and S-methadone were measured in femoral blood from 90 postmortem cases, mainly drug users. The R-enantiomer concentrations significantly exceeded that of the S-enantiome......We investigated toxicological and pharmacogenetic factors that could influence methadone toxicity using postmortem samples. R- and S-methadone were measured in femoral blood from 90 postmortem cases, mainly drug users. The R-enantiomer concentrations significantly exceeded that of the S...

  10. Higher concentrations of nanoscale zero-valent iron (nZVI) in soil induced rice chlorosis due to inhibited active iron transportation

    International Nuclear Information System (INIS)

    Wang, Jie; Fang, Zhanqiang; Cheng, Wen; Yan, Xiaomin; Tsang, Pokeung Eric; Zhao, Dongye

    2016-01-01

    In this study, the effects of concentrations 0, 100, 250, 500, 750 and 1000 mg kg"−"1 of nanoscale zero-valent iron (nZVI) on germination, seedlings growth, physiology and toxicity mechanisms were investigated. The results showed that nZVI had no effect on germination, but inhibited the rice seedlings growth in higher concentrations (>500 mg kg"−"1 nZVI). The highest suppression rate of the length of roots and shoots reached 46.9% and 57.5%, respectively. The 1000mg kg"−"1 nZVI caused the highest suppression rates for chlorophyll and carotenoids, at 91.6% and 85.2%, respectively. In addition, the activity of antioxidant enzymes was altered by the translocation of nanoparticles and changes in active iron content. Visible symptoms of iron deficiency were observed at higher concentrations, at which the active iron content decreased 61.02% in the shoots, but the active iron content not decreased in roots. Interestingly, the total and available amounts of iron in the soil were not less than those in the control. Therefore, the plants iron deficiency was not caused by (i) deficiency of available iron in the soil and (ii) restraint of the absorption that plant takes in the available iron, while induced by (ⅲ) the transport of active iron from the root to the shoot was blocked. The cortex tissues were seriously damaged by nZVI which was transported from soil to the root, these were proved by scanning electron microscopy (SEM), transmission electron microscopy (TEM) and energy dispersive spectroscopy (EDS). This current study shows that the mechanism of iron deficiency in rice seedling was due to transport of active iron from the root to the shoot blocked, which was caused by the uptake of nZVI. - Highlights: • Higher concentrations of nZVI induced iron deficiency in rice seedlings visibly. • nZVI was taken in rice seedlings and transported form root to shoot. • The pathway of active iron transport from root to shoot was inhibited. • The cortex tissues

  11. Drugs in breast milk.

    Science.gov (United States)

    Hervada, A R; Feit, E; Sagraves, R

    1978-09-01

    The amount of drug excreted into breast milk is dependent upon the lipid solubility of the medication, the mechanism of transport, the degree of ionization, and change in plasma pH. The higher the lipid solubility, the greater the concentration in human milk. The majority of drugs are transported into mammary blood capillaries by passive diffusion. The rest are transported by reverse pinocytosis. Once the drug has entered the epithelial cells of breast tissue, the drug molecules are excreted into the human milk by active transport, passive diffusion, or apocrine secretion. The amount of free (active) drug available for transport depends on the degree of protein binding the plasma pH. Another factor affecting excretion of drugs is the time when breast feeding occurs. In the 1st few days of life, when colostrum is present, water-soluble drugs pass through the breast more easily than afterwards when milk is produced. Then lipid-soluble drugs cross in higher concentrations. The effect on nursing infants is dependent on the amount excreted into the milk, the total amount absorbed by the infant, and the toxicity of the drug. The use of the following drugs in breast feeding mothers is reviewed: anticoagulants, antihypertensives and diuretics, antimicrobials, drugs affecting the central nervous system (alcohol, chloral hydrate, meprobamate, lithium, and aspirin), marijuana, other drugs (antihistamines, atropine, ergot alkaloids, laxatives, nicotine, iodides, propylthiouracil, theophylline), hormones (insulin, thyroxine, and oral contraceptives), and radiopharmaceuticals.

  12. Usefulness of saliva for measurement of 3,4-methylenedioxymethamphetamine and its metabolites: correlation with plasma drug concentrations and effect of salivary pH.

    Science.gov (United States)

    Navarro, M; Pichini, S; Farré, M; Ortuño, J; Roset, P N; Segura, J; de la Torre, R

    2001-10-01

    Saliva is an alternative biologic matrix for drugs-of-abuse testing that offers the advantages of noninvasive, rapid, and easy sampling. We studied the excretion profile of 3,4-methylenedioxymethamphetamine (MDMA) and its metabolites in both saliva and plasma, as well the effect of the drug on salivary pH. Saliva and plasma samples were obtained from eight healthy MDMA consumers after ingestion of a single 100-mg dose of the drug. Concentrations of MDMA and its main metabolites, 3,4-methylenedioxyamphetamine (MDA) and 4-hydroxy-3-methoxymethamphetamine (HMMA), in saliva and plasma were measured by gas chromatography-mass spectrometry. Apparent pharmacokinetic parameters for MDMA in saliva were estimated, and the saliva-to-plasma ratio at each time interval was calculated and correlated with salivary pH. MDMA, MDA, and HMMA were detected in saliva. Salivary concentrations of MDMA were 1728.9-6510.6 microg/L and peaked at 1.5 h after drug intake. This was followed by a progressive decrease, with a mean concentration of 126.2 microg/L at 24 h. The saliva-to-plasma ratio was 32.3-1.2, with a peak of 18.1 at 1.5 h after drug administration. Salivary pH seemed to be affected by MDMA administration; pH values decreased by 0.6 units (mean pH values of 6.9 and 6.8 at 1.5 and 4 h after drug administration vs predose pH of 7.4). Measurement of MDMA in saliva is a valuable alternative to determination of plasma drug concentrations in both clinical and toxicologic studies. On-site testing is also facilitated by noninvasive and rapid collection of salivary specimens.

  13. Mixed microalgae consortia growth under higher concentration of CO2 from unfiltered coal fired flue gas: Fatty acid profiling and biodiesel production.

    Science.gov (United States)

    Aslam, Ambreen; Thomas-Hall, Skye R; Manzoor, Maleeha; Jabeen, Faiza; Iqbal, Munawar; Uz Zaman, Qamar; Schenk, Peer M; Asif Tahir, M

    2018-02-01

    Biodiesel is produced by transesterification of fatty acid methyl esters (FAME) from oleaginous microalgae feedstock. Biodiesel fuel properties were studied and compared with biodiesel standards. Qualitative analysis of FAME was done while cultivating mixed microalgae consortia under three concentrations of coal fired flue gas (1%, 3.0% and 5.5% CO 2 ). Under 1% CO 2 concentration (flue gas), the FAME content was 280.3 μg/mL, whereas the lipid content was 14.03 μg/mL/D (day). Both FAMEs and lipid contents were low at other CO 2 concentrations (3.0 and 5.5%). However, mixed consortia in the presence of phosphate buffer and flue gas (PB + FG) showed higher saturated fatty acids (SFA) (36.28%) and unsaturated fatty acids (UFA) (63.72%) versus 5.5% CO 2 concentration, which might be responsible for oxidative stability of biodiesel. Subsequently, higher cetane number (52) and low iodine value (136.3 gI 2 /100 g) biodiesel produced from mixed consortia (PB + FG) under 5.5% CO 2 along with 50 mM phosphate buffer were found in accordance with European (EN 14214) standard. Results revealed that phosphate buffer significantly enhanced the biodiesel quality, but reduced the FAME yield. This study intended to develop an integrated approach for significant improvement in biodiesel quality under surplus phosphorus by utilizing waste flue gas (as CO 2 source) using microalgae. The CO 2 sequestration from industrial flue gas not only reduced greenhouse gases, but may also ensure the sustainable and eco-benign production of biodiesel. Copyright © 2018. Published by Elsevier B.V.

  14. Parallel monitoring of plasma and intraluminal drug concentrations in man after oral administration of fosamprenavir in the fasted and fed state.

    Science.gov (United States)

    Brouwers, Joachim; Tack, Jan; Augustijns, Patrick

    2007-10-01

    The purpose of this study was to explore the feasibility of linking the pharmacokinetic profile of a drug with its gastrointestinal behavior by simultaneously monitoring plasma and intraluminal drug concentrations. Fosamprenavir, a phosphate ester prodrug of the poorly water-soluble HIV-inhibitor amprenavir, was selected as model compound. A single tablet of fosamprenavir (Telzir) was administered to 5 volunteers in the fasted and fed state (simulated by intake of a nutritional drink). Gastric and duodenal fluids were aspirated in function of time and characterized with respect to the concentration of (fos)amprenavir, inorganic phosphate and pH. In parallel, blood samples were collected and analyzed for amprenavir. The observed plasma concentration-time profiles suggested a food-induced delay in the absorption of amprenavir: in the fed state, mean tmax increased by more than 150 min compared to the fasted state. A similar delay was seen in the duodenal appearance of fosamprenavir (concentrations in mM-range) and, after dephosphorylation, amprenavir (concentrations below 160 microM). This observation could be related to the behavior of fosamprenavir in the stomach. In the fasted state, gastric dissolution of fosamprenavir started immediately, resulting in a Cmax of 4 +/- 2 mM after 43 +/- 15 min; however, in the fed state, the fosamprenavir concentration remained below 20 microM for the first 90 min after drug intake. The postponed gastric dissolution may be attributed to a food-induced delay in tablet disintegration. For the first time, the pharmacokinetic profile of a drug was monitored in parallel with its gastrointestinal concentrations. The observed food effect in the plasma concentration-time profile of amprenavir after intake of its phosphate ester prodrug could be related to a food-induced delay in gastric dissolution of fosamprenavir.

  15. Nonsmoker Exposure to Secondhand Cannabis Smoke. III. Oral Fluid and Blood Drug Concentrations and Corresponding Subjective Effects.

    Science.gov (United States)

    Cone, Edward J; Bigelow, George E; Herrmann, Evan S; Mitchell, John M; LoDico, Charles; Flegel, Ronald; Vandrey, Ryan

    2015-09-01

    The increasing use of highly potent strains of cannabis prompted this new evaluation of human toxicology and subjective effects following passive exposure to cannabis smoke. The study was designed to produce extreme cannabis smoke exposure conditions tolerable to drug-free nonsmokers. Six experienced cannabis users smoked cannabis cigarettes [5.3% Δ(9)-tetrahydrocannabinol (THC) in Session 1 and 11.3% THC in Sessions 2 and 3] in a closed chamber. Six nonsmokers were seated alternately with smokers during exposure sessions of 1 h duration. Sessions 1 and 2 were conducted with no ventilation and ventilation was employed in Session 3. Oral fluid, whole blood and subjective effect measures were obtained before and at multiple time points after each session. Oral fluid was analyzed by ELISA (4 ng/mL cutoff concentration) and by LC-MS-MS (limit of quantitation) for THC (1 ng/mL) and total THCCOOH (0.02 ng/mL). Blood was analyzed by LC-MS-MS (0.5 ng/mL) for THC, 11-OH-THC and free THCCOOH. Positive tests for THC in oral fluid and blood were obtained for nonsmokers up to 3 h following exposure. Ratings of subjective effects correlated with the degree of exposure. Subjective effect measures and amounts of THC absorbed by nonsmokers (relative to smokers) indicated that extreme secondhand cannabis smoke exposure mimicked, though to a lesser extent, active cannabis smoking. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  16. Relation between CYP2D6 Genotype, Phenotype and Therapeutic Drug Concentrations among Nortriptyline and Venlafaxine Users in Old Age Psychiatry

    NARCIS (Netherlands)

    Berm, E; Kok, R.; Hak, E; Wilffert, B

    2016-01-01

    Objectives: To determine relations between drug concentrations and the cytochrome P450-CYP2D6 genotype or phenotype among elderly patients treated with nortriptyline or venlafaxine. Methods: A post-hoc analysis of a clinical trial was performed. Patients were grouped into phenotypes according to the

  17. Substantially Higher and Earlier Occurrence of Anti-Tuberculosis Drug-Related Adverse Reactions in HIV Coinfected Tuberculosis Patients: A Matched-Cohort Study.

    Science.gov (United States)

    Matono, Takashi; Nishijima, Takeshi; Teruya, Katsuji; Morino, Eriko; Takasaki, Jin; Gatanaga, Hiroyuki; Kikuchi, Yoshimi; Kaku, Mitsuo; Oka, Shinichi

    2017-11-01

    Little information exists on the frequency, severity, and timing of first-line anti-tuberculosis drug-related adverse events (TB-AEs) in HIV-tuberculosis coinfected (HIV-TB) patients in the antiretroviral therapy (ART) era. This matched-cohort study included HIV-TB patients as cases and HIV-uninfected tuberculosis (non-HIV-TB) patients as controls. Tuberculosis was culture-confirmed in both groups. Cases were matched to controls in a 1:4 ratio on age, sex, and year of diagnosis. TB-AEs were defined as Grade 2 or higher requiring drug discontinuation/regimen change. From 2003 to 2015, 94 cases and 376 controls were analyzed (95% men, 98% Asians). Standard four-drug combination therapy was initiated in 91% of cases and 89% of controls (p = 0.45). Cases had a higher frequency of TB-AE [51% (48/94) vs. 10% (39/376), p tuberculosis treatment. HIV infection was an independent risk factor for TB-AEs in the multivariate Cox analysis [adjusted HR (aHR): 6.96; 95% confidence interval: 3.93-12.3]. TB-AEs occurred more frequently in HIV-TB than in non-HIV-TB patients, and were more severe. The majority of TB-AEs occurred within 4 weeks of initiating anti-tuberculosis treatment. Because TB-AEs may delay ART initiation, careful monitoring during this period is warranted in coinfected patients.

  18. Superior integrin activating capacity and higher adhesion to fibrinogen matrix in buffy coat-derived platelet concentrates (PCs) compared to PRP-PCs.

    Science.gov (United States)

    Beshkar, Pezhman; Hosseini, Ehteramolsadat; Ghasemzadeh, Mehran

    2018-02-01

    Regardless of different sources, methods or devices which are applied for preparation of therapeutic platelets, these products are generally isolated from whole blood by the sedimentation techniques which are based on PRP or buffy coat (BC) separation. As a general fact, platelet preparation and storage are also associated with some deleterious changes that known as platelet storage lesion (PSL). Although these alternations in platelet functional activity are aggravated during storage, whether technical issues within preparation can affect integrin activation and platelet adhesion to fibrinogen were investigated in this study. PRP- and BC-platelet concentrates (PCs) were subjected to flowcytometry analysis to examine the expression of platelet activation marker, P-selectin as well as active confirmation of the GPIIb/IIIa (α IIb β 3 ) on day 0, 1, 3 and 5 post-storage. Platelet adhesion to fibrinogen matrix was evaluated by fluorescence microscopy. Glucose concentration and LDH activity were also measured by colorimetric methods. The increasing P-selectin expression during storage was in a reverse correlation with PAC-1 binding (r = -0.67; p = .001). PRP-PCs showed the higher level of P-selectin expression than BC-PCs, whereas the levels of PAC-1 binding and platelet adhesion to fibrinogen matrix were significantly lower in PRP-PCs. Higher levels of active confirmation of the GPIIb/IIIa in BC-PCs were also associated with greater concentration of glucose in these products. We demonstrated the superior capacities of integrin activation and adhesion to fibrinogen for BC-PCs compared to those of PRP-PCs. These findings may provide more advantages for BC method of platelet preparation. Copyright © 2017 Elsevier Ltd. All rights reserved.

  19. A natively paired antibody library yields drug leads with higher sensitivity and specificity than a randomly paired antibody library.

    Science.gov (United States)

    Adler, Adam S; Bedinger, Daniel; Adams, Matthew S; Asensio, Michael A; Edgar, Robert C; Leong, Renee; Leong, Jackson; Mizrahi, Rena A; Spindler, Matthew J; Bandi, Srinivasa Rao; Huang, Haichun; Tawde, Pallavi; Brams, Peter; Johnson, David S

    2018-04-01

    Deep sequencing and single-chain variable fragment (scFv) yeast display methods are becoming more popular for discovery of therapeutic antibody candidates in mouse B cell repertoires. In this study, we compare a deep sequencing and scFv display method that retains native heavy and light chain pairing with a related method that randomly pairs heavy and light chain. We performed the studies in a humanized mouse, using interleukin 21 receptor (IL-21R) as a test immunogen. We identified 44 high-affinity binder scFv with the native pairing method and 100 high-affinity binder scFv with the random pairing method. 30% of the natively paired scFv binders were also discovered with the randomly paired method, and 13% of the randomly paired binders were also discovered with the natively paired method. Additionally, 33% of the scFv binders discovered only in the randomly paired library were initially present in the natively paired pre-sort library. Thus, a significant proportion of "randomly paired" scFv were actually natively paired. We synthesized and produced 46 of the candidates as full-length antibodies and subjected them to a panel of binding assays to characterize their therapeutic potential. 87% of the antibodies were verified as binding IL-21R by at least one assay. We found that antibodies with native light chains were more likely to bind IL-21R than antibodies with non-native light chains, suggesting a higher false positive rate for antibodies from the randomly paired library. Additionally, the randomly paired method failed to identify nearly half of the true natively paired binders, suggesting a higher false negative rate. We conclude that natively paired libraries have critical advantages in sensitivity and specificity for antibody discovery programs.

  20. The growth of hydroxyapatite on alkaline treated Ti-6Al-4V soaking in higher temperature with concentrated Ca2+/HPO42- simulated body fluid

    International Nuclear Information System (INIS)

    Lin, F.-H.; Hsu, Y.-S.; Lin, S.-H.; Chen, T.-M.

    2004-01-01

    In this study, calcium and phosphorous ions in the simulated body fluid (SBF) was be increased to increase the rate of precipitation of hydroxyapatite (HA). The soaking temperature in concentrated calcium and phosphorous ion-SBF (CP-SBF) was increased to reduce the nucleation energy of the HA, which lead to an early precipitation to shorten the treatment process. When the metallic substrates treated with 10 M NaOH aqueous solution and subsequently heated at 600 deg. C, a thin sodium titanium oxide layer was formed on the surfaces as the linking layer for HA and Ti-6Al-4V alloys. After Ti-6Al-4V alloys treated with alkali solution, it would soak into a simulated body fluid with higher concentration of calcium and phosphorous ions (CP-SBF) to increase the possibility of nucleation of HA. When Ti-6Al-4V alloys treated with alkali solution, subsequently heated at 600 deg. C, and then soaked into CP-SBF at a temperature of 80 deg. C, it could form a dense and thick (50 μm) bone-like hydroxyapatite layer on the surface. The HA layer was appeared on the surface of the Ti-alloy at the first week soaking, which was greatly shorten the coating process. In the research, the characteristics of the coating layer will be analyzed by the results of X-ray diffractometer (XRD), scanning electron microscope (SEM), and Fourier transformation infrared (FT-IR)

  1. Dimethadione embryotoxicity in the rat is neither correlated with maternal systemic drug concentrations nor embryonic tissue levels

    Energy Technology Data Exchange (ETDEWEB)

    Ozolinš, Terence R.S., E-mail: ozolinst@queensu.ca [Department of Biomedical and Molecular Sciences, Program in Pharmacology and Toxicology, Queen’s University, Botterell Hall, Kingston, ON K7L 3N6 (Canada); Weston, Andrea D. [Currently at Applied Biotechnology/Lead Discovery, Bristol-Myers Squibb, 5 Research Pkwy Wallingford, CT 06492-1996 (United States); Perretta, Anthony [Currently at Pfizer Research and Development, Eastern Point Road, Groton, CT 06340 (United States); Thomson, Jason J. [Currently at Yale Stem Cell Center, Yale School of Medicine, PO Box 208073, New Haven, CT 06520-8073 (United States); Brown, Nigel A. [Division of Basic Medical Sciences, St. George’s University of London, UK SW17 0RE (United Kingdom)

    2015-11-15

    Pregnant rats treated with dimethadione (DMO), the N-demethylated metabolite of the anticonvulsant trimethadione, produce offspring having a 74% incidence of congenital heart defects (CHD); however, the incidence of CHD has high inter-litter variability (40–100%) that presents a challenge when studying the initiating events prior to the presentation of an abnormal phenotype. We hypothesized that the variability in CHD incidence was the result of differences in maternal systemic concentrations or embryonic tissue concentrations of DMO. To test this hypothesis, dams were administered 300 mg/kg DMO every 12 h from the evening of gestational day (GD) 8 until the morning of GD 11 (six total doses). Maternal serum levels of DMO were assessed on GD 11, 12, 13, 14, 15, 18 and 21. Embryonic tissue concentrations of DMO were assessed on GD 11, 12, 13 and 14. In a separate cohort of GD 12 embryos, DMO concentrations and parameters of growth and development were assessed to determine if tissue levels of DMO were correlated with these endpoints. Embryos were exposed directly to different concentrations of DMO with whole embryo culture (WEC) and their growth and development assessed. Key findings were that neither maternal systemic concentrations nor tissue concentrations of DMO identified embryos that were sensitive or resistant to DMO in vivo. Direct exposure of embryos to DMO via WEC also failed to show correlations between embryonic concentrations of DMO with developmental outcomes in vitro. We conclude that neither maternal serum nor embryonic tissue concentrations of DMO predict embryonic outcome. - Highlights: • Dimethadione (DMO) induces septation defects (VSD) in rat offspring. • Despite high rate of VSD defects inter-litter variability is 40–100%. • Maternal and embryonic concentrations of DMO were assessed. • Neither serum nor tissue levels of DMO were correlated with embryotoxicity.

  2. Dimethadione embryotoxicity in the rat is neither correlated with maternal systemic drug concentrations nor embryonic tissue levels

    International Nuclear Information System (INIS)

    Ozolinš, Terence R.S.; Weston, Andrea D.; Perretta, Anthony; Thomson, Jason J.; Brown, Nigel A.

    2015-01-01

    Pregnant rats treated with dimethadione (DMO), the N-demethylated metabolite of the anticonvulsant trimethadione, produce offspring having a 74% incidence of congenital heart defects (CHD); however, the incidence of CHD has high inter-litter variability (40–100%) that presents a challenge when studying the initiating events prior to the presentation of an abnormal phenotype. We hypothesized that the variability in CHD incidence was the result of differences in maternal systemic concentrations or embryonic tissue concentrations of DMO. To test this hypothesis, dams were administered 300 mg/kg DMO every 12 h from the evening of gestational day (GD) 8 until the morning of GD 11 (six total doses). Maternal serum levels of DMO were assessed on GD 11, 12, 13, 14, 15, 18 and 21. Embryonic tissue concentrations of DMO were assessed on GD 11, 12, 13 and 14. In a separate cohort of GD 12 embryos, DMO concentrations and parameters of growth and development were assessed to determine if tissue levels of DMO were correlated with these endpoints. Embryos were exposed directly to different concentrations of DMO with whole embryo culture (WEC) and their growth and development assessed. Key findings were that neither maternal systemic concentrations nor tissue concentrations of DMO identified embryos that were sensitive or resistant to DMO in vivo. Direct exposure of embryos to DMO via WEC also failed to show correlations between embryonic concentrations of DMO with developmental outcomes in vitro. We conclude that neither maternal serum nor embryonic tissue concentrations of DMO predict embryonic outcome. - Highlights: • Dimethadione (DMO) induces septation defects (VSD) in rat offspring. • Despite high rate of VSD defects inter-litter variability is 40–100%. • Maternal and embryonic concentrations of DMO were assessed. • Neither serum nor tissue levels of DMO were correlated with embryotoxicity.

  3. Higher Urinary Heavy Metal, Phthalate, and Arsenic but Not Parabens Concentrations in People with High Blood Pressure, U.S. NHANES, 2011–2012

    Directory of Open Access Journals (Sweden)

    Ivy Shiue

    2014-06-01

    Full Text Available Link between environmental chemicals and human health has emerged but not been completely examined in risk factors. Therefore, it was aimed to study the relationships of different sets of urinary environmental chemical concentrations and risk of high blood pressure (BP in a national, population-based study. Data were retrieved from United States National Health and Nutrition Examination Surveys, 2011–2012 including demographics, BP readings, and urinary environmental chemical concentrations. Analyses included chi-square test, t-test and survey-weighted logistic regression modeling. After full adjustment (adjusting for urinary creatinine, age, sex, ethnicity, and body mass index, urinary cesium (OR 1.56, 95%CI 1.11–2.20, P = 0.014, molybden (OR 1.46, 95%CI 1.06–2.01, P = 0.023, manganese (OR 1.42, 95%CI 1.09–1.86, P = 0.012, lead (OR 1.58, 95%CI 1.28–1.96, P < 0.001, tin (OR 1.44, 95%CI 1.25–1.66, P < 0.001, antimony (OR 1.39, 95%CI 1.10–1.77, P = 0.010, and tungsten (OR 1.49, 95%CI 1.25–1.77, P < 0.001 concentrations were observed to be associated with high BP. People with higher urinary mono-2-ethyl-5-carboxypentyl phthalate (OR 1.33, 95%CI 1.00–1.62, P = 0.006, mono-n-butyl phthalate (OR 1.35, 95%CI 1.13–1.62, P = 0.002, mono-2-ethyl-5-hydroxyhexyl (OR 1.25, 95%CI 1.05–1.49, P = 0.014, mono-n-methyl phthalate (OR 1.26, 95%CI 1.07–1.48, P = 0.007, mono-2-ethyl-5-oxohexyl (OR 1.25, 95%CI 1.07–1.48, P = 0.009, and monobenzyl phthalate (OR 1.40, 95%CI 1.15–1.69, P = 0.002 tended to have high BP as well. However, there are no clear associations between environmental parabens and high BP, nor between pesticides and high BP. In addition, trimethylarsine oxide (OR 2.47, 95%CI 1.27–4.81, P = 0.011 and dimethylarsonic acid concentrations (OR 1.42, 95%CI 1.12–1.79, P = 0.006 were seen to be associated with high BP. In sum, urinary heavy metal, phthalate, and arsenic concentrations were associated with high BP, although the

  4. A dynamic model for the nitrification of higher concentrated wastewaters and control by experiments; Ein dynamisches Prozessmodell fuer die Nitrifikation hoeher belasteter Abwaesser und praktische Anwendungen

    Energy Technology Data Exchange (ETDEWEB)

    Pirsing, A. [Siemens AG, Anlagentechnik ANL A73, Karlsruhe (Germany); Wiesmann, U. [Inst. fuer Verfahrenstechnik, Technische Univ. Berlin (Germany)

    1995-07-01

    Wastewater with high ammonia concentration is produced by many industries. However, the removal of higher loaded industrial effluents still poses many questions. Dynamic modelling is helpful to understand the process of nitrification and to investigate algorithms of process control. Therefore, a dynamic model of nitrification in completely mixed reactors is proposed based on mass balances for the components ammonia, nitrite, nitrate, dissolved oxygen, carbon dioxide, pH, nitrosomonas and nitrobacter. The biological reaction rates consider oxygen limitation and substrate inhibition. The process model presented it tested by lab scale experiments using an aerated stirred tank reactor. (orig.) [Deutsch] Es wird ein mathematisches Prozessmodell fuer die Nitrifikation von Industrieabwaessern mit hoher Ammoniumkonzentration vorgestellt, das bislang vernachlaessigte Phaenomene wie z.B. Substratueberschusshemmung und Sauerstofflimitierung beruecksichtigt. Als theoretische Grundlage dienen Bilanzgleichungen fuer insgesamt acht Komponenten. Das Simulationsmodell wird durch den Vergleich mit experimentellen Ergebnissen aus einer Laborversuchsanlage auf seine Richtigkeit ueberprueft. In dem Beitrag werden auf diesem Modell basierende Anwendungsbeispiele behandelt. So werden die Moeglichkeiten der dynamischen Prozesssimulation zur Steigerung der Betriebsstabilitaet bei schwankenden Zulaufkonzentrationen und -volumenstroemen gezeigt. Darueber hinaus gelingt die Rekonstruktion der Umsatzraten r(O{sub 2}) und r(NH{sub 3}) aus der Sauerstoff- und Kohlendioxidkonzentration in der Abluft. (orig.)

  5. Biodegradable drug-eluting nanofiber-enveloped implants for sustained release of high bactericidal concentrations of vancomycin and ceftazidime: in vitro and in vivo studies

    Directory of Open Access Journals (Sweden)

    Hsu YH

    2014-09-01

    Full Text Available Yung-Heng Hsu,1,2 Dave Wei-Chih Chen,1 Chun-Der Tai,3 Ying-Chao Chou,1,2 Shih-Jung Liu,2 Steve Wen-Neng Ueng,1 Err-Cheng Chan4 1Department of Orthopedic Surgery, Chang Gung Memorial Hospital, Guishan Township, 2Department of Mechanical Engineering, Chang Gung University, Guishan Township, 3Graduate Institute of Medical Mechatronics, Chang Gung University, Guishan Township, 4School of Medical Technology, Chang Gung University, Guishan Township, Taiwan Abstract: We developed biodegradable drug-eluting nanofiber-enveloped implants that provided sustained release of vancomycin and ceftazidime. To prepare the biodegradable nanofibrous membranes, poly(D,L-lactide-co-glycolide and the antibiotics were first dissolved in 1,1,1,3,3,3-hexafluoro-2-propanol. They were electrospun into biodegradable drug-eluting membranes, which were then enveloped on the surface of stainless plates. An elution method and a high-performance liquid chromatography assay were employed to characterize the in vivo and in vitro release rates of the antibiotics from the nanofiber-enveloped plates. The results showed that the biodegradable nanofiber-enveloped plates released high concentrations of vancomycin and ceftazidime (well above the minimum inhibitory concentration for more than 3 and 8 weeks in vitro and in vivo, respectively. A bacterial inhibition test was carried out to determine the relative activity of the released antibiotics. The bioactivity ranged from 25% to 100%. In addition, the serum creatinine level remained within the normal range, suggesting that the high vancomycin concentration did not affect renal function. By adopting the electrospinning technique, we will be able to manufacture biodegradable drug-eluting implants for the long-term drug delivery of different antibiotics. Keywords: biodegradable nanofiber-enveloped plates, electrospinning, antibiotics, release characteristics

  6. Ketamine coadministration attenuates morphine tolerance and leads to increased brain concentrations of both drugs in the rat

    Science.gov (United States)

    Lilius, T O; Jokinen, V; Neuvonen, M S; Niemi, M; Kalso, E A; Rauhala, P V

    2015-01-01

    Background and Purpose The effects of ketamine in attenuating morphine tolerance have been suggested to result from a pharmacodynamic interaction. We studied whether ketamine might increase brain morphine concentrations in acute coadministration, in morphine tolerance and morphine withdrawal. Experimental Approach Morphine minipumps (6 mg·day–1) induced tolerance during 5 days in Sprague–Dawley rats, after which s.c. ketamine (10 mg·kg–1) was administered. Tail flick, hot plate and rotarod tests were used for behavioural testing. Serum levels and whole tissue brain and liver concentrations of morphine, morphine-3-glucuronide, ketamine and norketamine were measured using HPLC-tandem mass spectrometry. Key Results In morphine-naïve rats, ketamine caused no antinociception whereas in morphine-tolerant rats there was significant antinociception (57% maximum possible effect in the tail flick test 90 min after administration) lasting up to 150 min. In the brain of morphine-tolerant ketamine-treated rats, the morphine, ketamine and norketamine concentrations were 2.1-, 1.4- and 3.4-fold, respectively, compared with the rats treated with morphine or ketamine only. In the liver of morphine-tolerant ketamine-treated rats, ketamine concentration was sixfold compared with morphine-naïve rats. After a 2 day morphine withdrawal period, smaller but parallel concentration changes were observed. In acute coadministration, ketamine increased the brain morphine concentration by 20%, but no increase in ketamine concentrations or increased antinociception was observed. Conclusions and Implications The ability of ketamine to induce antinociception in rats made tolerant to morphine may also be due to increased brain concentrations of morphine, ketamine and norketamine. The relevance of these findings needs to be assessed in humans. PMID:25297798

  7. Reduced antituberculosis drug concentrations in HIV-infected patients who are men or have low weight: implications for international dosing guidelines.

    Science.gov (United States)

    McIlleron, Helen; Rustomjee, Roxana; Vahedi, Mahnaz; Mthiyane, Thuli; Denti, Paolo; Connolly, Catherine; Rida, Wasima; Pym, Alexander; Smith, Peter J; Onyebujoh, Philip C

    2012-06-01

    Reduced antituberculosis drug concentrations may contribute to unfavorable treatment outcomes among HIV-infected patients with more advanced immune suppression, and few studies have evaluated pharmacokinetics of the first-line antituberculosis drugs in such patients given fixed-dose combination tablets according to international guidelines using weight bands. In this study, pharmacokinetics were evaluated in 60 patients on 4 occasions during the first month of antituberculosis therapy. Multilevel linear mixed-effects regression analysis was used to examine the effects of age, sex, weight, drug dose/kilogram, CD4(+) lymphocyte count, treatment schedule (5 versus 7 days/week), and concurrent antiretrovirals (efavirenz plus lamivudine plus zidovudine) on the area under the concentration-time curve from 0 to 12 h (AUC(0-12)) of the respective antituberculosis drugs and to compare AUC(0-12)s at day 8, day 15, and day 29 with the day 1 AUC(0-12). Median (range) age, weight, and CD4(+) lymphocyte count were 32 (18 to 47) years, 55.2 (34.4 to 98.7) kg, and 252 (12 to 500)/μl. For every 10-kg increase in body weight, the predicted day 29 AUC(0-12) increased by 14.1% (95% confidence interval [CI], 7.5, 20.8), 14.1% (95% CI, -0.7, 31.1), 6.1% (95% CI, 2.7, 9.6) and 6.0% (95% CI, 0.8, 11.3) for rifampin, isoniazid, pyrazinamide, and ethambutol, respectively. Males had day 29 AUC(0-12)s 19.3% (95% CI, 3.6, 35.1) and 14.0% (95% CI, 5.6, 22.4) lower than females for rifampin and pyrazinamide, respectively. Level of immune suppression and concomitant antiretrovirals had little effect on the concentrations of the antituberculosis agents. As they had reduced drug concentrations, it is important to review treatment responses in patients in the lower weight bands and males to inform future treatment guidelines, and revision of doses in these patients should be considered.

  8. AIDS Diarrhea and Antiretroviral Drug Concentrations: A Matched-Pair Cohort Study in Port au Prince, Haiti

    Science.gov (United States)

    Dillingham, Rebecca; Leger, Paul; Beauharnais, Carole-Anne; Miller, Erica; Kashuba, Angela; Jennings, Steven; Dupnik, Kathryn; Samie, Amidou; Eyma, Etna; Guerrant, Richard; Pape, Jean; Fitzgerald, Daniel

    2011-01-01

    Diarrhea in patients with acquired immunodeficiency syndrome (AIDS) may cause malabsorption of medications and failure of antiretroviral therapy (ART). We prospectively evaluated human immunodeficiency virus-1 (HIV-1)-infected patients with and without chronic diarrhea initiating ART in Haiti. We report mean plasma antiretroviral concentrations at 2 and 4 weeks. We measured plasma HIV-1 RNA levels at four points. Fifty-two HIV-1-infected patients (26 matched pairs) were enrolled. No differences in antiretroviral concentrations were detected. At week 24, 18/25 (72%) cases and 16/24 (68%) controls had undetectable plasma HIV-1 RNA levels (P = 0.69). Patients with plasma HIV-1 RNA levels > 50 copies/mL at week 24 had lower early efavirenz concentrations than patients with undetectable HIV-1 RNA (2,621 ng/mL versus 5,278 ng/mL; P = 0.02). Diarrhea at ART initiation does not influence plasma concentrations of the medications evaluated. Virologic outcome at Week 24 does correlate with efavirenz concentrations early in therapy but not with the presence of chronic diarrhea. PMID:21633022

  9. Population pharmacokinetics/pharmacodynamics of erlotinib and pharmacogenomic analysis of plasma and cerebrospinal fluid drug concentrations in Japanese patients with non-small cell lung cancer.

    Science.gov (United States)

    Fukudo, Masahide; Ikemi, Yasuaki; Togashi, Yosuke; Masago, Katsuhiro; Kim, Young Hak; Mio, Tadashi; Terada, Tomohiro; Teramukai, Satoshi; Mishima, Michiaki; Inui, Ken-Ichi; Katsura, Toshiya

    2013-07-01

    Erlotinib shows large inter-patient pharmacokinetic variability, but the impact of early drug exposure and genetic variations on the clinical outcomes of erlotinib remains fully investigated. The primary objective of this study was to clarify the population pharmacokinetics/pharmacodynamics of erlotinib in Japanese patients with non-small cell lung cancer (NSCLC). The secondary objective was to identify genetic determinant(s) for the cerebrospinal fluid (CSF) permeability of erlotinib and its active metabolite OSI-420. A total of 88 patients treated with erlotinib (150 mg/day) were enrolled, and CSF samples were available from 23 of these patients with leptomeningeal metastases. Plasma and CSF concentrations of erlotinib and OSI-420 were measured by high-performance liquid chromatography with UV detection. Population pharmacokinetic analysis was performed with the nonlinear mixed-effects modelling program NONMEM. Germline mutations including ABCB1 (1236C>T, 2677G>T/A, 3435C>T), ABCG2 (421C>A), and CYP3A5 (6986A>G) polymorphisms, as well as somatic EGFR activating mutations if available, were examined. Early exposure to erlotinib and its safety/efficacy relationship were evaluated. The apparent clearance of erlotinib and OSI-420 were significantly decreased by 24 and 35 % in patients with the ABCG2 421A allele, respectively (p OSI-420 (p model showed that erlotinib trough (C0) levels on day 8 were an independent risk factor for the development of grade ≥2 diarrhea (p = 0.037) and skin rash (p = 0.031). Interstitial lung disease (ILD)-like events occurred in 3 patients (3.4 %), and the median value of erlotinib C0 levels adjacent to these events was approximately 3 times higher than that in patients who did not develop ILD (3253 versus 1107 ng/mL; p = 0.014). The objective response rate in the EGFR wild-type group was marginally higher in patients achieving higher erlotinib C0 levels (≥1711 ng/mL) than that in patients having lower erlotinib C0

  10. Andrographis paniculata Extract and Andrographolide Modulate the Hepatic Drug Metabolism System and Plasma Tolbutamide Concentrations in Rats

    Directory of Open Access Journals (Sweden)

    Haw-Wen Chen

    2013-01-01

    Full Text Available Andrographolide is the most abundant terpenoid of A. paniculata which is used in the treatment of diabetes. In this study, we investigated the effects of A. paniculata extract (APE and andrographolide on the expression of drug-metabolizing enzymes in rat liver and determined whether modulation of these enzymes changed the pharmacokinetics of tolbutamide. Rats were intragastrically dosed with 2 g/kg/day APE or 50 mg/kg/day andrographolide for 5 days before a dose of 20 mg/kg tolbutamide was given. APE and andrographolide reduced the AUC0–12 h of tolbutamide by 37% and 18%, respectively, compared with that in controls. The protein and mRNA levels and enzyme activities of CYP2C6/11, CYP1A1/2, and CYP3A1/2 were increased by APE and andrographolide. To evaluate whether APE or andrographolide affected the hypoglycemic action of tolbutamide, high-fat diet-induced obese mice were used and treated in the same manner as the rats. APE and andrographolide increased CYP2C6/11 expression and decreased plasma tolbutamide levels. In a glucose tolerance test, however, the hypoglycemic effect of tolbutamide was not changed by APE or andrographolide. These results suggest that APE and andrographolide accelerate the metabolism rate of tolbutamide through increased expression and activity of drug-metabolizing enzymes. APE and andrographolide, however, do not impair the hypoglycemic effect of tolbutamide.

  11. Application of Hill's equation for estimating area under the concentration-time curve (AUC) and use of time to AUC 90% for expressing kinetics of drug disposition.

    Science.gov (United States)

    Cheng, Hsien C

    2009-01-01

    Half life and its derived pharmacokinetic parameters are calculated on an assumption that the terminal phase of drug disposition follows a constant rate of disposition. In reality, this assumption may not necessarily be the case. A new method is needed for analyzing PK parameters if the disposition does not follow a first order PK kinetic. Cumulative area under the concentration-time curve (AUC) is plotted against time to yield a hyperbolic (or sigmoidal) AUC-time relationship curve which is then analyzed by Hill's equation to yield AUC(inf), time to achieving AUC50% (T(AUC50%)) or AUC90% (T(AUC90%)), and the Hill's slope. From these parameters, an AUC-time relationship curve can be reconstructed. Projected plasma concentration can be calculated for any time point. Time at which cumulative AUC reaches 90% (T(AUC90%)) can be used as an indicator for expressing how fast a drug is cleared. Clearance is calculated in a traditional manner (i.v. dose/AUC(inf)), and the volume of distribution is proposed to be calculated at T(AUC50%) (0.5 i.v. dose/plasma concentration at T(AUC50%)). This method of estimating AUC is applicable for both i.v. and oral data. It is concluded that the Hill's equation can be used as an alternative method for estimating AUC and analysis of PK parameters if the disposition does not follow a first order kinetic. T(AUC90%) is proposed to be used as an indicator for expressing how fast a drug is cleared from the system.

  12. Effect of pH and comedication on gastrointestinal absorption of posaconazole: monitoring of intraluminal and plasma drug concentrations.

    Science.gov (United States)

    Walravens, Jeroen; Brouwers, Joachim; Spriet, Isabel; Tack, Jan; Annaert, Pieter; Augustijns, Patrick

    2011-11-01

    Posaconazole (Noxafil®) is an extended-spectrum triazole antifungal agent for prevention and treatment of invasive fungal infections. An inadequate dietary intake and abnormal gastric pH levels are common in critically ill patients receiving antifungal treatment with posaconazole, resulting in unpredictable bioavailability and sub-therapeutic plasma concentrations. This study was carried out to elucidate the impact of pH on posaconazole absorption and to explore the underlying mechanisms of enhanced intestinal absorption when coadministering an acidic carbonated beverage. In contrast to previously published studies, in which only plasma concentrations were determined, we also explored the gastric and intestinal behaviour of posaconazole after a single oral dose. A crossover study was performed in five healthy subjects. A single dose (10 mL) of posaconazole suspension (40 mg/mL) was administered orally in four different conditions: with 330 mL of water (condition 1); with 330 mL of a cola beverage [Coca-Cola®] (condition 2); with 330 mL of water following intake of the proton pump inhibitor esomeprazole 40 mg once daily for 3 days (condition 3); or with 330 mL of Coca-Cola® following intake of esomeprazole 40 mg once daily for 3 days (condition 4). After administration, gastrointestinal fluid and plasma samples were collected at regular time points, and posaconazole concentrations were determined. Compared with administration with water, coadministration of Coca-Cola® did not alter the pH of the intraluminal environment but did significantly increase posaconazole gastric concentrations (+102%; p Coca-Cola® and prolonged gastric residence. Coadministration of esomeprazole led to an increased gastric pH, which was accompanied by decreased posaconazole absorption; the mean plasma and gastric area under the concentration-time curve (AUC) values decreased by 37% and 84%, respectively. Simultaneous intake of Coca-Cola® could not completely compensate for the

  13. Treatment-associated polymorphisms in protease are significantly associated with higher viral load and lower CD4 count in newly diagnosed drug-naive HIV-1 infected patients

    NARCIS (Netherlands)

    K. Theys (Kristof); K. Deforche; J. Vercauteren (Jurgen); P. Libin (Pieter); D.A.M.C. van de Vijver (David); J. Albert (Jan); B. Åsjö (Birgitta); M. Bruckova (Marie); R.J. Camacho (Ricardo Jorge); B. Clotet (Bonaventura); Z. Grossman (Zehava); A. Horban (Andrzej); C. Kücherer (Claudia); D. Paraskevis (Dimitrios); E. Puchhammer-Stöckl (Elisabeth); C. Riva (Chiara); L. Ruiz (Lidia); J.-C. Schmit (Jean-Claude); R. Schuurman (Rob); A. Sonnerborg (Anders); D. Stanekova (Danica); D. Struck (Daniel); K. van Laethem (Kristel); A.M.J. Wensing (Annemarie); E. Puchhammer-Stockl E. (Elisabeth); M. Sarcletti (M.); B. Schmied (B.); M. Geit (M.); G. Balluch (G.); A.M. Vandamme (Anne Mieke); I. Derdelinck (Inge); A. Sasse (A.); M. Bogaert (M.); H. Ceunen (H.); A. de Roo (Annie); M. De Wit (Meike); F. Echahidi (F.); K. Fransen (K.); J.-C. Goffard (J.); P. Goubau (Patrick); E. Goudeseune (E.); J.-C. Yombi (J.); P. Lacor (Patrick); C. Liesnard (C.); M. Moutschen (M.); L.A. Pierard; R. Rens (R.); J. Schrooten; D. Vaira (D.); A. van den Heuvel (A.); B. van der Gucht (B.); M. van Ranst (Marc); E. van Wijngaerden (Eric); T. Vandercam; M. Vekemans (M.); C. Verhofstede; N. Clumeck (N.); K. van Laethem (K.); L.G. Kostrikis (Leondios); I. Demetriades (I.); I. Kousiappa (Ioanna); V.L. Demetriou (Victoria); J. Hezka (Johana); M. Linka (Marek); L. Machala (L.); L.B. Jrgensen (L.); J. Gerstoft (J.); L. Mathiesen (L.); C. Pedersen (Court); C. Nielsen (Claus); A. Laursen (A.); B. Kvinesdal (B.); K. Liitsola (Kirsi); M. Ristola (M.); J. Suni (J.); J. Sutinen (J.); K. Korn (Klaus); C. K̈ucherer (C.); P. Braun (P.); G. Poggensee (G.); M. Däumer (M.); D. Eberle (David); O. Hamouda (Osamah); H. Heiken (H.); R. Kaiser (Rolf); H. Knechten (H.); H. M̈uller (H.); S. Neifer (S.); H. Walter (Hauke); B. Gunsenheimer-Bartmeyer (B.); T. Harrer (T.); A. Hatzakis (Angelos); E. Hatzitheodorou (E.); C. Issaris (C.); C. Haida (C.); A. Zavitsanou (A.); G. Magiorkinis (Gkikas); M. Lazanas (M.); L. Chini; N. Magafas (N.); N. Tsogas (N.); V. Paparizos (V.); S. Kourkounti (S.); A. Antoniadou (A.); A. Papadopoulos (A.); P. Panagopoulos (P.); G. Poulakou (G.); V. Sakka (V.); G. Chryssos (G.); S. Drimis (S.); P. Gargalianos (P.); M. Lelekis (M.); G. Xilomenos (G.); M. Psichogiou (M.); G.L. Daikos (George); G. Panos (G.); G. Haratsis (G.); T. Kordossis (T.); A. Kontos (Angelos); G. Koratzanis (G.); M. Theodoridou (M.); G. Mostrou (G.); V. Spoulou (V.); W. Hall (W.); C. de Gascun (Cillian); C. Byrne (C.); M. Duffy (M.); P. Bergin; D. Reidy (D.); G. Farrell; J. Lambert (Julien); E. O'Connor (E.); A. Rochford (A.); J. Low (J.); P. Coakely (P.); S. Coughlan (Suzie); I. Levi (I.); D. Chemtob (D.); C. Balotta (Claudia); C. Mussini (C.); I. Caramma (I.); A. Capetti (A.); M.C. Colombo (M.); C. Rossi (Cesare); F. Prati (Francesco); F. Tramuto (F.); F. Vitale (F.); M. Ciccozzi (M.); G. Angarano (Guiseppe); G. Rezza (G.); R. Hemmer (R.); V. Arendt (V.); T. Staub (T.); F. Schneider (F.); F. Roman (Francois); C.A.B. Boucher (Charles); P.H.M. van Bentum (P. H M); K. Brinkman (Kees); E.L.M. Op de Coul (Eline); M.E. van der Ende (Marchina); I.M. Hoepelman (Ilja Mohandas); M.E.E. van Kasteren (Marjo); J. Juttmann (Job); M. Kuipers (M.); N. Langebeek (Nienke); C. Richter (C.); R.M.W.J. Santegoets (R. M W J); L. Schrijnders-Gudde (L.); R. Schuurman (Rob); B.J.M. van de Ven (B. J M); B. Asjö (Birgitta); V. Ormaasen (Vidar); P. Aavitsland (P.); J. Stanczak (J.); G.P. Stanczak (G.); E. Firlag-Burkacka (E.); A. Wiercinska-Drapalo (A.); E. Jablonowska (E.); E. Malolepsza (E.); M. Leszczyszyn-Pynka (M.); W. Szata (W.); A. de Palma (Andre); F. Borges (F.); T. Paix̃ao (T.); V. Duque (V.); F. Aráujo (F.); M. Stanojevic (Maja); D.J. Jevtovic (D.); D. Salemovic (D.); M. Habekova (M.); M. Mokras (M.); P. Truska (P.); M. Poljak (Mario); D.Z. Babic (Dunja); J. Tomazic (J.); S. Vidmar (Suzanna); P. Karner (P.); C. Gutíerrez (C.); C. deMendoza (C.); I. Erkicia (I.); P. Domingo (P.); X. Camino (X.); M.A. Galindo (Miguel Angel); J.L. Blanco (J.); M. Leal (M.); A. Masabeu (A.); A. Guelar (A.); J.M. Llibre (Josep M.); N. Margall (N.); C. Iribarren (Carlos); S. Gutierrez (S.); J.F. Baldov́i (J.); C.E. Pedreira (Carlos Eduardo); J.M. Gatell (J.); S. Moreno (S.); C. de Mendoza (Carmen); V. Soriano (Virtudes); A. Blaxhult (A.); A. Heidarian (A.); A. Karlsson (A.); K. Aperia-Peipke (K.); I.-M. Bergbrant (I.); M. Gissĺen (M.); M. Svennerholm (M.); P. Bj̈orkman (P.); G. Bratt (G.); M. Carlsson (M.); H. Ekvall (H.); M. Ericsson (M.); M. Ḧofer (M.); B. Johansson (Bert); N. Kuylenstierna (N.); K. Ljungberg (Karl); S. Mäkitalo (S.); A. Strand; K. Öberg (Kjell); T. Berg (Trine)

    2012-01-01

    textabstractBackground: The effect of drug resistance transmission on disease progression in the newly infected patient is not well understood. Major drug resistance mutations severely impair viral fitness in a drug free environment, and therefore are expected to revert quickly. Compensatory

  14. Vectorization efforts to increase Gram-negative intracellular drug concentration: a case study on HldE-K inhibitors.

    Science.gov (United States)

    Atamanyuk, Dmytro; Faivre, Fabien; Oxoby, Mayalen; Ledoussal, Benoit; Drocourt, Elodie; Moreau, François; Gerusz, Vincent

    2013-03-14

    In this paper, we present different strategies to vectorize HldE kinase inhibitors with the goal to improve their gram-negative intracellular concentration. Syntheses and biological effects of siderophoric, aminoglycosidic, amphoteric, and polycationic vectors are discussed. While siderophoric and amphoteric vectorization efforts proved to be disappointing in this series, aminoglycosidic and polycationic vectors were able for the first time to achieve synergistic effects of our inhibitors with erythromycin. Although these effects proved to be nonspecific, this study provides information about the required stereoelectronic arrangement of the polycationic amines and their basicity requirements to fulfill outer membrane destabilization resulting in better erythromycin synergies.

  15. 3D modeling of effects of increased oxygenation and activity concentration in tumors treated with radionuclides and antiangiogenic drugs

    Energy Technology Data Exchange (ETDEWEB)

    Lagerloef, Jakob H.; Kindblom, Jon; Bernhardt, Peter [Department of Radiation Physics, Goeteborg University, Goeteborg 41345 (Sweden); Department of Oncology, Sahlgrenska University Hospital, Goeteborg 41345 (Sweden); Department of Radiation Physics, Goeteborg University, Goeteborg, Sweden and Department of Nuclear Medicine, Sahlgrenska University Hospital, Goeteborg 41345 (Sweden)

    2011-08-15

    Purpose: Formation of new blood vessels (angiogenesis) in response to hypoxia is a fundamental event in the process of tumor growth and metastatic dissemination. However, abnormalities in tumor neovasculature often induce increased interstitial pressure (IP) and further reduce oxygenation (pO{sub 2}) of tumor cells. In radiotherapy, well-oxygenated tumors favor treatment. Antiangiogenic drugs may lower IP in the tumor, improving perfusion, pO{sub 2} and drug uptake, by reducing the number of malfunctioning vessels in the tissue. This study aims to create a model for quantifying the effects of altered pO{sub 2}-distribution due to antiangiogenic treatment in combination with radionuclide therapy. Methods: Based on experimental data, describing the effects of antiangiogenic agents on oxygenation of GlioblastomaMultiforme (GBM), a single cell based 3D model, including 10{sup 10} tumor cells, was developed, showing how radionuclide therapy response improves as tumor oxygenation approaches normal tissue levels. The nuclides studied were {sup 90}Y, {sup 131}I, {sup 177}Lu, and {sup 211}At. The absorbed dose levels required for a tumor control probability (TCP) of 0.990 are compared for three different log-normal pO{sub 2}-distributions: {mu}{sub 1} = 2.483, {sigma}{sub 1} = 0.711; {mu}{sub 2} = 2.946, {sigma}{sub 2} = 0.689; {mu}{sub 3} = 3.689, and {sigma}{sub 3} = 0.330. The normal tissue absorbed doses will, in turn, depend on this. These distributions were chosen to represent the expected oxygen levels in an untreated hypoxic tumor, a hypoxic tumor treated with an anti-VEGF agent, and in normal, fully-oxygenated tissue, respectively. The former two are fitted to experimental data. The geometric oxygen distributions are simulated using two different patterns: one Monte Carlo based and one radially increasing, while keeping the log-normal volumetric distributions intact. Oxygen and activity are distributed, according to the same pattern. Results: As tumor pO{sub 2

  16. Hepatitis C virus NS3 protease genotyping and drug concentration determination during triple therapy with telaprevir or boceprevir for chronic infection with genotype 1 viruses, southeastern France.

    Science.gov (United States)

    Aherfi, Sarah; Solas, Caroline; Motte, Anne; Moreau, Jacques; Borentain, Patrick; Mokhtari, Saadia; Botta-Fridlund, Danielle; Dhiver, Catherine; Portal, Isabelle; Ruiz, Jean-Marie; Ravaux, Isabelle; Bregigeon, Sylvie; Poizot-Martin, Isabelle; Stein, Andreas; Gérolami, René; Brouqui, Philippe; Tamalet, Catherine; Colson, Philippe

    2014-11-01

    Telaprevir and boceprevir, the two first hepatitis C virus (HCV) NS3 protease inhibitors (PIs), considerably increase rates of sustained virologic response in association with pegylated interferon and ribavirin in chronic HCV genotype 1 infections. The 30 first patients treated by telaprevir or boceprevir including anti-HCV therapies since 2011 in Marseille University hospitals, France, were monitored. HCV loads and plasmatic concentrations of telaprevir and boceprevir were determined on sequential blood samples. HCV NS3 protease gene population sequencing was performed at baseline of treatment and in case of treatment failure. Fifteen patients (including 7 co-infected with HIV) received telaprevir and the other 15 patients (including 4 co-infected with HIV) received boceprevir. At baseline, HCV NS3 protease from six patients harbored amino acid substitutions associated with PI-resistance. Treatment failure occurred at week 12 for 7 patients. Amino acid substitutions associated with PI-resistance were observed in six of these cases. HCV NS3 R155K and T54A/S mutants, all of genotype 1a, were found from four patients. Median (interquartile range) plasma concentrations were 3,092 ng/ml (2,320-3,525) for telaprevir and 486 ng/ml (265-619) for boceprevir. For HIV-HCV co-infected patients, median concentrations were 3,162 ng/ml (2,270-4,232) for telaprevir and 374 ng/ml (229-519) for boceprevir. Plasma drug concentration monitoring revealed undetectable concentrations for two patients at week 4, and probable non-adherence to therapy for another patient. These findings indicate that routine HCV NS3 protease sequencing and plasma PI concentration monitoring might be helpful to characterize cases of therapy failure, at a cost dramatically low compared to that of anti-HCV therapy. © 2014 Wiley Periodicals, Inc.

  17. The Female Genital Tract Microbiome Is Associated With Vaginal Antiretroviral Drug Concentrations in Human Immunodeficiency Virus-Infected Women on Antiretroviral Therapy.

    Science.gov (United States)

    Donahue Carlson, Renee; Sheth, Anandi N; Read, Timothy D; Frisch, Michael B; Mehta, C Christina; Martin, Amy; Haaland, Richard E; Patel, Anar S; Pau, Chou-Pong; Kraft, Colleen S; Ofotokun, Igho

    2017-11-15

    The female genital tract (FGT) microbiome may affect vaginal pH and other factors that influence drug movement into the vagina. We examined the relationship between the microbiome and antiretroviral concentrations in the FGT. Over one menstrual cycle, 20 human immunodeficiency virus (HIV)-infected women virologically suppressed on tenofovir (TFV) disoproxil fumarate/emtricitabine and ritonavir-boosted atazanavir (ATV) underwent serial paired cervicovaginal and plasma sampling for antiretroviral concentrations using high-performance liquid chromatography-tandem mass spectrometry. Analysis of 16S ribosomal RNA gene sequencing of cervicovaginal lavage clustered each participant visit into a unique microbiome community type (mCT). Participants were predominantly African American (95%), with a median age of 38 years. Cervicovaginal lavage sequencing (n = 109) resulted in a low-diversity mCT dominated by Lactobacillus (n = 40), and intermediate-diversity (n = 28) and high-diversity (n = 41) mCTs with abundance of anaerobic taxa. In multivariable models, geometric mean FGT:plasma ratios varied significantly by mCT for all 3 drugs. For both ATV and TFV, FGT:plasma was significantly lower in participant visits with high- and low-diversity mCT groups (all P < .02). For emtricitabine, FGT:plasma was significantly lower in participant visits with low- vs intermediate-diversity mCT groups (P = .002). Certain FGT mCTs are associated with decreased FGT antiretroviral concentrations. These findings are relevant for optimizing antiretrovirals used for biomedical HIV prevention in women. © The Author 2017. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.

  18. Comparison of Drug Concentrations in Human Aqueous Humor after the Administration of 0.3% Gatifloxacin Ophthalmic Gel, 0.3% Gatifloxacin and 0.5% Levofloxacin Ophthalmic Solutions.

    Science.gov (United States)

    Ding, Wenting; Ni, Weiling; Chen, Huilian; Yuan, Jingqun; Huang, Xiaodan; Zhang, Zheng; Wang, Yao; Yu, Yibo; Yao, Ke

    2015-01-01

    To investigate the penetration of 0.3% gatifloxacin ophthalmic gel, 0.3% gatifloxacin ophthalmic solution and 0.5% levofloxacin ophthalmic solution into aqueous humor after topical application. Age-related cataract patients (150 eyes in 150 cases) receiving phacoemulsification were randomly divided into three groups: a 0.3% gatifloxacin gel group (n=50), a 0.3% gatifloxacin solution group (n=50), and a 0.5% levofloxacin solution group (n=50). Each group was administered one drop of gel or solution every 15 minutes for four doses. Aqueous samples were collected at different time points after the last drop. High pressure liquid chromatography (HPLC) was applied to determine the concentrations. The one-way ANOVA analysis was performed. Our data indicated that the concentration of the gatifloxacin gel group was higher than that of the gatifloxacin solution group at all time points (P solution group at 120.0 min and 180.0 min (Psolutions reached their peak values at 60.0 min. 0.3% gatifloxacin ophthalmic gel application produced highest aqueous humor drug concentration, maintained the longest time, had the best penetration and bioavailability.

  19. Concentrations of higher dicarboxylic acids C5–C13 in fresh snow samples collected at the High Alpine Research Station Jungfraujoch during CLACE 5 and 6

    Directory of Open Access Journals (Sweden)

    K. Sieg

    2009-03-01

    Full Text Available Samples of freshly fallen snow were collected at the high alpine research station Jungfraujoch (Switzerland in February and March 2006 and 2007, during the Cloud and Aerosol Characterization Experiments (CLACE 5 and 6. In this study a new technique has been developed and demonstrated for the measurement of organic acids in fresh snow. The melted snow samples were subjected to solid phase extraction and resulting solutions analysed for organic acids by HPLC-MS-TOF using negative electrospray ionization. A series of linear dicarboxylic acids from C5 to C13 and phthalic acid, were identified and quantified. In several samples the biogenic acid pinonic acid was also observed. In fresh snow the median concentration of the most abundant acid, adipic acid, was 0.69 μg L−1 in 2006 and 0.70 μg L−1 in 2007. Glutaric acid was the second most abundant dicarboxylic acid found with median values of 0.46 μg L−1 in 2006 and 0.61 μg L−1 in 2007, while the aromatic acid phthalic acid showed a median concentration of 0.34 μg L−1 in 2006 and 0.45 μg L−1 in 2007. The concentrations in the samples from various snowfall events varied significantly, and were found to be dependent on the back trajectory of the air mass arriving at Jungfraujoch. Air masses of marine origin showed the lowest concentrations of acids whereas the highest concentrations were measured when the air mass was strongly influenced by boundary layer air.

  20. Low iron stores are related to higher blood concentrations of manganese, cobalt and cadmium in non-smoking, Norwegian women in the HUNT 2 study

    Energy Technology Data Exchange (ETDEWEB)

    Margrete Meltzer, Helle, E-mail: helle.margrete.meltzer@fhi.no [Division of Environmental Medicine, Department of Food Safety and Nutrition, Norwegian Institute of Public Health, PO Box 4404 Nydalen, N-0403 Oslo (Norway); Lise Brantsaeter, Anne [Division of Environmental Medicine, Department of Food Safety and Nutrition, Norwegian Institute of Public Health, PO Box 4404 Nydalen, N-0403 Oslo (Norway); Borch-Iohnsen, Berit [Institute of Basic Medical Sciences, Department of Nutrition, University of Oslo, PO Box 1046 Blindern, N-0316 Oslo (Norway); Ellingsen, Dag G. [National Institute of Occupational Health, PO Box 8149 Dep, N-0033 Oslo (Norway); Alexander, Jan [Division of Environmental Medicine, Department of Food Safety and Nutrition, Norwegian Institute of Public Health, PO Box 4404 Nydalen, N-0403 Oslo (Norway); Thomassen, Yngvar [National Institute of Occupational Health, PO Box 8149 Dep, N-0033 Oslo (Norway); Stigum, Hein [Division of Epidemiology, Department of Chronic Diseases, Norwegian Institute of Public Health, PO Box 4404 Nydalen, N-0403 Oslo (Norway); Ydersbond, Trond A. [Statistics Norway, P.Box 8131 Dep, N-0033 Oslo (Norway)

    2010-07-15

    Low iron (Fe) stores may influence absorption or transport of divalent metals in blood. To obtain more knowledge about such associations, the divalent metal ions cadmium (Cd), manganese (Mn), cobalt (Co), copper (Cu), zinc (Zn) and lead (Pb) and parameters of Fe metabolism (serum ferritin, haemoglobin (Hb) and transferrin) were investigated in 448 healthy, menstruating non-smoking women, age 20-55 years (mean 38 years), participating in the Norwegian HUNT 2 study. The study population was stratified for serum ferritin: 257 were iron-depleted (serum ferritin <12 {mu}g/L) and 84 had iron deficiency anaemia (serum ferritin <12 {mu}g/L and Hb<120 g/L). The low ferritin group had increased blood concentrations of Mn, Co and Cd but normal concentrations of Cu, Zn and Pb. In multiple regression models, ferritin emerged as the main determinant of Mn, Co and Cd (p<0.001), while no significant associations with Cu, Zn and Pb were found. Adjusted r{sup 2} for the models were 0.28, 0.48 and 0.34, respectively. Strong positive associations between blood concentrations of Mn, Co and Cd were observed, also when controlled for their common association with ferritin. Apart from these associations, the models showed no significant interactions between the six divalent metals studied. Very mild anaemia (110{<=}Hb<120 g/L) did not seem to have any effect independent of low ferritin. Approximately 26% of the women with iron deficiency anaemia had high concentrations of all of Mn, Co and Cd as opposed to 2.3% of iron-replete subjects. The results confirm that low serum ferritin may have an impact on body kinetics of certain divalent metal ions, but not all. Only a fraction of women with low iron status exhibited an increased blood concentration of divalent metals, providing indication of complexities in the body's handling of these metals.

  1. Relationship of peak serum methotrexate concentration to prognosis and drug tolerance in non-metastatic extremity osteosarcomas.

    Science.gov (United States)

    Wang, Bo; Yao, Hao; Xie, Xianbiao; Yin, Junqiang; Zou, Changye; Huang, Gang; Shen, Jingnan

    2018-05-28

    This study aimed to explore whether peak serum methotrexate concentration (C max ) correlated with adverse events, overall survival (OS) and event-free survival (EFS) in patients with primary extremity osteosarcoma. Patients with extremity osteosarcoma who were treated at our center between 2005 and 2015 were retrospectively studied. All the patients were Enneking stage II and had received standard perioperative chemotherapy composed of high-dose methotrexate, doxorubicin, cisplatin and ifosfamide. C max and treatment-associated toxicities of each cycle were recorded. OS and EFS were estimated and compared by Kaplan-Meier survival analysis, and Cox regression models were performed for univariate comparisons. In total, 567 patients were followed for an average of 53 months (24-104 months). The estimated 3- and 5-year EFS were 71.7 and 63.1%, and the 3- and 5-year OS were 78.2 and 72.9%, respectively. C max ranged from 527 to 2495 µmol/L with a mean value of 931 ± 106 µmol/L. No significant differences in EFS and OS (p = 0.18 and p = 0.28) were observed among patients with a mean C max  > 1500, > 1000, > 700 and  1500 µmol/L had significantly increased rates of grade 3-5 toxicity. In the univariate analysis, C max was not a prognostic factor for EFS (p = 0.08) or OS (p = 0.16). C max did not correlate significantly with the oncologic prognosis of non-metastatic extremity osteosarcoma patients treated by multi-agent chemotherapy; however, C max correlated closely with toxicities and complications. The persistent inclusion of methotrexate in classical multidisciplinary chemotherapy was questioned and should be examined in future trials.

  2. An alkaline comet assay study on the antimalarial drug atovaquone in human peripheral blood lymphocytes: a study based on clinically relevant concentrations.

    Science.gov (United States)

    Dinter, Domagoj; Gajski, Goran; Garaj-Vrhovac, Vera

    2013-01-01

    Atovaquone, a hydroxynaphthoquinone, is an anti-parasite drug, selectively targeting the mitochondrial respiratory chain of malaria parasite. It is used for both the treatment and prevention of malaria, usually in a fixed combination with proguanil. Although atovaquone has not often been associated with severe adverse reactions in the recommended dosages and has a relatively favorable side effect profile, the present study was undertaken to evaluate its cytogenotoxic potential towards human peripheral blood lymphocytes. Two different concentrations of atovaquone found in plasma when used in fixed-dose combination with proguanile hydrochloride were used with and without S9 metabolic activation: 2950 ng ml(-1) used for prophylactic treatment and 11 800 ng ml(-1) used in treatment of malaria. The results showed that lymphocyte viability was not affected after the treatment, suggesting that atovaquone was not cytotoxic in the given concentrations. With the alkaline comet assay we demonstrated that in human peripheral blood lymphocytes no significant changes in comet parameters occurred after the treatment. There were no differences in tested parameters with the addition of S9 metabolic activation, indicating that atovaquone either has no metabolite or it is not toxic in the given concentrations. Since no effects were observed after the treatment, it is to be concluded that atovaquone is safe from the aspect of genototoxicity in the recommended dosages. Copyright © 2011 John Wiley & Sons, Ltd.

  3. Optimisation of cosolvent concentration for topical drug delivery III--influence of lipophilic vehicles on ibuprofen permeation.

    Science.gov (United States)

    Watkinson, R M; Guy, R H; Oliveira, G; Hadgraft, J; Lane, M E

    2011-01-01

    Previously, we have reported the effects of water, ethanol, propylene glycol and various binary and ternary mixtures of these solvents on the permeation of ibuprofen in model membranes and in skin. The present study investigates the influence of lipophilic vehicles on the transport of ibuprofen in silicone membrane and in human skin. The permeation of ibuprofen was measured from mineral oil (MO), Miglyol® 812 (MG) and binary mixtures of MO and MG. The solubility of ibuprofen was 5-fold higher in MG than in MO, however, the permeation of ibuprofen from the pure vehicles and combinations of both was comparable in silicone membrane. Additionally, there were no significant differences in skin permeation for MO and MG vehicles. When the permeation of various hydrophilic and lipophilic vehicles is considered, a trend between flux values for the model membrane and skin is evident (r(2) = 0.71). The findings suggest that silicone membrane may provide information on qualitative trends in skin permeation for vehicles of diverse solubility and partition characteristics. Copyright © 2010 S. Karger AG, Basel.

  4. Cow allergen (Bos d2) and endotoxin concentrations are higher in the settled dust of homes proximate to industrial-scale dairy operations.

    Science.gov (United States)

    Williams, D' Ann L; McCormack, Meredith C; Matsui, Elizabeth C; Diette, Gregory B; McKenzie, Shawn E; Geyh, Alison S; Breysse, Patrick N

    2016-01-01

    Airborne contaminants produced by industrial agricultural facilities contain chemical and biological compounds that can impact the health of residents living in close proximity. Settled dust can be a reservoir for these contaminants and can influence long-term exposures. In this study, we sampled the indoor- and outdoor-settled dust from 40 homes that varied in proximity to industrial-scale dairies (ISD; industrial-scale dairy, a term used in this paper to describe a large dairy farm and adjacent waste sprayfields, concentrated animal feeding operation or animal feeding operation, that uses industrial processes) in the Yakima Valley, Washington. We analyzed settled dust samples for cow allergen (Bos d2, a cow allergen associated with dander, hair, sweat and urine, it is a member of the lipocalin family of allergens associated with mammals), mouse allergen (Mus m1; major mouse allergen, a mouse urinary allergen, in the lipocalin family), dust mite allergens (Der p1 (Dermatophagoides pteronissinus 1) and Der f1 (Dermatophagoides farinae 1)), and endotoxin (a component of the cell walls of gram negative bacteria, lipopolysaccharide, which can be found in air and dust and can produce a strong inflammatory response). A concentration gradient was observed for Bos d2 and endotoxin measured in outdoor-settled dust samples based on proximity to ISD. Indoor-settled dust concentrations of Bos d2 and endotoxin were also highest in proximal homes. While the associated health effects of exposure to cow allergen in settled dust is unknown, endotoxin at concentrations observed in these proximal homes (100 EU/mg) has been associated with increased negative respiratory health effects. These findings document that biological contaminants emitted from ISDs are elevated in indoor- and outdoor-settled dust samples at homes close to these facilities and extend to as much as three miles (4.8 km) away.

  5. Activation of PKA in cell requires higher concentration of cAMP than in vitro: implications for compartmentalization of cAMP signalling.

    Science.gov (United States)

    Koschinski, Andreas; Zaccolo, Manuela

    2017-10-26

    cAMP is a ubiquitous second messenger responsible for the cellular effects of multiple hormones and neurotransmitters via activation of its main effector, protein kinase A (PKA). Multiple studies have shown that the basal concentration of cAMP in several cell types is about 1 μM. This value is well above the reported concentration of cAMP required to half-maximally activate PKA, which measures in the 100-300 nM range. Several hypotheses have been suggested to explain this apparent discrepancy including inaccurate measurements of intracellular free cAMP, inaccurate measurement of the apparent activation constant of PKA or shielding of PKA from bulk cytosolic cAMP via localization of the enzyme to microdomains with lower basal cAMP concentration. However, direct experimental evidence in support of any of these models is limited and a firm conclusion is missing. In this study we use multiple FRET-based reporters for the detection of cAMP and PKA activity in intact cells and we establish that the sensitivity of PKA to cAMP is almost twenty times lower when measured in cell than when measured in vitro. Our findings have important implications for the understanding of compartmentalized cAMP signalling.

  6. Low iron stores are related to higher blood concentrations of manganese, cobalt and cadmium in non-smoking, Norwegian women in the HUNT 2 study

    International Nuclear Information System (INIS)

    Margrete Meltzer, Helle; Lise Brantsaeter, Anne; Borch-Iohnsen, Berit; Ellingsen, Dag G.; Alexander, Jan; Thomassen, Yngvar; Stigum, Hein; Ydersbond, Trond A.

    2010-01-01

    Low iron (Fe) stores may influence absorption or transport of divalent metals in blood. To obtain more knowledge about such associations, the divalent metal ions cadmium (Cd), manganese (Mn), cobalt (Co), copper (Cu), zinc (Zn) and lead (Pb) and parameters of Fe metabolism (serum ferritin, haemoglobin (Hb) and transferrin) were investigated in 448 healthy, menstruating non-smoking women, age 20-55 years (mean 38 years), participating in the Norwegian HUNT 2 study. The study population was stratified for serum ferritin: 257 were iron-depleted (serum ferritin 2 for the models were 0.28, 0.48 and 0.34, respectively. Strong positive associations between blood concentrations of Mn, Co and Cd were observed, also when controlled for their common association with ferritin. Apart from these associations, the models showed no significant interactions between the six divalent metals studied. Very mild anaemia (110≤Hb<120 g/L) did not seem to have any effect independent of low ferritin. Approximately 26% of the women with iron deficiency anaemia had high concentrations of all of Mn, Co and Cd as opposed to 2.3% of iron-replete subjects. The results confirm that low serum ferritin may have an impact on body kinetics of certain divalent metal ions, but not all. Only a fraction of women with low iron status exhibited an increased blood concentration of divalent metals, providing indication of complexities in the body's handling of these metals.

  7. Higher Concentrations of BCAAs and 3-HIB Are Associated with Insulin Resistance in the Transition from Gestational Diabetes to Type 2 Diabetes

    Directory of Open Access Journals (Sweden)

    Ulrika Andersson-Hall

    2018-01-01

    Full Text Available Aim. Determine the metabolic profile and identify risk factors of women transitioning from gestational diabetes mellitus (GDM to type 2 diabetes mellitus (T2DM. Methods. 237 women diagnosed with GDM underwent an oral glucose tolerance test (OGTT, anthropometrics assessment, and completed lifestyle questionnaires six years after pregnancy. Blood was analysed for clinical variables (e.g., insulin, glucose, HbA1c, adiponectin, leptin, and lipid levels and NMR metabolomics. Based on the OGTT, women were divided into three groups: normal glucose tolerance (NGT, impaired glucose tolerance (IGT, and T2DM. Results. Six years after GDM, 19% of subjects had T2DM and 19% IGT. After BMI adjustment, the IGT group had lower HDL, higher leptin, and higher free fatty acid (FFA levels, and the T2DM group higher triglyceride, FFA, and C-reactive protein levels than the NGT group. IGT and T2DM groups reported lower physical activity. NMR measurements revealed that levels of branched-chain amino acids (BCAAs and the valine metabolite 3-hydroxyisobyturate were higher in T2DM and IGT groups and correlated with measures of insulin resistance and lipid metabolism. Conclusion. In addition to well-known clinical risk factors, BCAAs and 3-hydroxyisobyturate are potential markers to be evaluated as predictors of metabolic risk after pregnancy complicated by GDM.

  8. Blood haemoglobin concentrations are higher in smokers and heavy alcohol consumers than in non-smokers and abstainers-should we adjust the reference range?

    DEFF Research Database (Denmark)

    Milman, N.; Pedersen, Agnes N.

    2009-01-01

    The blood haemoglobin concentration is one of the most frequently used laboratory parameters in clinical practice. There is evidence that haemoglobin levels are influenced by tobacco smoking. The objective of this study was to evaluate the impact of smoking and alcohol consumption on haemoglobin.......001) and women (r = 0.08, p = 0.05). In non-smokers, alcohol consumption > 14 drinks/week and more than seven drinks/week for men and women, respectively, increased mean haemoglobin by 1.3% in men and by average 1.9% in women compared with those consuming a parts per thousand currency sign14 and less than...... small changes in haemoglobin do not justify the use of separate reference ranges in smokers and alcohol consumers....

  9. Matrix solid-phase dispersion on column clean-up/pre-concentration as a novel approach for fast isolation of abuse drugs from human hair.

    Science.gov (United States)

    Míguez-Framil, Martha; Moreda-Piñeiro, Antonio; Bermejo-Barrera, Pilar; Alvarez-Freire, Iván; Tabernero, María Jesús; Bermejo, Ana María

    2010-10-08

    A simple and fast sample pre-treatment method based on matrix solid-phase dispersion (MSPD) for isolating cocaine, benzoylecgonine (BZE), codeine, morphine and 6-monoacethylmorphine (6-MAM) from human hair has been developed. The MSPD approach consisted of using alumina (1.80 g) as a dispersing agent and 0.6M hydrochloric acid (4 mL) as an extracting solvent. For a fixed hair sample mass of 0.050 g, the alumina mass to sample mass ratio obtained was 36. A previously conditioned Oasis HLB cartridge (2 mL methanol, plus 2 mL ultrapure water, plus 1 mL of 0.2M/0.2M sodium hydroxide/boric acid buffer solution at pH 9.2) was attached to the end of the MSPD syringe for on column clean-up of the hydrochloric acid extract and for transferring the target compounds to a suitable solvent for gas chromatography (GC) analysis. Therefore, the adsorbed analytes were directly eluted from the Oasis HLB cartridges with 2 mL of 2% acetic acid in methanol before concentration by N(2) stream evaporation and dry extract derivatization with N-methyl-tert-butylsilyltrifluoroacetamide (BSTFA) and chlorotrimethylsilane (TMCS). The optimization/evaluation of all the factors affecting the MSPD and on column clean-up procedures has led to a fast sample treatment, and analytes extraction and pre-concentration can be finished in approximately 30 min. The developed method has been applied to eight hair samples from poli-drug abusers and measured analyte concentrations have been found to be statistically similar (95% confidence interval) to those obtained after a conventional enzymatic hydrolysis method (Pronase E). Copyright © 2010. Published by Elsevier B.V.

  10. A new application of micellar liquid chromatography in the determination of free ampicillin concentration in the drug-human serum albumin standard solution in comparison with the adsorption method.

    Science.gov (United States)

    Stępnik, Katarzyna E; Malinowska, Irena; Maciejewska, Małgorzata

    2016-06-01

    The determination of free drug concentration is a very important issue in the field of pharmacology because only the unbound drug fraction can achieve a pharmacological effect. Due to the ability to solubilize many different compounds in micellar aggregates, micellar liquid chromatography (MLC) can be used for direct determination of free drug concentration. Proteins are not retained on the stationary phase probably due to the formation of protein - surfactant complexes which are excluded from the pores of stationary phase. The micellar method is simple and fast. It does not require any pre-preparation of the tested samples for analysis. The main aim of this paper is to demonstrate a completely new applicability of the analytical use of MLC concerning the determination of free drug concentration in the standard solution of human serum albumin. The well-known adsorption method using RP-HPLC and the spectrophotometric technique was applied as the reference method. The results show that the free drug concentration value obtained in the MLC system (based on the RP-8 stationary phase and CTAB) is similar to that obtained by the adsorption method: both RP-HPLC (95.83μgmL(-1), 79.86% of free form) and spectrophotometry (95.71μgmL(-1), 79.76%). In the MLC the free drug concentration was 93.98μgmL(-1) (78.3%). This indicates that the obtained results are within the analytical range of % of free ampicillin fraction and the MLC with direct sample injection can be treated like a promising method for the determination of free drug concentration. Copyright © 2016 Elsevier B.V. All rights reserved.

  11. 乙炔提浓装置高级炔管线堵塞原因浅析%Analysis on causes of higher acetylene pipe blocking of acetylene concentration system

    Institute of Scientific and Technical Information of China (English)

    谢全兵

    2011-01-01

    Causes of higher alkyne pipe blocking of acetylene concentration system in the natural gas-based acetylene production plant were found out by analyzing higher alkyne gas component concentration variation. Corresponding measures were proposed to prevent higher alkyne polymerization in the pipe and thus prolong the equipment operation cycle.%通过对高级炔气体组分含量变化进行分析,找出天然气制乙炔装置乙炔浓缩系统高级炔管线堵塞的原因,并提出了防止高级炔气体在管线内聚合、延长装置运行周期的措施.

  12. Effect of higher minimum inhibitory concentrations of quaternary ammonium compounds in clinical E. coli isolates on antibiotic susceptibilities and clinical outcomes.

    Science.gov (United States)

    Buffet-Bataillon, S; Branger, B; Cormier, M; Bonnaure-Mallet, M; Jolivet-Gougeon, A

    2011-10-01

    Quaternary ammonium compounds (QACs) are cationic surfactants used as preservatives and environmental disinfectants. Limited data are available regarding the effect of QACs in the clinical setting. We performed a prospective cohort study in 153 patients with Escherichia coli bacteraemia from February to September 2008 at University Hospital in Rennes. The minimum inhibitory concentrations (MICs) of antibiotics and QACs alkyldimethylbenzylammonium chloride (ADBAC) and didecyldimethylammonium chloride (DDAC) were determined by the agar dilution method. The capacity of biofilm production was assayed using the Crystal Violet method, and mutation frequencies by measuring the capacity of strains to generate resistance to rifampicin. Logistic regression analysis showed that one of the significant factors related to low MICs for ADBAC (≤16 mg/L) and DDAC (≤8 mg/L), was cotrimoxazole susceptibility (odds ratio: 3.72; 95% confidence interval: 1.22-11.24; P=0.02 and OR: 3.61; 95% CI: 1.56-7.56; PAntibiotic susceptibility to cotrimoxazole was strongly associated with susceptibility to amoxicillin and nalidixic acid (PE. coli isolates and antibiotic resistance. Copyright © 2011 The Healthcare Infection Society. Published by Elsevier Ltd. All rights reserved.

  13. Towards a better prediction of peak concentration, volume of distribution and half-life after oral drug administration in man, using allometry.

    Science.gov (United States)

    Sinha, Vikash K; Vaarties, Karin; De Buck, Stefan S; Fenu, Luca A; Nijsen, Marjoleen; Gilissen, Ron A H J; Sanderson, Wendy; Van Uytsel, Kelly; Hoeben, Eva; Van Peer, Achiel; Mackie, Claire E; Smit, Johan W

    2011-05-01

    It is imperative that new drugs demonstrate adequate pharmacokinetic properties, allowing an optimal safety margin and convenient dosing regimens in clinical practice, which then lead to better patient compliance. Such pharmacokinetic properties include suitable peak (maximum) plasma drug concentration (C(max)), area under the plasma concentration-time curve (AUC) and a suitable half-life (t(½)). The C(max) and t(½) following oral drug administration are functions of the oral clearance (CL/F) and apparent volume of distribution during the terminal phase by the oral route (V(z)/F), each of which may be predicted and combined to estimate C(max) and t(½). Allometric scaling is a widely used methodology in the pharmaceutical industry to predict human pharmacokinetic parameters such as clearance and volume of distribution. In our previous published work, we have evaluated the use of allometry for prediction of CL/F and AUC. In this paper we describe the evaluation of different allometric scaling approaches for the prediction of C(max), V(z)/F and t(½) after oral drug administration in man. Twenty-nine compounds developed at Janssen Research and Development (a division of Janssen Pharmaceutica NV), covering a wide range of physicochemical and pharmacokinetic properties, were selected. The C(max) following oral dosing of a compound was predicted using (i) simple allometry alone; (ii) simple allometry along with correction factors such as plasma protein binding (PPB), maximum life-span potential or brain weight (reverse rule of exponents, unbound C(max) approach); and (iii) an indirect approach using allometrically predicted CL/F and V(z)/F and absorption rate constant (k(a)). The k(a) was estimated from (i) in vivo pharmacokinetic experiments in preclinical species; and (ii) predicted effective permeability in man (P(eff)), using a Caco-2 permeability assay. The V(z)/F was predicted using allometric scaling with or without PPB correction. The t(½) was estimated from

  14. Real-time investigation of human topoisomerase I reaction kinetics using an optical sensor: a fast method for drug screening and determination of active enzyme concentrations

    Science.gov (United States)

    Kristoffersen, Emil L.; Jørgensen, Line A.; Franch, Oskar; Etzerodt, Michael; Frøhlich, Rikke; Bjergbæk, Lotte; Stougaard, Magnus; Ho, Yi-Ping; Knudsen, Birgitta R.

    2015-05-01

    Human DNA topoisomerase I (hTopI) is a nuclear enzyme that catalyzes relaxation of super helical tension that arises in the genome during essential DNA metabolic processes. This is accomplished through a common reaction mechanism shared among the type IB topoisomerase enzymes, including eukaryotic and poxvirus topoisomerase I. The mechanism of hTopI is specifically targeted in cancer treatment using camptothecin derivatives. These drugs convert the hTopI activity into a cellular poison, and hence the cytotoxic effects of camptothecin derivatives correlate with the hTopI activity. Therefore, fast and reliable techniques for high throughput measurements of hTopI activity are of high clinical interest. Here we demonstrate potential applications of a fluorophore-quencher based DNA sensor designed for measurement of hTopI cleavage-ligation activities, which are the catalytic steps affected by camptothecin. The kinetic analysis of the hTopI reaction with the DNA sensor exhibits a characteristic burst profile. This is the result of a two-step ping-pong reaction mechanism, where a fast first reaction, the one creating the signal, is followed by a slower second reaction necessary for completion of the catalytic cycle. Hence, the burst profile holds information about two reactions in the enzymatic mechanism. Moreover, it allows the amount of active enzyme in the reaction to be determined. The presented results pave the way for future high throughput drug screening and the potential of measuring active hTopI concentrations in clinical samples for individualized treatment.Human DNA topoisomerase I (hTopI) is a nuclear enzyme that catalyzes relaxation of super helical tension that arises in the genome during essential DNA metabolic processes. This is accomplished through a common reaction mechanism shared among the type IB topoisomerase enzymes, including eukaryotic and poxvirus topoisomerase I. The mechanism of hTopI is specifically targeted in cancer treatment using

  15. Real-time investigation of human topoisomerase I reaction kinetics using an optical sensor: a fast method for drug screening and determination of active enzyme concentrations.

    Science.gov (United States)

    Kristoffersen, Emil L; Jørgensen, Line A; Franch, Oskar; Etzerodt, Michael; Frøhlich, Rikke; Bjergbæk, Lotte; Stougaard, Magnus; Ho, Yi-Ping; Knudsen, Birgitta R

    2015-06-07

    Human DNA topoisomerase I (hTopI) is a nuclear enzyme that catalyzes relaxation of super helical tension that arises in the genome during essential DNA metabolic processes. This is accomplished through a common reaction mechanism shared among the type IB topoisomerase enzymes, including eukaryotic and poxvirus topoisomerase I. The mechanism of hTopI is specifically targeted in cancer treatment using camptothecin derivatives. These drugs convert the hTopI activity into a cellular poison, and hence the cytotoxic effects of camptothecin derivatives correlate with the hTopI activity. Therefore, fast and reliable techniques for high throughput measurements of hTopI activity are of high clinical interest. Here we demonstrate potential applications of a fluorophore-quencher based DNA sensor designed for measurement of hTopI cleavage-ligation activities, which are the catalytic steps affected by camptothecin. The kinetic analysis of the hTopI reaction with the DNA sensor exhibits a characteristic burst profile. This is the result of a two-step ping-pong reaction mechanism, where a fast first reaction, the one creating the signal, is followed by a slower second reaction necessary for completion of the catalytic cycle. Hence, the burst profile holds information about two reactions in the enzymatic mechanism. Moreover, it allows the amount of active enzyme in the reaction to be determined. The presented results pave the way for future high throughput drug screening and the potential of measuring active hTopI concentrations in clinical samples for individualized treatment.

  16. The soluble receptor for vitamin B12 uptake (sCD320) increases during pregnancy and occurs in higher concentration in urine than in serum

    DEFF Research Database (Denmark)

    Abuyaman, Omar; Andreasen, Birgitte H; Kronborg, Camilla

    2013-01-01

    BACKGROUND: Cellular uptake of vitamin B12 (B12) demands binding of the vitamin to transcobalamin (TC) and recognition of TC-B12 (holoTC) by the receptor CD320, a receptor expressed in high quantities on human placenta. We have identified a soluble form of CD320 (sCD320) in serum and here we...... gestational weeks 17-41. sCD320, holoTC, total TC and complex formation between holoTC and sCD320 were measured by in-house ELISA methods, while creatinine was measured on the automatic platform Cobas 6000. Size exclusion chromatography was performed on a Superdex 200 column. RESULTS: Median (range) of serum...... was around two fold higher than in serum. Urinary sCD320/creatinine ratio correlated with serum sCD320 and reached a peak median level of 53 (30-101) pmol/mmol creatinine (week 35). sCD320 present in serum and urine showed the same elution pattern upon size exclusion chromatography. CONCLUSION: We report...

  17. Measurement of adherence, drug concentrations and the effectiveness of artemether-lumefantrine, chlorproguanil-dapsone or sulphadoxine-pyrimethamine in the treatment of uncomplicated malaria in Malawi

    Directory of Open Access Journals (Sweden)

    Chimpeni Phillips

    2009-08-01

    Full Text Available Abstract Background Sulphadoxine-pyrimethamine (SP is the only single dose therapy for uncomplicated malaria, but there is widespread resistance. At the time of this study, artemether-lumefantrine (AL and chlorproguanil-dapsone (CPD, both multi-dose regimes, were considered possible alternatives to SP in Malawi. The aim of this study was to investigate the impact of poor adherence on the effectiveness of AL and CPD. Methods Children ≥12 months and adults with uncomplicated malaria were randomized to receive AL, CPD or SP. Adherence was measured using a questionnaire and electronic monitoring devices, MEMS™, pill bottles that recorded the date and time of opening. Day-7 plasma dapsone or lumefantrine concentrations were measured to examine their relationship with adherence and clinical response. Results 841 patients were recruited. The day-28 adequate clinical and parasitological response (ACPR rates, using intention to treat analysis (missing data treated as failure, were AL 85.2%, CPD 63.7% and SP 50%. ACPR rates for AL were higher than CPD or SP on days 28 and 42 (p ≤ 0.002 for all comparisons. CPD was more effective than SP on day-28 (p = 0.01, but not day-42. Very high adherence was reported using the questionnaire, 100% for AL treated patients and 99.2% for the CPD group. Only three CPD participants admitted missing any doses. 164/181 (90.6% of CPD treated patients took all their doses out of the MEMS™ container and they were more likely to have a day-28 ACPR than those who did not take all their medication out of the container, p = 0.024. Only 7/87 (8% AL treated patients did not take all of their doses out of their MEMS™ container and none had treatment failure. Median day-7 dapsone concentrations were higher in CPD treated patients with ACPR than in treatment failures, p = 0.012. There were no differences in day-7 dapsone or lumefantrine concentrations between those who took all their doses from the MEMS™ container and those

  18. Payment for antiretroviral drugs is associated with a higher rate of patients lost to follow-up than those offered free-of-charge therapy in Nairobi, Kenya

    NARCIS (Netherlands)

    Zachariah, R.; van Engelgem, I.; Massaquoi, M.; Kocholla, L.; Manzi, M.; Suleh, A.; Phillips, M.; Borgdorff, M.

    2008-01-01

    This retrospective analysis of routine programme data from Mbagathi District Hospital, Nairobi, Kenya shows the difference in rates of loss to follow-up between a cohort that paid 500 shillings/month (approximately US$7) for antiretroviral drugs (ART) and one that received medication free of charge.

  19. Eimeria Oocyst Concentrations and Species Composition in Litter from Commercial Broiler Farms During Anticoccidial Drug or Live Eimeria Oocyst Vaccine Control Programs.

    Science.gov (United States)

    Jenkins, Mark C; Parker, Carolyn; Ritter, Donald

    2017-06-01

    The purpose of this study was to determine if Eimeria oocyst concentrations and species composition in commercial broiler house litter changed during different cycles of anticoccidial drug (ACD) or live Eimeria oocyst vaccine (VAC) control programs and if there was a correlation between Eimeria oocyst levels and broiler performance. Litter samples were collected from a total of 15 different broiler farms encompassing a total of 45 individual houses during at least one complete grow-out cycle over a 21-mo period. Of these 15 broiler farms, three were followed for the entire 21-mo period spanning three ACD and four VAC cycles. Samples were collected at 2, 4, and 7-8 wk of grow-out corresponding to starter, grower, and withdraw periods of the ACD cycle. On a number of occasions, litter samples were obtained just prior to chick placement. Eimeria oocysts were isolated from all samples, counted by microscopy, and extracted for DNA to identify Eimeria species by ITS1 PCR. In general, Eimeria oocyst concentration in litter reached peak levels at 2-4 wk of grow-out regardless of coccidiosis control measure being used. However, peak oocyst numbers were sometimes delayed until 7-8 wk, indicating some level of Eimeria spp. drug resistance or incomplete vaccine coverage. Eimeria maxima , Eimeria acervulina , Eimeria praecox, and Eimeria tenella were generally present in all samples, and no difference in the species composition was noted between houses on a particular farm. While Eimeria species composition was similar among houses, Eimeria spp. oocyst levels exhibited sporadic peaks in one house of a given location's houses. Of particular interest was the observed correlation between E. maxima oocyst abundance and chick mortality. However, no correlation was observed in E. maxima oocyst levels, and the performance parameters adjusted feed conversion ratio and average daily weight gain. This study showed that understanding the dynamics of Eimeria spp. oocyst levels and species

  20. Cytogenetic and oxidative status of human lymphocytes after exposure to clinically relevant concentrations of antimalarial drugs atovaquone and proguanil hydrochloride in vitro.

    Science.gov (United States)

    Dinter, Domagoj; Gajski, Goran; Domijan, Ana-Marija; Garaj-Vrhovac, Vera

    2015-12-01

    Atovaquone (ATO) and proguanil hydrochloride (PROG) is the fixed combination for the prevention and treatment of Plasmodium falciparum malaria. As safe and effective antimalarial drugs are needed in both the treatment and the prophylaxis of malaria, this study was performed to investigate their possible cyto/genotoxic potential towards human lymphocytes and the possible mechanism responsible for it. Two different concentrations of ATO and PROG were used with and without S9 metabolic activation. The concentrations used were those found in human plasma when a fixed-dose combination of ATO and PROG was used: 2950/130 ng/mL after prophylactic treatment and 11 800/520 ng/mL after treatment of malaria, respectively. Possible cellular and DNA-damaging effects were evaluated by cell viability and alkaline comet assays, while oxidative stress potential was evaluated by formamidopyrimidine-DNA glycosylase (Fpg)-modified comet assay, in addition to measuring malondialdehyde and glutathione levels. According to our results, the ATO/PROG combination displayed only weak cyto/genotoxic potential towards human lymphocytes with no impact on oxidative stress parameters, suggesting that oxidative stress is not implicated in their mechanism of action towards human lymphocytes. Given that the key portion of the damaging effects was induced after S9 metabolic activation, it is to presume that the principal metabolite of PROG, cycloguanil, had the greatest impact. The obtained results indicate that the ATO/PROG combination is relatively safe for the consumption from the aspect of cyto/genotoxicity, especially if used for prophylactic treatment. Nevertheless, further cytogenetic research and regular patient monitoring are needed to minimize the risk of adverse events especially among frequent travellers. © 2015 Société Française de Pharmacologie et de Thérapeutique.

  1. [PK/PD breakpoints and clinical/bacteriological effects of cefcapene pivoxil fine granules for children at free drug concentrations in pediatric patients with respiratory infection].

    Science.gov (United States)

    Toyonaga, Yoshikiyo; Iwai, Naoichi; Motohiro, Takashi; Sunakawa, Keisuke; Fujii, Ryochi

    2008-06-01

    A post-marketing clinical study was previously conducted in pediatric patients with respiratory infection to evaluate the pharmacokinetics, efficacy and safety of cefcapene pivoxil (CFPN-PI) fine granules for children. Based on the results from this study, we evaluated PK/PD breakpoints and clinical/bacteriological effects of CFPN-PI at free drug concentrations in pediatric patients with respiratory infection to determine an effective and safe dosage regimen of CFPN-PI. The following results were obtained from 61 pediatric patients evaluated in our research. 1) The response rate of pediatric respiratory infection to CFPN-PI was 100% for laryngopharyngitis, 84.6% for acute bronchitis, 100% for tonsillitis, 100% for pneumonia and 95.8% for all. 2) The bacteriological response (eradication rate of Haemophilus influenzae, Streptococcus pyogenes, Moraxella catarrhalis, Streptococcus pneumoniae, etc.) of pediatric respiratory infection to CFPN-PI was 87.5% for laryngopharyngitis, 66.7% for acute bronchitis, 75.0% for tonsillitis, 63.6% for pneumonia and 73.8% for all. 3) The blood concentration simulation demonstrated that the PK/PD breakpoint exceeding the time above MIC (TAM) of 40% after administration of CFPN-PI 3 mg/kg three times daily was 0.27 microg/mL. 4) The pediatric patients with respiratory infection were stratified by the TAM (%) of CFPN-PI into 40% to 100% (TAM > or = 40% group) and 0% to 40% (TAM or = 40% group, and 88.9% and 62.5% in the TAM or = 40% group than in the TAM < 40% group, although the between-group difference was not statistically significant.

  2. Competing pathways in drug metabolism. I. Effect of input concentration on the conjugation of gentisamide in the once-through in situ perfused rat liver preparation

    International Nuclear Information System (INIS)

    Morris, M.E.; Yuen, V.; Tang, B.K.; Pang, K.S.

    1988-01-01

    Sulfation and glucuronidation are two parallel pathways for the metabolism of phenolic substrates. Gentisamide (GAM) was used as a model compound to examine the effects of parallel competing pathways on drug disappearance and metabolite formation in the once-through perfused rat liver preparation. GAM was found to form one glucuronide (GAM-5G) and two sulfate (GAM-2S and GAM-5S) conjugates. These GAM conjugates were biosynthesized in recirculating rat liver preparations, and were isolated by preparative high-performance liquid chromatography. Specific incorporation of 35S-sodium sulfate and [14C]glucose into GAM sulfate and glucuronide conjugates revealed corresponding elution patterns as labeled GAM metabolites. Their identities were characterized by enzymatic and acid hydrolyses and by NMR spectroscopy. Gentisamide-5-sulfate (GAM-5S) and gentisamide-5-glucuronide (GAM-5G) are major metabolites, and gentisamide-2-sulfate (GAM-2S) is a minor metabolite. Single-pass rat liver perfusions were used to examine the effect of stepwise increases/decreases of input GAM concentration (CIn) on the extraction ratio (E) of GAM and formation of metabolites. The E of GAM remained constant (about 0.89) at input concentrations from 0.9 to 120 microM and decreased at CIn greater than 120 microM. Metabolite patterns, however, changed with GAM CIn, even when E was constant at CIn up to 120 microM. GAM-5S was present as the major metabolite of GAM at all GAM CInS in most liver preparations but the proportions of GAM-5S and GAM-2S decreased at increasing CIn; the proportion of GAM-5G, a minor metabolite at low CIn, increased with increasing CIn. Biliary excretion rates at steady state accounted for 5.3 +/- 2.7% (mean +/- S.D.) of the input rate: GAM-5G was the predominant metabolite found

  3. An in vitro drug sensitivity test using a higher 3H-TdR incorporation and a modified human tumor stem cell assay

    International Nuclear Information System (INIS)

    Wang Enzhong

    1991-01-01

    An in vitro drug sensitivity test was developed to evaluate the lethal effects of drugs on human pulmonary carcinoma cells (HPCC). This method was a variant and combination of Human Tumor Stem (HTSCA) and a short-term test using 3 H-TdR incorporation. It consisted of a cell containing liquid top layer and a soft agar bottom layer in 24-well microplates. The medium was RPMI 1640 supplemented with 20% malignant pleural effusion, which could enhance 3 H-TdR incorporation into malignant cells. When 50%, 40%, 30% and 30% of cell survival rate defined as sensitivity-threshold for VCR, MMC, DDP and ADM respectively, in the vitro effectiveness were close to those of clinical single-drug treatment in HPCC by Wright et al. This method was also compared with HTSCA in ten human lung cancer cell lines and four pulmonary carcinoma tissues. The agreement rates were 83% and 100% respectively. Thus we presume this system is more useful for oncological clinics than the others

  4. Effect of therapeutic plasma concentrations of non-steroidal anti-inflammatory drugs on the production of reactive oxygen species by activated rat neutrophils

    Directory of Open Access Journals (Sweden)

    Paino I.M.M.

    2005-01-01

    Full Text Available The release of reactive oxygen specie (ROS by activated neutrophil is involved in both the antimicrobial and deleterious effects in chronic inflammation. The objective of the present investigation was to determine the effect of therapeutic plasma concentrations of non-steroidal anti-inflammatory drugs (NSAIDs on the production of ROS by stimulated rat neutrophils. Diclofenac (3.6 µM, indomethacin (12 µM, naproxen (160 µM, piroxicam (13 µM, and tenoxicam (30 µM were incubated at 37ºC in PBS (10 mM, pH 7.4, for 30 min with rat neutrophils (1 x 10(6 cells/ml stimulated by phorbol-12-myristate-13-acetate (100 nM. The ROS production was measured by luminol and lucigenin-dependent chemiluminescence. Except for naproxen, NSAIDs reduced ROS production: 58 ± 2% diclofenac, 90 ± 2% indomethacin, 33 ± 3% piroxicam, and 45 ± 6% tenoxicam (N = 6. For the lucigenin assay, naproxen, piroxicam and tenoxicam were ineffective. For indomethacin the inhibition was 52 ± 5% and diclofenac showed amplification in the light emission of 181 ± 60% (N = 6. Using the myeloperoxidase (MPO/H2O2/luminol system, the effects of NSAIDs on MPO activity were also screened. We found that NSAIDs inhibited both the peroxidation and chlorinating activity of MPO as follows: diclofenac (36 ± 10, 45 ± 3%, indomethacin (97 ± 2, 100 ± 1%, naproxen (56 ± 8, 76 ± 3%, piroxicam (77 ± 5, 99 ± 1%, and tenoxicam (90 ± 2, 100 ± 1%, respectively (N = 3. These results show that therapeutic levels of NSAIDs are able to suppress the oxygen-dependent antimicrobial or oxidative functions of neutrophils by inhibiting the generation of hypochlorous acid.

  5. Higher intake of vitamin B-6 and dairy products and lower intake of green and oolong tea are independently associated with lower serum homocysteine concentration in young Japanese women.

    Science.gov (United States)

    Murakami, Kentaro; Sasaki, Satoshi; Uenishi, Kazuhiro

    2013-08-01

    Little is known about the relation of modifiable dietary factors to circulating homocysteine concentrations, particularly in young adults and non-Western populations. We investigated the hypothesis that intakes of nutrients and foods are associated with serum homocysteine concentration in a group of young Japanese women. This cross-sectional study included 1050 female Japanese dietetic students aged 18 to 22 years. Dietary intake was assessed using a validated, self-administered, comprehensive diet history questionnaire. Fasting blood samples were collected, and serum homocysteine concentrations were measured. Adjustment was made for survey year, region, municipality level, current smoking, current alcohol drinking, dietary supplement use, physical activity, body mass index, energy intake, and intakes of other nutrients or foods. After adjustment for nondietary confounding factors, intakes of all B vitamins (folate, vitamin B-6, vitamin B-12, and riboflavin) were inversely associated with homocysteine concentration. However, only vitamin B-6 remained significant after further adjustment for other B vitamins. Marine-origin n-3 polyunsaturated fatty acid intake showed an inverse association, but this was not independent of intakes of B vitamins. For foods, pulses, fish and shellfish, and vegetables were independently and inversely associated with homocysteine concentration, but these associations disappeared after adjustment for intakes of other foods. Conversely, an inverse association for dairy products and a positive association for green and oolong tea remained even after adjustment for other foods. To conclude, in a group of young Japanese women, higher intake of vitamin B-6 and dairy products and lower intake of green and oolong tea were independently associated with lower serum homocysteine concentration. Copyright © 2013 Elsevier Inc. All rights reserved.

  6. Measurements of Neuronal Soma Size and Estimated Peptide Concentrations in Addition to Cell Abundance Offer a Higher Resolution of Seasonal and Reproductive Influences of GnRH-I and GnIH in European Starlings.

    Science.gov (United States)

    Amorin, Nelson; Calisi, Rebecca M

    2015-08-01

    Hypothalamic neuropeptides involved in vertebrate reproduction, gonadotropin releasing hormone (GnRH-I) and gonadotropin-inhibitory hormone (GnIH), can vary in the abundance of immunoreactive cells as a function of the reproductive status and nest box occupation of European starlings (Sturnus vulgaris). While using the abundance of cells as an indicator of the activity of neurohormones is informative, incorporating information on cell size (readily observed using immunohistochemistry) can offer a more detailed understanding of environmentally-mediated changes in hormonal dynamics. In this study, we tested the hypothesis that the size of cells' somas and the estimated concentration of peptides in cells immunoreactive (ir) for GnRH-I and GnIH would vary throughout the breeding season and as a function of nest-box status (resident or not). In the absence of a direct assay of protein, we estimated an index of the concentration of hypothalamic peptides via the relative optical density (i.e., the difference between the mean optical density and the optical density of background staining). In support of our hypothesis, we found that GnRH-I- and GnIH-ir soma size and peptide concentration changed both in males and females throughout the breeding season. Somas were largest and estimated peptide concentration was highest mid-season when compared with earlier in the season or to the non-breeding period. For nest-box residents, GnIH-ir soma size and peptide concentration were higher during the middle of the breeding season than earlier in the breeding season, although residence in the nest box was not related to GnRH-I-ir variables. Our results confirm that previously reported changes in cell abundance mimic changes we see in GnRH-I and GnIH-ir soma size and our proxy for peptide concentration. However, investigating changes in the soma of GnRH-I-ir cells revealed a peak in size during the middle of the breeding season, a change not evident when solely examining data on the

  7. Comparative assessment of image quality for coronary CT angiography with iobitridol and two contrast agents with higher iodine concentrations: iopromide and iomeprol. A multicentre randomized double-blind trial

    Energy Technology Data Exchange (ETDEWEB)

    Achenbach, Stephan [Friedrich-Alexander-Universitaet Erlangen-Nuernberg, Department of Cardiology, Erlangen (Germany); Paul, Jean-Francois [Centre Chirurgical Marie Lannelongue, Department of Radiology, Le Plessis Robinson (France); Laurent, Francois [University of Bordeaux, Centre de Recherche Cardio-Thoracique de Bordeaux, U1045, Bordeaux (France); CHU de Bordeaux, Service d' Imagerie Thoracique et Cardiovasculaire, Pessac (France); Becker, Hans-Christoph [University Hospital Grosshadern, Department of Clinical Radiology, Munich (Germany); Rengo, Marco [Sapienza - University of Rome, ICOT Hospital, Department of Radiological Sciences, Oncology and Pathology, Latina (Italy); Caudron, Jerome [University Hospital of Rouen, Department of Radiology, Rouen (France); Leschka, Sebastian [Saint Gallen Hospital, Department of Radiology, Saint Gallen (Switzerland); Vignaux, Olivier [Cochin Hospital, Department of Radiology, Paris (France); Knobloch, Gesine [La Charite, Department of Radiology, Berlin (Germany); Benea, Giorgio [Ospedale del Delta, Ferrara (Italy); Schlosser, Thomas [Elisabeth-Krankenhaus Hospital, Essen (Germany); Andreu, Jordi [Hospital Vall d' Hebron, Barcelona (Spain); Cabeza, Beatriz [Hospital Clinico San Carlos, Madrid (Spain); Jacquier, Alexis [La Timone Adult Hospital, Department of Radiology, Marseille (France); Souto, Miguel [Complejo Hospitalario Universitario, Santiago de Compostela (Spain); Revel, Didier [Louis Pradel Hospital, Department of Radiology, Lyon (France); Qanadli, Salah Dine [University of Lausanne, Department of Radiology, Lausanne (Switzerland); Cademartiri, Filippo [Giovanni XXIII Hospital, Department of Radiology, Monastier di Treviso (Italy); Collaboration: X-ACT Study Group

    2017-02-15

    To demonstrate non-inferiority of iobitridol 350 for coronary CT angiography (CTA) compared to higher iodine content contrast media regarding rate of patients evaluable for the presence of coronary artery stenoses. In this multicentre trial, 452 patients were randomized to receive iobitridol 350, iopromide 370 or iomeprol 400 and underwent coronary CTA using CT systems with 64-detector rows or more. Two core lab readers assessed 18 coronary segments per patient regarding image quality (score 0 = non diagnostic to 4 = excellent quality), vascular attenuation, signal and contrast to noise ratio (SNR, CNR). Patients were considered evaluable if no segment had a score of 0. Per-patient, the rate of fully evaluable CT scans was 92.1, 95.4 and 94.6 % for iobitridol, iopromide and iomeprol, respectively. Non-inferiority of iobitridol over the best comparator was demonstrated with a 95 % CI of the difference of [-8.8 to 2.1], with a pre-specified non-inferiority margin of -10 %. Although average attenuation increased with higher iodine concentrations, average SNR and CNR did not differ between groups. With current CT technology, iobitridol 350 mg iodine/ml is not inferior to contrast media with higher iodine concentrations in terms of image quality for coronary stenosis assessment. (orig.)

  8. [Drugs and occupational accident].

    Science.gov (United States)

    Bratzke, H; Albers, C

    1996-02-01

    In a case of a fatal occupational accident (construction worker, fall from roof, urine test positive for cocaine and THC, e.g. cannabis) the question arised to what extent those drug-related occupational accidents occur. In the literature only few cases, mainly dealing with cannabis influence, have been reported, however, a higher number is suspected. Cocaine and other stimulating drugs (amphetamine) are more often used to increase physical fitness. By direct or indirect interference with vigilance these compounds may provoke accidents. Due to the lack of a legal basis proving of the influence of drugs at the working place is still very limited, although highly sensitive chemical-toxicological assay procedures are available to detect even the chronic abuse (in hair). In the general conditions of accident insurances a compensation is excluded when alcohol is involved, but drugs are not mentioned. It is indeed difficult to establish a concentration limit for drugs like that existing for alcohol (1.1%). In each case the assay of the drug involved and exact knowledge of its specific effects is in an essential prerequisite to prove the causal relationship.

  9. A review on the relation between the brain-serum concentration ratio of drugs and the influence of P-glycoprotein

    DEFF Research Database (Denmark)

    Ejsing, Thomas Broeng; Morling, Niels; Linnet, Kristian

    2007-01-01

    This overview on the brain-serum relationship for drugs illustrates the importance of the drug transporter P-glycoprotein at the blood-brain barrier. Generally, an inverse relationship exists between the magnitude of the brain-serum ratio and the influence of P-glycoprotein. Concerning the pharma...... the pharmacogenomics of P-glycoprotein, no clear effect of single nucleotide polymorphisms (SNPs) has been demonstrated in humans....

  10. The analysis of a trace amount of elements in crude drugs

    International Nuclear Information System (INIS)

    Wakayama, I.; Akagawa, J.; Yase, Y.; Yoshida, S.; Sasajima, Kazuhisa

    2001-01-01

    The concentrations and the pharmacological actions of iron and zinc in nearly 30 kinds of crude drugs of Chinese medicine are studied using the neutron activation analysis, quantitatively. The quantitative analytical results are also compared with the semi-quantitative analytical results of iron and zinc obtained by particle induced X-ray emission spectroscopy. The crude drugs with higher iron concentration were almost drugs for the mentality. The crude drugs with highest zinc concentration were also the drugs for the mentality. (H. Katsuta)

  11. Exfoliation in ecstasy: liquid crystal formation and concentration-dependent debundling observed for single-wall nanotubes dispersed in the liquid drug γ-butyrolactone

    Science.gov (United States)

    Bergin, Shane D.; Nicolosi, Valeria; Giordani, Silvia; de Gromard, Antoine; Carpenter, Leslie; Blau, Werner J.; Coleman, Jonathan N.

    2007-11-01

    Large-scale debundling of single-walled nanotubes has been demonstrated by dilution of nanotube dispersions in the solvent γ-butyrolactone. This liquid, sometimes referred to as 'liquid ecstasy', is well known for its narcotic properties. At high concentrations the dispersions form an anisotropic, liquid crystalline phase which can be removed by mild centrifugation. At lower concentrations an isotropic phase is observed with a biphasic region at intermediate concentrations. By measuring the absorbance before and after centrifugation, as a function of concentration, the relative anisotropic and isotropic nanotube concentrations can be monitored. The upper limit of the pure isotropic phase was CNT~0.004 mg ml-1, suggesting that this can be considered the nanotube dispersion limit in γ-butyrolactone. After centrifugation, the dispersions are stable against sedimentation and further aggregation for a period of 8 weeks at least. Atomic-force-microscopy studies on films deposited from the isotropic phase reveal that the bundle diameter distribution decreases dramatically as concentration is decreased. Detailed data analysis suggests the presence of an equilibrium bundle number density. A population of individual nanotubes is always observed which increases with decreasing concentration until almost 40% of all dispersed objects are individual nanotubes at a concentration of 6 × 10-4 mg ml-1. The number density of individual nanotubes peaks at a concentration of ~6 × 10-3 mg ml-1 where almost 10% of the nanotubes by mass are individualized.

  12. Exfoliation in ecstasy: liquid crystal formation and concentration-dependent debundling observed for single-wall nanotubes dispersed in the liquid drug γ-butyrolactone

    International Nuclear Information System (INIS)

    Bergin, Shane D; Nicolosi, Valeria; Giordani, Silvia; Gromard, Antoine de; Carpenter, Leslie; Blau, Werner J; Coleman, Jonathan N

    2007-01-01

    Large-scale debundling of single-walled nanotubes has been demonstrated by dilution of nanotube dispersions in the solvent γ-butyrolactone. This liquid, sometimes referred to as 'liquid ecstasy', is well known for its narcotic properties. At high concentrations the dispersions form an anisotropic, liquid crystalline phase which can be removed by mild centrifugation. At lower concentrations an isotropic phase is observed with a biphasic region at intermediate concentrations. By measuring the absorbance before and after centrifugation, as a function of concentration, the relative anisotropic and isotropic nanotube concentrations can be monitored. The upper limit of the pure isotropic phase was C NT ∼0.004 mg ml -1 , suggesting that this can be considered the nanotube dispersion limit in γ-butyrolactone. After centrifugation, the dispersions are stable against sedimentation and further aggregation for a period of 8 weeks at least. Atomic-force-microscopy studies on films deposited from the isotropic phase reveal that the bundle diameter distribution decreases dramatically as concentration is decreased. Detailed data analysis suggests the presence of an equilibrium bundle number density. A population of individual nanotubes is always observed which increases with decreasing concentration until almost 40% of all dispersed objects are individual nanotubes at a concentration of 6 x 10 -4 mg ml -1 . The number density of individual nanotubes peaks at a concentration of ∼6 x 10 -3 mg ml -1 where almost 10% of the nanotubes by mass are individualized

  13. Possibility of Predicting Serotonin Transporter Occupancy From the In Vitro Inhibition Constant for Serotonin Transporter, the Clinically Relevant Plasma Concentration of Unbound Drugs, and Their Profiles for Substrates of Transporters.

    Science.gov (United States)

    Yahata, Masahiro; Chiba, Koji; Watanabe, Takao; Sugiyama, Yuichi

    2017-09-01

    Accurate prediction of target occupancy facilitates central nervous system drug development. In this review, we discuss the predictability of serotonin transporter (SERT) occupancy in human brain estimated from in vitro K i values for human SERT and plasma concentrations of unbound drug (C u,plasma ), as well as the impact of drug transporters in the blood-brain barrier. First, the geometric means of in vitro K i values were compared with the means of in vivo K i values (K i,u,plasma ) which were calculated as C u,plasma values at 50% occupancy of SERT obtained from previous clinical positron emission tomography/single photon emission computed tomography imaging studies for 6 selective serotonin transporter reuptake inhibitors and 3 serotonin norepinephrine reuptake inhibitors. The in vitro K i values for 7 drugs were comparable to their in vivo K i,u,plasma values within 3-fold difference. SERT occupancy was overestimated for 5 drugs (P-glycoprotein substrates) and underestimated for 2 drugs (presumably uptake transporter substrates, although no evidence exists as yet). In conclusion, prediction of human SERT occupancy from in vitro K i values and C u,plasma was successful for drugs that are not transporter substrates and will become possible in future even for transporter substrates, once the transporter activities will be accurately estimated from in vitro experiments. Copyright © 2017 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

  14. Optimization of a model of red blood cells for the study of anti-oxidant drugs, in terms of concentration of oxidant and phosphate buffer.

    Science.gov (United States)

    Bureau, A; Lahet, J-J; Lenfant, F; Bouyer, F; Petitjean, M; Chaillot, B; Freysz, M

    2005-08-01

    The aggression of erythrocytes by an oxidative stress induces hemolysis. This paper aims to valid a model of erythrocytes in terms of composition of the phosphate buffer solution and of concentration of a well-known oxidant, AAPH. Three compositions of phosphate buffer solution are mixed with three concentrations of oxidant. The influence of these two parameters on hemolysis is independently studied by a variance analysis and a Kruskal-Wallis test when ANOVA is not available. The hemolysis rate increases with time at fixed oxidant concentration, but is not influenced by the composition of the buffer solution. The highest hemolysis rate, 90%, was only measured within 2 h with the highest oxidant concentration. If we retain this concentration of oxidant, the lower concentration of the buffer can by eliminated by a significant less hemolysis and the highest concentration of the buffer can by chosen in regard of the better precision for a similar hemolysis compared to the mean buffer. We hope to study the effect of anti-oxidant agent with such a model of erythrocytes.

  15. Exfoliation in ecstasy: liquid crystal formation and concentration-dependent debundling observed for single-wall nanotubes dispersed in the liquid drug {gamma}-butyrolactone

    Energy Technology Data Exchange (ETDEWEB)

    Bergin, Shane D [School of Physics, Trinity College Dublin, University of Dublin, Dublin 2 (Ireland); Nicolosi, Valeria [School of Physics, Trinity College Dublin, University of Dublin, Dublin 2 (Ireland); Giordani, Silvia [School of Physics, Trinity College Dublin, University of Dublin, Dublin 2 (Ireland); Gromard, Antoine de [School of Physics, Trinity College Dublin, University of Dublin, Dublin 2 (Ireland); Carpenter, Leslie [School of Physics, Trinity College Dublin, University of Dublin, Dublin 2 (Ireland); Blau, Werner J [School of Physics, Trinity College Dublin, University of Dublin, Dublin 2 (Ireland); Coleman, Jonathan N [School of Physics, Trinity College Dublin, University of Dublin, Dublin 2 (Ireland)

    2007-11-14

    Large-scale debundling of single-walled nanotubes has been demonstrated by dilution of nanotube dispersions in the solvent {gamma}-butyrolactone. This liquid, sometimes referred to as 'liquid ecstasy', is well known for its narcotic properties. At high concentrations the dispersions form an anisotropic, liquid crystalline phase which can be removed by mild centrifugation. At lower concentrations an isotropic phase is observed with a biphasic region at intermediate concentrations. By measuring the absorbance before and after centrifugation, as a function of concentration, the relative anisotropic and isotropic nanotube concentrations can be monitored. The upper limit of the pure isotropic phase was C{sub NT}{approx}0.004 mg ml{sup -1}, suggesting that this can be considered the nanotube dispersion limit in {gamma}-butyrolactone. After centrifugation, the dispersions are stable against sedimentation and further aggregation for a period of 8 weeks at least. Atomic-force-microscopy studies on films deposited from the isotropic phase reveal that the bundle diameter distribution decreases dramatically as concentration is decreased. Detailed data analysis suggests the presence of an equilibrium bundle number density. A population of individual nanotubes is always observed which increases with decreasing concentration until almost 40% of all dispersed objects are individual nanotubes at a concentration of 6 x 10{sup -4} mg ml{sup -1}. The number density of individual nanotubes peaks at a concentration of {approx}6 x 10{sup -3} mg ml{sup -1} where almost 10% of the nanotubes by mass are individualized.

  16. Determination of the total concentration of highly protein-bound drugs in plasma by on-line dialysis and column liquid chromatography: application to non-steroidal anti-inflammatory drugs.

    NARCIS (Netherlands)

    Herraez-Hernandez, R.; van de Merbel, N.C.; Brinkman, U.A.T.

    1995-01-01

    The potential of on-line dialysis as a sample preparation procedure for compounds highly bound to plasma proteins is evaluated, using non-steroidal anti-inflammatory drugs as model compounds and column liquid chromatography as the separation technique. Different strategies to reduce the degree of

  17. Determination of the total concentration of highly protein-bound drugs in plasma by on-line dialysis and column liquid chromatography : application to non-steroidal anti-inflammatory drugs

    NARCIS (Netherlands)

    Herráez-Hernández, R; van de Merbel, N C; Brinkman, U A

    1995-01-01

    The potential of on-line dialysis as a sample preparation procedure for compounds highly bound to plasma proteins is evaluated, using non-steroidal anti-inflammatory drugs as model compounds and column liquid chromatography as the separation technique. Different strategies to reduce the degree of

  18. Fertility drugs and ovarian cancer.

    Science.gov (United States)

    Ali, Aus Tariq

    2017-06-20

    The aetiology of ovarian cancer is multifactorial with both endogenous and exogenous risk factors playing an important role. The exact pathogenesis of ovarian cancer is still not well understood, despite the number of hypotheses published. Due to an increase in the number of women using fertility drugs, much attention has been focused on the long-term health effects of such drugs. Although fertility drugs facilitate the ovulation process, it is however associated with a significant increase in hormone concentrations, placing exposed women at increased risk of gynaecological cancer. Many clinical and epidemiological studies have examined the association between fertility drugs and ovarian cancer risk. Results from these studies have been contradictory, as some studies have reported an increased risk of ovarian cancer while others reported no increased risk. Nevertheless, recent studies have shown that women who used fertility drugs and did not conceive had a higher risk of developing ovarian cancer, compared to women who used fertility drugs and conceived and delivered successfully. This review discusses the effect of fertility drugs on the risk of developing ovarian cancer, providing details on four possible scenarios associated with fertility treatment. In addition, the limitations of previous studies and their impact on our understanding of the association between fertility drugs and ovarian cancer also have been highlighted. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  19. Determination of optical properties, drug concentration, and tissue oxygenation in human pleural tissue before and after Photofrin-mediated photodynamic therapy

    Science.gov (United States)

    Ong, Yi Hong; Padawer-Curry, Jonah; Finlay, Jarod C.; Kim, Michele M.; Dimofte, Andreea; Cengel, Keith; Zhu, Timothy C.

    2018-02-01

    PDT efficacy depends on the concentration of photosensitizer, oxygen, and light delivery in patient tissues. In this study, we measure the in-vivo distribution of important dosimetric parameters, namely the tissue optical properties (absorption μa (λ) and scattering μs ' (λ) coefficients), photofrin concentration (cphotofrin), blood oxygen saturation (%StO2), and total hemoglobin concentration (THC), before and after PDT. We characterize the inter- and intra-patient heterogeneity of these quantities and explore how these properties change as a result of PDT treatment. The result suggests the need for real-time dosimetry during PDT to optimize the treatment condition depending on the optical and physiological properties.

  20. An integrated approach to care attracts people living with HIV who use illicit drugs in an urban centre with a concentrated HIV epidemic

    Directory of Open Access Journals (Sweden)

    S. Fernando

    2016-11-01

    Full Text Available Abstract Background People living with HIV (PLHIV who are also marginalized by social and structural inequities often face barriers to accessing and adhering to HIV treatment and care. The Dr. Peter Centre (DPC is a non-profit integrated care facility with a supervised injection room that serves PLHIV experiencing multiple barriers to social and health services in Vancouver, Canada. This study examines whether the DPC is successful in drawing in PLHIV with complex health issues, including addiction. Methods Using data collected by the Longitudinal Investigations into Supportive and Ancillary health services (LISA study from July 2007 to January 2010, linked with clinical variables available through the British Columbia Centre for Excellence in HIV/AIDS Drug Treatment Program, we identified DPC and non-DPC clients with a history of injection drug use. Bivariable and multivariable logistic regression analyses compared socio-demographic and clinical characteristics of DPC clients (n = 76 and non-DPC clients (n = 482 with a history of injection drug use. Results Of the 917 LISA participants included within this analysis, 100 (10.9% reported being a DPC client, of which 76 reported a history of injection drug use. Adjusted results found that compared to non-DPC clients with a history of injection drug use, DPC-clients were more likely to be male (AOR: 4.18, 95% CI = 2.09–8.37; use supportive services daily vs. less than daily (AOR: 3.16, 95% CI = 1.79–5.61; to have been diagnosed with a mental health disorder (AOR: 2.11; 95% CI: 1.12–3.99; to have a history of interpersonal violence (AOR: 2.76; 95% CI: 1.23–6.19; and to have ever experienced ART interruption longer than 1 year (AOR: 2.39; 95% CI: 1.38–4.15. Conclusions Our analyses suggest that the DPC operating care model engages PLHIV with complex care needs, highlighting that integrated care facilities are needed to support the multiple intersecting vulnerabilities faced

  1. Higher Education

    African Journals Online (AJOL)

    Kunle Amuwo: Higher Education Transformation: A Paradigm Shilt in South Africa? ... ty of such skills, especially at the middle management levels within the higher ... istics and virtues of differentiation and diversity. .... may be forced to close shop for lack of capacity to attract ..... necessarily lead to racial and gender equity,.

  2. Subtoxic Concentrations of Hepatotoxic Drugs Lead to Kupffer Cell Activation in a Human In Vitro Liver Model: An Approach to Study DILI

    Directory of Open Access Journals (Sweden)

    Victoria Kegel

    2015-01-01

    Full Text Available Drug induced liver injury (DILI is an idiosyncratic adverse drug reaction leading to severe liver damage. Kupffer cells (KC sense hepatic tissue stress/damage and therefore could be a tool for the estimation of consequent effects associated with DILI. Aim of the present study was to establish a human in vitro liver model for the investigation of immune-mediated signaling in the pathogenesis of DILI. Hepatocytes and KC were isolated from human liver specimens. The isolated KC yield was 1.2±0.9×106 cells/g liver tissue with a purity of >80%. KC activation was investigated by the measurement of reactive oxygen intermediates (ROI, DCF assay and cell activity (XTT assay. The initial KC activation levels showed broad donor variability. Additional activation of KC using supernatants of hepatocytes treated with hepatotoxic drugs increased KC activity and led to donor-dependent changes in the formation of ROI compared to KC incubated with supernatants from untreated hepatocytes. Additionally, a compound- and donor-dependent increase in proinflammatory cytokines or in anti-inflammatory cytokines was detected. In conclusion, KC related immune signaling in hepatotoxicity was successfully determined in a newly established in vitro liver model. KC were able to detect hepatocyte stress/damage and to transmit a donor- and compound-dependent immune response via cytokine production.

  3. Subtoxic Concentrations of Hepatotoxic Drugs Lead to Kupffer Cell Activation in a Human In Vitro Liver Model: An Approach to Study DILI

    Science.gov (United States)

    Kegel, Victoria; Pfeiffer, Elisa; Burkhardt, Britta; Liu, Jia L.; Zeilinger, Katrin; Nüssler, Andreas K.; Seehofer, Daniel; Damm, Georg

    2015-01-01

    Drug induced liver injury (DILI) is an idiosyncratic adverse drug reaction leading to severe liver damage. Kupffer cells (KC) sense hepatic tissue stress/damage and therefore could be a tool for the estimation of consequent effects associated with DILI. Aim of the present study was to establish a human in vitro liver model for the investigation of immune-mediated signaling in the pathogenesis of DILI. Hepatocytes and KC were isolated from human liver specimens. The isolated KC yield was 1.2 ± 0.9 × 106 cells/g liver tissue with a purity of >80%. KC activation was investigated by the measurement of reactive oxygen intermediates (ROI, DCF assay) and cell activity (XTT assay). The initial KC activation levels showed broad donor variability. Additional activation of KC using supernatants of hepatocytes treated with hepatotoxic drugs increased KC activity and led to donor-dependent changes in the formation of ROI compared to KC incubated with supernatants from untreated hepatocytes. Additionally, a compound- and donor-dependent increase in proinflammatory cytokines or in anti-inflammatory cytokines was detected. In conclusion, KC related immune signaling in hepatotoxicity was successfully determined in a newly established in vitro liver model. KC were able to detect hepatocyte stress/damage and to transmit a donor- and compound-dependent immune response via cytokine production. PMID:26491234

  4. Effects of Spray-Drying and Choice of Solid Carriers on Concentrations of Labrasol® and Transcutol® in Solid Self-Microemulsifying Drug Delivery Systems (SMEDDS

    Directory of Open Access Journals (Sweden)

    Christopher Wai-Kei Lam

    2013-01-01

    Full Text Available Solid self-microemulsifying drug delivery systems (SMEDDS have been used increasingly for improving the bioavailability of hydrophobic drugs. Labrasol® and Transcutol® are used widely as surfactant and solubilizer in the formulation of solid SMEDDS. We investigated the effects of spray-drying and the use of different solid carriers on concentrations of Labrasol® and Transcutol® in solid SMEDDS with scutellarin as the formulated drug. Liquid and gas chromatography tandem mass spectrometry (LC-MS and GC-MS methods were developed for measuring low concentrations of Labrasol® and Transcutol®. In the preparation of solid SMEDDS, lactose, hydroxypropylmethyl cellulose (HPMC and microcrystalline cellulose (MCC were used as solid carriers. Judging from the retention ratios of Labrasol® and Transcutol®, the droplet size of solid SMEDDS increased after spray-drying of liquid SMEDDS, and concentrations of these excipients decreased after the solidifying procedure. In such reduction, Lactose and HPMC were found to preserve Labrasol® and Transcutol® better than MCC during spray-drying, and the resultant droplet sizes were smaller than that of MCC. Labrasol® and Transcutol® showed good thermal stability at 60 °C degree for 10 days. It can be concluded that spray-drying could increase the droplet size of solid SMEDDS and decreased the concentration of Labrasol® and Transcutol® therein, while water-soluble solid carriers could preserve Labrasol® and Transcutol® better than insoluble carriers in the solid SMEDDS.

  5. Drug adsorption to plastic containers and retention of drugs in cultured cells under in vitro conditions.

    Science.gov (United States)

    Palmgrén, Joni J; Mönkkönen, Jukka; Korjamo, Timo; Hassinen, Anssi; Auriola, Seppo

    2006-11-01

    Loss of drug content during cell culture transport experiment can lead to misinterpretations in permeability analysis. This study analyses drug adsorption to various plastic containers and drug retention in cultured cells under in vitro conditions. The loss of various drugs to polystyrene tubes and well plates was compared to polypropylene and glass tubes both in deionised water and buffer solution. In cellular uptake experiments, administered drugs were obtained from cultured cells by liquid extraction. Samples were collected at various time points and drug concentrations were measured by a new HPLC-MS/MS method. Acidic drugs (hydrochlorothiazide, naproxen, probenicid, and indomethacin) showed little if any sorption to all tested materials in either water or buffer. In the case of basic drugs, substantial loss to polystyrene tubes and well plates was observed. After 4.5 h, the relative amount remaining in aqueous test solution stored in polystyrene tubes was 64.7 +/- 6.8%, 38.4 +/- 9.1%, 31.9 +/- 6.7%, and 23.5 +/- 6.1% for metoprolol, medetomidine, propranolol, and midazolam, respectively. Interestingly, there was no significant loss of drugs dissolved in buffer to any of the tested materials indicating that buffer reduced surficial interaction. The effect of drug concentration to sorption was also tested. Results indicated that the higher the concentration in the test solution the lower the proportional drug loss, suggesting that the polystyrene contained a limited amount of binding sites. Cellular uptake studies showed considerable retention of drugs in cultured cells. The amounts of absorbed drugs in cellular structures were 0.45%, 4.88%, 13.15%, 43.80%, 23.57% and 11.22% for atenolol, metoprolol, medetomidine, propranolol, midazolam, and diazepam, respectively. Overall, these findings will benefit development and validation of further in vitro drug permeation experiments.

  6. Human drug metabolism: an introduction

    National Research Council Canada - National Science Library

    Coleman, Michael D

    2010-01-01

    ... metabolism and its impact on patient welfare. After underlining the relationship between efficacy, toxicity and drug concentration, the book then considers how metabolizing systems operate and how they impact upon drug concentration...

  7. Intracellular Drug Bioavailability: Effect of Neutral Lipids and Phospholipids.

    Science.gov (United States)

    Treyer, Andrea; Mateus, André; Wiśniewski, Jacek R; Boriss, Hinnerk; Matsson, Pär; Artursson, Per

    2018-06-04

    Intracellular unbound drug concentrations are the pharmacologically relevant concentrations for targets inside cells. Intracellular drug concentrations are determined by multiple processes, including the extent of drug binding to intracellular structures. The aim of this study was to evaluate the effect of neutral lipid (NL) and phospholipid (PL) levels on intracellular drug disposition. The NL and/or PL content of 3T3-L1 cells were enhanced, resulting in phenotypes (in terms of morphology and proteome) reminiscent of adipocytes (high NL and PL) or mild phospholipidosis (only high PL). Intracellular bioavailability ( F ic ) was then determined for 23 drugs in these cellular models and in untreated wild-type cells. A higher PL content led to higher intracellular drug binding and a lower F ic . The induction of NL did not further increase drug binding but led to altered F ic due to increased lysosomal pH. Further, there was a good correlation between binding to beads coated with pure PL and intracellular drug binding. In conclusion, our results suggest that PL content is a major determinant of drug binding in cells and that PL beads may constitute a simple alternative to estimating this parameter. Further, the presence of massive amounts of intracellular NLs did not influence drug binding significantly.

  8. Higher Education

    Science.gov (United States)

    & Development (LDRD) National Security Education Center (NSEC) Office of Science Programs Richard P Databases National Security Education Center (NSEC) Center for Nonlinear Studies Engineering Institute Scholarships STEM Education Programs Teachers (K-12) Students (K-12) Higher Education Regional Education

  9. Administration of the non-steroidal anti-inflammatory drug ibuprofen increases macrophage concentrations but reduces necrosis during modified muscle use

    Science.gov (United States)

    Cheung, E. V.; Tidball, J. G.

    2003-01-01

    OBJECTIVE: To test the hypothesis that ibuprofen administration during modified muscle use reduces muscle necrosis and invasion by select myeloid cell populations. METHODS: Rats were subjected to hindlimb unloading for 10 days, after which they experienced muscle reloading by normal weight-bearing to induce muscle inflammation and necrosis. Some animals received ibuprofen by intraperitoneal injection 8 h prior to the onset of muscle reloading, and then again at 8 and 16 h following the onset of reloading. Other animals received buffer injection at 8 h prior to reloading and then ibuprofen at 8 and 16 h following the onset of reloading. Control animals received buffer only at each time point. Quantitative immunohistochemical analysis was used to assess the presence of necrotic muscle fibers, total inflammatory infiltrate, neutrophils, ED1+ macrophages and ED2+ macrophages at 24 h following the onset of reloading. RESULT: Administration of ibuprofen beginning 8 h prior to reloading caused significant reduction in the concentration of necrotic fibers, but increased the concentration of inflammatory cells in muscle. The increase in inflammatory cells was attributable to a 2.6-fold increase in the concentration of ED2+ macrophages. Animals treated with ibuprofen 8 h following the onset of reloading showed no decrease in muscle necrosis or increase in ED2+ macrophage concentrations. CONCLUSION: Administration of ibuprofen prior to increased muscle loading reduces muscle damage, but increases the concentration of macrophages that express the ED2 antigen. The increase in ED2+ macrophage concentration and decrease in necrosis may be mechanistically related because ED2+ macrophages have been associated with muscle regeneration and repair.

  10. Drug Facts

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    Full Text Available ... Why Is It So Hard to Quit Drugs? Effects of Drugs Drug Use and Other People Drug ... Unborn Children Drug Use and Your Health Other Effects on the Body Drug Use Hurts Brains Drug ...

  11. Modeling the drug transport in the anterior segment of the eye.

    Science.gov (United States)

    Avtar, Ram; Tandon, Deepti

    2008-10-02

    The aim of the present work is the development of a simple mathematical model for the time course concentration profile of topically administered drugs in the anterior chamber aqueous humor and investigation of the effects of various model parameters on the aqueous humor concentration of lipophilic and hydrophilic drugs. A simple pharmacokinetic model for the transient drug transport in the anterior segment has been developed by using the conservation of mass in the precorneal tear film, Fick's law of diffusion and Michaelis-Menten kinetics of drug metabolism in cornea, and the conservation of mass in the anterior chamber. An analytical solution describing the drug concentration in the anterior chamber has been obtained. The model predicts that an increase in the drug metabolic (consumption) rate in the corneal epithelium reduces the drug concentration in the anterior chamber for both lipophilic and hydrophilic molecules. A decrease in the clearance rate and distribution volume of the drug in the anterior chamber raises the aqueous humor concentration significantly. It is also observed that decay rate of drug concentration in the anterior chamber is higher for lipophilic molecules than that for hydrophilic molecules. The bioavailability of drugs applied topically to the eye may be improved by a rise in the precorneal tear volume, diffusion coefficient in corneal epithelium and distribution coefficient across the endothelium anterior chamber interface, and by reducing the drug metabolism, drug clearance rate and distribution volume in anterior chamber.

  12. Indian women with higher serum concentrations of folate and vitamin B12 are significantly less likely to be infected with carcinogenic or high-risk (HR types of human papillomaviruses (HPVs

    Directory of Open Access Journals (Sweden)

    Chandrika J Piyathilake

    2010-01-01

    , type of fuel used for cooking and smoking status.Results: Women with higher concentrations of serum folate (>6 ng/mL and vitamin B12 (>356 pg/mL were at lower risk of being positive for HR-HPVs compared to those with serum folate ≤6 ng/mL and serum vitamin B12 ≤ 356 pg/mL (odds ratio = 0.26; 95% confidence interval: 0.08–0.89; P = 0.03.Conclusions: These results demonstrated that improving folate and vitamin B12 status in Indian women may have a beneficial impact on the prevention of CC. Micronutrient based interventions for control of HR-HPV infections may represent feasible alternatives to vaccine based approaches to HPV disease prevention, which are currently unaffordable for use in resource limited areas in rural India.Keywords: folate, vitamin B12, human papillomavirus, cervical cancer

  13. In vitro killing of Escherichia coli, Staphylococcus pseudintermedius and Pseudomonas aeruginosa by enrofloxacin in combination with its active metabolite ciprofloxacin using clinically relevant drug concentrations in the dog and cat.

    Science.gov (United States)

    Blondeau, J M; Borsos, S; Blondeau, L D; Blondeau, B J

    2012-03-23

    Enrofloxacin is a fluoroquinolone antibacterial agent used to treat infections in companion animals. Enrofloxacin's antimicrobial spectrum includes Gram positive and Gram-negative bacteria and demonstrates concentration-dependent bacteriocidal activity. In dogs and cats, enrofloxacin is partially metabolized to ciprofloxacin and both active agents circulate simultaneously in treated animals at ratios of approximately 60-70% enrofloxacin to 30-40% ciprofloxacin. We were interested in determining the killing of companion animal isolates of Escherichia coli, Staphylococcus pseudintermedius and Pseudomonas aeruginosa by enrofloxacin and ciprofloxacin combined using clinically relevant drug concentrations and ratios. For E. coli isolates exposed to 2.1 and 4.1μg/ml of enrofloxacin/ciprofloxacin at 50:50, 60:40 and 70:30 ratios, a 1.7-2.5log(10) reduction (94-99% kill) was seen following 20min of drug exposure; 0.89-1.7log(10) (92-99% kill) of S. pseudintermedius following 180min of drug exposure; 0.85-3.4log(10) (98-99% kill) of P. aeruginosa following 15min of drug exposure. Killing of S. pseudintermedius was enhanced in the presence of enrofloxacin whereas killing of P. aeruginosa was enhanced in the presence of ciprofloxacin. Antagonism was not seen when enrofloxacin and ciprofloxacin were used in kill assays. The unique feature of partial metabolism of enrofloxacin to ciprofloxacin expands the spectrum of enhanced killing of common companion animal pathogens. Copyright © 2011 Elsevier B.V. All rights reserved.

  14. Polymorphism 1936A > G in the AKAP10 gene (encoding A-kinase-anchoring protein 10) is associated with higher cholesterol cord blood concentration in Polish full-term newsborns.

    Science.gov (United States)

    Łoniewska, Beata; Kaczmarczyk, Mariusz; Clark, Jeremy Simon; Kordek, Agnieszka; Ciechanowicz, Andrzej

    2013-03-01

    A-Kinase anchoring proteins (AKAPs) coordinate the specificity of protein kinase A signaling by localizing the kinase to subcellular sites. The 1936G (V646) AKAP10 allele has been associated with adults with low cholinergic/vagus nerve sensitivity and with newborns with increased blood pressure. Decreased activity of the parasympathetic system is associated with risk of metabolic syndrome. The aim of this study was to answer the question of whether 1936A > G AKAP10 polymorphism is associated with metabolic changes in full-term newborns that are predictive factors for the metabolic phenotype in adulthood. The study included 114 consecutive healthy Polish newborns born after the end of the 37 th week of gestation to healthy women with uncomplicated pregnancies. At birth, cord blood of neonates was obtained for isolation of genomic DNA and cholesterol as well as triglyceride concentration. The cholesterol level in homozygotes GG was significantly higher than that in 1936A variant carriers (AG + AA, recessive mode of inheritance). Our results demonstrate a possible association between the 1936G AKAP10 variant and the total cholesterol level in the cord blood of the Polish newborn population.

  15. Concentrations of trimethoprim and sulphadoxine in tissues from goats and a cow

    International Nuclear Information System (INIS)

    Nielsen, P.; Rasmussen, F.

    1975-01-01

    The concentration of trimethoprim and sulphadoxine in plasma and tissue from goats and a cow have been determined after a single intravenous injection. Furthermore, the concentration of the two drugs and their metabolites in plasma and tissues have been determined after continuous intravenous infusion for 2 1/2 - 3 hrs. Trimethoprim was present in all tissues but brain at higher concentrations than in plasma while the concentration of sulphadoxine in the different tissues were lower than in plasma. The highest concentration of the 2 drugs and their metabolites was found in the kidney. The distribution pattern of trimethoprim and sulphadoxine was similar in cow and goats. (author)

  16. Concentrations of trimethoprim and sulphadoxine in tissues from goats and a cow

    Energy Technology Data Exchange (ETDEWEB)

    Nielsen, P; Rasmussen, F [Kongelige Veterinaer- og Landbohoejskole, Copenhagen (Denmark)

    1975-01-01

    The concentration of trimethoprim and sulphadoxine in plasma and tissue from goats and a cow have been determined after a single intravenous injection. Furthermore, the concentration of the two drugs and their metabolites in plasma and tissues have been determined after continuous intravenous infusion for 2 1/2 - 3 hrs. Trimethoprim was present in all tissues but brain at higher concentrations than in plasma while the concentration of sulphadoxine in the different tissues were lower than in plasma. The highest concentration of the 2 drugs and their metabolites was found in the kidney. The distribution pattern of trimethoprim and sulphadoxine was similar in cow and goats.

  17. Higher Education.

    Science.gov (United States)

    Hendrickson, Robert M.

    This chapter reports 1982 cases involving aspects of higher education. Interesting cases noted dealt with the federal government's authority to regulate state employees' retirement and raised the questions of whether Title IX covers employment, whether financial aid makes a college a program under Title IX, and whether sex segregated mortality…

  18. Production of human metabolites by gastrointestinal bacteria as a potential source of post-mortem alteration of antemortem drug/metabolite concentrations.

    Science.gov (United States)

    Martindale, Stephanie M; Powers, Robert H; Bell, Suzanne C

    2015-01-01

    Previous studies have demonstrated that bacterial species are capable of transforming complex chemical substances. Several of these species, native to the human gastrointestinal tract, are active in postmortem decomposition. They have potential to cause biotransformations affecting compound-to-metabolite ratios within the human body, especially after death. Investigation of postmortem effects could supply valuable information, especially concerning compound identification and confirmation. The purpose of this research was to investigate the effects of Escherichia coli, Bacteroides fragilis, and Clostridium perfringens on diazepam and flunitrazepam in Reinforced Clostridial Medium, and to compare bacterial biotransformation products to those of human metabolism. A decrease in diazepam concentration between pre- and post-incubation was observed for samples inoculated with Escherichia coli (14.7-20.2%) as well as Bacteroides fragilis (13.9-25.7%); however there was no corresponding increase in concentration for the monitored human metabolites. Flunitrazepam demonstrated a greater concentration loss when incubated with individual bacterial species as well as mixed culture (79.2-100.0%). Samples incubated with Bacteroides fragilis, Clostridium perfringens, and mixed culture resulted in nearly complete conversion of flunitrazepam. Increased 7-aminoflunitrazepam concentrations accounted for the majority of the conversion; however discrepancies in the mass balance of the reaction suggested the possibility of a minor metabolite that was not monitored in the current analysis. These experiments served as a pilot study and proof of concept that can be adapted and applied to a realm of possibilities. Ultimately, this methodology would be ideal to study compounds that are too toxic or lethal for animal and human metabolic investigations. Copyright © 2014 John Wiley & Sons, Ltd.

  19. Effect of paracentesis on ocular cloxacillin concentration

    International Nuclear Information System (INIS)

    Salminen, L.

    1978-01-01

    The effect of interior chamber puncture on cloxacillin concentration in the rabbit eye after intravenous injection was studied using a radioactive tracer method. The enhancement in drug concentration caused by paracentesis was most immediate and significant in the iris-ciliary body preparation. It was soon followed by high cloxacillin concentration in the aqueous humour, which contributed to elevated cloxacillin levels in the cornea, lens and anterior vitreous body, when compared to normal material. Contrary to normal eyes, cloxacillin concentration in the cornea of the punctured eyes was higher than in the limbal area. The morphological changes occurring after paracentesis are discussed. The breakdown of the hydrodynamic equilibrium in the eye, suggested as the only change after paracentesis by Raviola (1974), cannot merely explain the cloxacillin concentration changes measured in the punctured eye. (author)

  20. Study on drug resistance of mycobacterium tuberculosis in patients with pulmonary tuberculosis by drug resistance gene detecting

    International Nuclear Information System (INIS)

    Wang Wei; Li Hongmin; Wu Xueqiong; Wang Ansheng; Ye Yixiu; Wang Zhongyuan; Liu Jinwei; Chen Hongbing; Lin Minggui; Wang Jinhe; Li Sumei; Jiang Ping; Feng Bai; Chen Dongjing

    2004-01-01

    To investigate drug resistance of mycobacterium tuberculosis in different age group, compare detecting effect of two methods and evaluate their the clinical application value, all of the strains of mycobacterium tuberculosis were tested for resistance to RFP, INH SM PZA and EMB by the absolute concentration method on Lowenstein-Jensen medium and the mutation of the rpoB, katG, rpsL, pncA and embB resistance genes in M. tuberculosis was tested by PCR-SSCP. In youth, middle and old age group, the rate of acquired drug resistance was 89.2%, 85.3% and 67.6% respectively, the gene mutation rate was 76.2%, 81.3% and 63.2% respectively. The rate of acquired drug resistance and multiple drug resistance in youth group was much higher than those in other groups. The gene mutation was correlated with drug resistance level of mycobacterium tuberculosis. The gene mutation rate was higher in strains isolated from high concentration resistance than those in strains isolated from low concentration resistance. The more irregular treatment was longer, the rate of drug resistance was higher. Acquired drug resistance varies in different age group. It suggested that surveillance of drug resistence in different age group should be taken seriously, especially in youth group. PCR - SSCP is a sensitive and specific method for rapid detecting rpoB, katG, rpsL, pncA and embB genes mutations of MTB. (authors)

  1. Drug Facts

    Medline Plus

    Full Text Available ... Get Addicted to Drugs? Does Addiction Run in Families? Why Is It So Hard to Quit Drugs? ... Drug Use and Other People Drug Use and Families Drug Use and Kids Drug Use and Unborn ...

  2. Drug Facts

    Medline Plus

    Full Text Available ... Facts Search form Search Menu Home Drugs That People Abuse Alcohol Facts Bath Salts Facts Cocaine (Coke, ... Drugs? Effects of Drugs Drug Use and Other People Drug Use and Families Drug Use and Kids ...

  3. Drug Facts

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    Full Text Available ... People Drug Use and Families Drug Use and Kids Drug Use and Unborn Children Drug Use and ... Children and Teens Stay Drug-Free Talking to Kids About Drugs: What to Say if You Used ...

  4. Effect of vitamin D3, other drugs altering serum calcium or phosphorus concentrations, and desoxycorticosterone on the distribution of Tc-99m pyrophosphate between target and nontarget tissues

    International Nuclear Information System (INIS)

    Carr, E.A. Jr.; Carroll, M.; Montes, M.

    1981-01-01

    Radioactive imaging agents are chemically designed for selective distribution. Another approach to selectivity is to find stable compounds that favorably influence this distribution. Using a rat model of myocardial necrosis, we studied effects of various stable compounds (as a single, large dose or fractionated into short series) on the ratio, uptake of Tc-99m pyrophosphate (PPi) by the target lesion/uptake by the principal nontarget, bone (L/B). Vitamin D3s ability to increase L/B was mediated by the hypercalcemia and hyperphosphatemia that it caused. The hypercalcemia was accompanied by increased [Ca] in the lesion. In contrast, pulse doses of desoxycorticosterone acetate (DOCA) at 7 and 6 hr before killing increased uptake by lesion, increasing L/B from 0.19 +/- 0.03 to 0.45 +/- 0.08 (p less than 0.01), with no change in serum [Ca] and minimal changes in serum [P], [Na], and [K]. DOCA also increased the lesion-to-blood ratio from 6.5 +/- 0.07 to 15.4 +/- 3.9 (p less than 0.05). These results encourage further study of DOCA's effect and investigation of other stable drugs that may influence distribution of other imaging agents

  5. Effect of the anticarcinogenic drug 6-mercaptopurine on mineral metabolism

    International Nuclear Information System (INIS)

    Amemiya, K.

    1987-01-01

    The effect of 6-mercaptopurine (6-MP) on mineral metabolism was investigated using rats and mice. A single 6-mercaptopurine injection in pregnant rats on day 11 of gestation proved to be highly teratogenic. At term, fetuses from 6-MP injected dams had lower livers zinc concentrations than non-injected or vehicle injected controls while dams showed no differences in liver zinc. Fetuses from dams injected with 6-MP and fed supplemental levels of zinc had a lower frequency of malformations and had higher hepatic zinc concentrations than fetuses from dams fed less zinc with drug injection. Non-pregnant mice injected with 6-MP had higher zinc concentrations compared to controls. In addition, iron, copper and calcium concentrations were higher in the livers of 6-MP injected mice than in controls, indicating that the drug affected several elements. Hepatic concentrations of metallothionein (MT) were also elevated in 6-MP injected mice, suggesting that the change in zinc concentrations associated with drug administration was the result of a drug induction of MT. Dams injected with 6-MP on day 13 of pregnancy had livers which retained more of an absorbed dose of 65 zinc than non-injected dams. Plasma from these drug injected dams also retained less of the absorbed dose than control dams. In contrast, day 14 from dams injected with 6-MP, retained less of an absorbed dose than control embryos

  6. Hydrophobic Drug-Loaded PEGylated Magnetic Liposomes for Drug-Controlled Release

    Science.gov (United States)

    Hardiansyah, Andri; Yang, Ming-Chien; Liu, Ting-Yu; Kuo, Chih-Yu; Huang, Li-Ying; Chan, Tzu-Yi

    2017-05-01

    Less targeted and limited solubility of hydrophobic-based drug are one of the serious obstacles in drug delivery system. Thus, new strategies to enhance the solubility of hydrophobic drug and controlled release behaviors would be developed. Herein, curcumin, a model of hydrophobic drug, has been loaded into PEGylated magnetic liposomes as a drug carrier platform for drug controlled release system. Inductive magnetic heating (hyperthermia)-stimulated drug release, in vitro cellular cytotoxicity assay of curcumin-loaded PEGylated magnetic liposomes and cellular internalization-induced by magnetic guidance would be investigated. The resultant of drug carriers could disperse homogeneously in aqueous solution, showing a superparamagnetic characteristic and could inductive magnetic heating with external high-frequency magnetic field (HFMF). In vitro curcumin release studies confirmed that the drug carriers exhibited no significant release at 37 °C, whereas exhibited rapid releasing at 45 °C. However, it would display enormous (three times higher) curcumin releasing under the HFMF exposure, compared with that without HFMF exposure at 45 °C. In vitro cytotoxicity test shows that curcumin-loaded PEGylated magnetic liposomes could efficiently kill MCF-7 cells in parallel with increasing curcumin concentration. Fluorescence microscopy observed that these drug carriers could internalize efficiently into the cellular compartment of MCF-7 cells. Thus, it would be anticipated that the novel hydrophobic drug-loaded PEGylated magnetic liposomes in combination with inductive magnetic heating are promising to apply in the combination of chemotherapy and thermotherapy for cancer therapy.

  7. Reference Brain/Blood Concentrations of Citalopram, Duloxetine, Mirtazapine and Sertraline

    DEFF Research Database (Denmark)

    Nedahl, Michael; Johansen, Sys Stybe; Linnet, Kristian

    2018-01-01

    Postmortem blood samples may not accurately reflect antemortem drug concentrations, as the levels of some drugs increase due to postmortem redistribution (PMR). The brain has been suggested as an alternative sampling site. The anatomically secluded site of the brain limits redistribution and prol.......85), whereas the median citalopram/N-desmethylcitalopram ratio was higher in brain (9.1) than blood (4.1). The results of this study may serve as reference concentrations in brain for forensic cases....

  8. Drug: D08821 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available D08821 Drug Concentrated human red blood cells; Red cells concentrates -leukocytes... reduced (RCC-LR) (TN); Irradiated red cells concentrates -leukocytes reduced (Ir-RCC-LR) (TN) ... PubChem: 96025504 ...

  9. Higher risk of incident hepatitis C virus among young women who inject drugs compared with young men in association with sexual relationships: a prospective analysis from the UFO Study cohort.

    Science.gov (United States)

    Tracy, Daniel; Hahn, Judith A; Fuller Lewis, Crystal; Evans, Jennifer; Briceño, Alya; Morris, Meghan D; Lum, Paula J; Page, Kimberly

    2014-05-29

    Female injection drug users (IDUs) may report differences in injection behaviours that put them at greater risk for hepatitis C virus (HCV). Few studies have examined these in association with HCV incidence. Longitudinal data from a cohort of 417 HCV-uninfected IDU aged 30 or younger were analysed. Cox proportional hazards was used to model female sex as a predictor of new HCV infection. General estimating equation (GEE) analysis was used to model female sex as a predictor of HCV-associated risk behaviour prospectively. Women were significantly more likely than men to become infected with HCV during study follow-up (HR 1.4, p<0.05), and were also more likely than men to report high-risk injecting behaviours, especially in the context of sexual and injecting relationships. Sex differences in injecting behaviours appeared to explain the relationship between sex and HCV infection. Young women's riskier injection practices lead to their higher rates of HCV infection. Further study on the impact of intimate partnership on women's risk behaviour is warranted. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

  10. Characteristics and Service Use of Medicaid Buy-In Participants with Higher Incomes: A Descriptive Analysis

    OpenAIRE

    Denise Hoffman; Kristin Andrews; Valerie Cheh

    2013-01-01

    This study examined the characteristics and service use of Medicaid Buy-In participants with higher incomes (above 250 percent of the federal poverty line), relative to participants with lower incomes. The study found higher-income participants were less likely to enroll in Medicare and more likely to be enrolled in third-party insurance. Service use for higher-income Buy-In participants concentrated on prescription drugs and durable medical equipment, and Medicaid expenditures for a selected...

  11. Drug Facts

    Medline Plus

    Full Text Available ... Treatment and Recovery Resources? Prevention Help Children and Teens Stay Drug-Free Talking to Kids About Drugs: What to Say if You Used Drugs in the Past Drug Use ... Videos Information About Drugs Alcohol ...

  12. Drug Allergy

    Science.gov (United States)

    ... Loss of consciousness Other conditions resulting from drug allergy Less common drug allergy reactions occur days or ... you take the drug. Drugs commonly linked to allergies Although any drug can cause an allergic reaction, ...

  13. Effects of low concentrations of Regorafenib and Sorafenib on human HCC cell AFP, migration, invasion and growth in vitro

    Science.gov (United States)

    Carr, Brian Irving; D’Alessandro, Rosalba; Refolo, Maria Grazia; Iacovazzi, Palma Aurelia; Lippolis, Catia; Messa, Caterina; Cavallini, Aldo; Correale, Mario; Di Carlo, Antonio

    2012-01-01

    Sorafenib was shown in clinical trial to enhance survival in hepatocellular carcinoma (HCC) patients, but with minimal tumor shrinkage. To correlate several indices of HCC growth at various drug concentrations, HCC cells were grown in various low concentrations of two multi-kinase inhibitors, Regorafenib (Stivarga) and Sorafenib (Nexavar) and their effects were examined on alpha-fetoprotein (AFP), cell growth, migration and invasion. In two AFP positive human HCC cell lines, AFP was inhibited at 0.1–1µM drug concentrations. Cell migration and invasion were also inhibited at similar low drug concentrations. However, 10-fold higher drug concentrations were required to inhibit cell growth in both AFP positive and negative cells. To investigate this concentration discrepancy of effects, cells were then grown for prolonged times and sub-cultured in low drug concentrations and then their growth was re-tested. The growth in these drug-exposed cells was found to be slower than cells without prior drug exposure and they were also more sensitive to subsequent drug challenge. Evidence was also found for changes in cell signaling pathways in these slow-growth cells. Low multi-kinase inhibitor concentrations thus modulate several aspects of HCC cell biology. PMID:23169148

  14. Drug-Target Kinetics in Drug Discovery.

    Science.gov (United States)

    Tonge, Peter J

    2018-01-17

    The development of therapies for the treatment of neurological cancer faces a number of major challenges including the synthesis of small molecule agents that can penetrate the blood-brain barrier (BBB). Given the likelihood that in many cases drug exposure will be lower in the CNS than in systemic circulation, it follows that strategies should be employed that can sustain target engagement at low drug concentration. Time dependent target occupancy is a function of both the drug and target concentration as well as the thermodynamic and kinetic parameters that describe the binding reaction coordinate, and sustained target occupancy can be achieved through structural modifications that increase target (re)binding and/or that decrease the rate of drug dissociation. The discovery and deployment of compounds with optimized kinetic effects requires information on the structure-kinetic relationships that modulate the kinetics of binding, and the molecular factors that control the translation of drug-target kinetics to time-dependent drug activity in the disease state. This Review first introduces the potential benefits of drug-target kinetics, such as the ability to delineate both thermodynamic and kinetic selectivity, and then describes factors, such as target vulnerability, that impact the utility of kinetic selectivity. The Review concludes with a description of a mechanistic PK/PD model that integrates drug-target kinetics into predictions of drug activity.

  15. Concentrated Ownership

    DEFF Research Database (Denmark)

    Rose, Caspar

    2014-01-01

    This entry summarizes the main theoretical contributions and empirical findings in relation to concentrated ownership from a law and economics perspective. The various forms of concentrated ownership are described as well as analyzed from the perspective of the legal protection of investors......, especially minority shareholders. Concentrated ownership is associated with benefits and costs. Concentrated ownership may reduce agency costs by increased monitoring of top management. However, concentrated ownership may also provide dominating owners with private benefits of control....

  16. Investigations on the viscoelastic performance of pressure sensitive adhesives in drug-in-adhesive type transdermal films.

    Science.gov (United States)

    Wolff, Hans-Michael; Irsan; Dodou, Kalliopi

    2014-08-01

    We aimed to investigate the effect of solubility parameter and drug concentration on the rheological behaviour of drug-in-adhesive films intended for transdermal application. Films were prepared over a range of drug concentrations (5%, 10% and 20% w/w) using ibuprofen, benzoic acid, nicotinic acid and lidocaine as model drugs in acrylic (Duro-Tak 87-4287 and Duro-Tak 87900A) or silicone (Bio-PSA 7-4301 and Bio-PSA 7-4302) pressure sensitive adhesives (PSAs). Saturation status of films was determined using light microscopy. Viscoelastic parameters were measured in rheology tests at 32°C. Subsaturated films had lower viscoelastic moduli whereas saturated films had higher moduli than the placebo films and/or a concentration-dependent increase in their modulus. Saturation concentration of each drug in the films was reflected by decreasing/increasing viscoelastic patterns. The viscoelastic windows (VWs) of the adhesive and drug-in-adhesive films clearly depicted the effect of solubility parameter differences, molar concentration of drug in the adhesive film and differences in PSA chemistry. Drug solubility parameters and molar drug concentrations have an impact on rheological patterns and thus on the adhesive performance of tested pressure sensitive adhesives intended for use in transdermal drug delivery systems. Use of the Flory equation in its limiting form was appropriate to predict drug solubility in the tested formulations.

  17. Elliptical concentrators.

    Science.gov (United States)

    Garcia-Botella, Angel; Fernandez-Balbuena, Antonio Alvarez; Bernabeu, Eusebio

    2006-10-10

    Nonimaging optics is a field devoted to the design of optical components for applications such as solar concentration or illumination. In this field, many different techniques have been used to produce optical devices, including the use of reflective and refractive components or inverse engineering techniques. However, many of these optical components are based on translational symmetries, rotational symmetries, or free-form surfaces. We study a new family of nonimaging concentrators called elliptical concentrators. This new family of concentrators provides new capabilities and can have different configurations, either homofocal or nonhomofocal. Translational and rotational concentrators can be considered as particular cases of elliptical concentrators.

  18. Smart polyelectrolyte microcapsules as carriers for water-soluble small molecular drug.

    Science.gov (United States)

    Song, Weixing; He, Qiang; Möhwald, Helmuth; Yang, Yang; Li, Junbai

    2009-10-15

    Heat treatment is introduced as a simple method for the encapsulation of low molecular weight water-soluble drugs within layer-by-layer assembled microcapsules. A water-soluble drug, procainamide hydrochloride, could thus be encapsulated in large amount and enriched by more than 2 orders of magnitude in the assembled PDADMAC/PSS capsules. The shrunk capsules could control the unloading rate of drugs, and the drugs could be easily unloaded using ultrasonic treatment. The encapsulated amount could be quantitatively controlled via the drug concentration in the bulk. We also found that smaller capsules possess higher encapsulation capability.

  19. Drug Safety

    Science.gov (United States)

    ... 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 ...

  20. Drug Abuse

    Science.gov (United States)

    ... Cocaine Heroin Inhalants Marijuana Prescription drugs, including opioids Drug abuse also plays a role in many major social problems, such as drugged driving, violence, stress, and child abuse. Drug abuse can lead to ...

  1. Drug Facts

    Medline Plus

    Full Text Available ... Use and Unborn Children Drug Use and Your Health Other Effects on the Body Drug Use Hurts Brains Drug Use and Mental Health Problems Often Happen Together The Link Between Drug ...

  2. Drug Facts

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    Full Text Available ... Drug Use and Kids Drug Use and Unborn Children Drug Use and Your Health Other Effects on ... Someone Find Treatment and Recovery Resources? Prevention Help Children and Teens Stay Drug-Free Talking to Kids ...

  3. Club Drugs

    Science.gov (United States)

    ... uses. Other uses of these drugs are abuse. Club drugs are also sometimes used as "date rape" drugs, to make someone unable to say no to or fight back against sexual assault. Abusing these drugs can ...

  4. Concentration risk

    Directory of Open Access Journals (Sweden)

    Matić Vesna

    2016-01-01

    Full Text Available Concentration risk has been gaining a special dimension in the contemporary financial and economic environment. Financial institutions are exposed to this risk mainly in the field of lending, mostly through their credit activities and concentration of credit portfolios. This refers to the concentration of different exposures within a single risk category (credit risk, market risk, operational risk, liquidity risk.

  5. Local drug delivery - the early Berlin experience: single drug administration versus sustained release.

    Science.gov (United States)

    Speck, Ulrich; Scheller, Bruno; Rutsch, Wolfgang; Laule, Michael; Stangl, Verena

    2011-05-01

    Our initial investigations into restenosis inhibition by local drug delivery were prompted by reports on an improved outcome of coronary interventions, including a lower rate of target lesion revascularisation, when the intervention was performed with an ionic instead of non-ionic contrast medium. Although this was not confirmed in an animal study, the short exposure of the vessel wall to paclitaxel dissolved in contrast agent or coated on balloons proved to be efficacious. A study comparing three methods of local drug delivery to the coronary artery in pigs indicated the following order of efficacy in inhibiting neointimal proliferation: paclitaxel-coated balloons > sirolimus-eluting stents, sustained drug release > paclitaxel in contrast medium. Cell culture experiments confirmed that cell proliferation can be inhibited by very short exposure to the drug. Shorter exposure times require higher drug concentrations. Effective paclitaxel concentrations in porcine arteries are achieved when the drug is dissolved in contrast medium or coated on balloons. Paclitaxel is an exceptional drug in that it stays in the treated tissue for a long time. This may explain the long-lasting efficacy of paclitaxel-coated balloons, but does not disprove the hypothesis that the agent blocks a process initiating long-lasting excessive neointimal proliferation, which occurs early after vessel injury.

  6. Concentrator Photovoltaics

    CERN Document Server

    Luque, Antonio L

    2007-01-01

    Photovoltaic solar-energy conversion is one of the most promising technologies for generating renewable energy, and conversion of concentrated sunlight can lead to reduced cost for solar electricity. In fact, photovoltaic conversion of concentrated sunlight insures an efficient and cost-effective sustainable power resource. This book gives an overview of all components, e.g. cells, concentrators, modules and systems, for systems of concentrator photovoltaics. The authors report on significant results related to design, technology, and applications, and also cover the fundamental physics and market considerations. Specific contributions include: theory and practice of sunlight concentrators; an overview of concentrator PV activities; a description of concentrator solar cells; design and technology of modules and systems; manufacturing aspects; and a market study.

  7. Variable Linezolid Exposure in Intensive Care Unit Patients-Possible Role of Drug-Drug Interactions.

    Science.gov (United States)

    Töpper, Christoph; Steinbach, Cathérine L; Dorn, Christoph; Kratzer, Alexander; Wicha, Sebastian G; Schleibinger, Michael; Liebchen, Uwe; Kees, Frieder; Salzberger, Bernd; Kees, Martin G

    2016-10-01

    Standard doses of linezolid may not be suitable for all patient groups. Intensive care unit (ICU) patients in particular may be at risk of inadequate concentrations. This study investigated variability of drug exposure and its potential sources in this population. Plasma concentrations of linezolid were determined by high-performance liquid chromatography in a convenience sample of 20 ICU patients treated with intravenous linezolid 600 mg twice daily. Ultrafiltration applying physiological conditions (pH 7.4/37°C) was used to determine the unbound fraction. Individual pharmacokinetic (PK) parameters were estimated by population PK modeling. As measures of exposure to linezolid, area under the concentration-time curve (AUC) and trough concentrations (Cmin) were calculated and compared with published therapeutic ranges (AUC 200-400 mg*h/L, Cmin 2-10 mg/L). Coadministered inhibitors or inducers of cytochrome P450 and/or P-glycoprotein were noted. Data from 18 patients were included into the PK evaluation. Drug exposure was highly variable (median, range: AUC 185, 48-618 mg*h/L, calculated Cmin 2.92, 0.0062-18.9 mg/L), and only a minority of patients had values within the target ranges (6 and 7, respectively). AUC and Cmin were linearly correlated (R = 0.98), and classification of patients (underexposed/within therapeutic range/overexposed) according to AUC or Cmin was concordant in 15 cases. Coadministration of inhibitors was associated with a trend to higher drug exposure, whereas 3 patients treated with levothyroxine showed exceedingly low drug exposure (AUC ∼60 mg*h/L, Cmin linezolid is highly variable and difficult to predict in ICU patients, and therapeutic drug monitoring seems advisable. PK drug-drug interactions might partly be responsible and should be further investigated; protein binding appears to be stable and irrelevant.

  8. Drug allergies

    Science.gov (United States)

    Allergic reaction - drug (medication); Drug hypersensitivity; Medication hypersensitivity ... A drug allergy involves an immune response in the body that produces an allergic reaction to a medicine. The first time ...

  9. Study Drugs

    Science.gov (United States)

    ... to quit, they may have withdrawal symptoms like depression, thoughts of suicide, intense drug cravings, sleep problems, and fatigue. The health risks aren't the only downside to study drugs. Students caught with illegal prescription drugs may get suspended ...

  10. Drug Facts

    Medline Plus

    Full Text Available ... symptoms of someone with a drug use problem? How Does Drug Use Become an Addiction? What Makes Someone More Likely to Get Addicted to Drugs? Does Addiction Run in Families? Why Is It So Hard to ...

  11. Drug Facts

    Medline Plus

    Full Text Available ... Other Effects on the Body Drug Use Hurts Brains Drug Use and Mental Health Problems Often Happen ... to prescription drugs. The addiction slowly took over his life. I need different people around me. To ...

  12. Drug Reactions

    Science.gov (United States)

    ... problem is interactions, which may occur between Two drugs, such as aspirin and blood thinners Drugs and food, such as statins and grapefruit Drugs and supplements, such as ginkgo and blood thinners ...

  13. Drug Facts

    Science.gov (United States)

    ... Makes Someone More Likely to Get Addicted to Drugs? Does Addiction Run in Families? Why Is It So Hard ... the text to you. This website talks about drug abuse, addiction, and treatment. Watch Videos Information About Drugs Alcohol ...

  14. Conical electromagnetic radiation flux concentrator

    Science.gov (United States)

    Miller, E. R.

    1972-01-01

    Concentrator provides method of concentrating a beam of electromagnetic radiation into a smaller beam, presenting a higher flux density. Smaller beam may be made larger by sending radiation through the device in the reverse direction.

  15. Distribution of the anticancer drugs doxorubicin, mitoxantrone and topotecan in tumors and normal tissues.

    Science.gov (United States)

    Patel, Krupa J; Trédan, Olivier; Tannock, Ian F

    2013-07-01

    Pharmacokinetic analyses estimate the mean concentration of drug within a given tissue as a function of time, but do not give information about the spatial distribution of drugs within that tissue. Here, we compare the time-dependent spatial distribution of three anticancer drugs within tumors, heart, kidney, liver and brain. Mice bearing various xenografts were treated with doxorubicin, mitoxantrone or topotecan. At various times after injection, tumors and samples of heart, kidney, liver and brain were excised. Within solid tumors, the distribution of doxorubicin, mitoxantrone and topotecan was limited to perivascular regions at 10 min after administration and the distance from blood vessels at which drug intensity fell to half was ~25-75 μm. Although drug distribution improved after 3 and 24 h, there remained a significant decrease in drug fluorescence with increasing distance from tumor blood vessels. Drug distribution was relatively uniform in the heart, kidney and liver with substantially greater perivascular drug uptake than in tumors. There was significantly higher total drug fluorescence in the liver than in tumors after 10 min, 3 and 24 h. Little to no drug fluorescence was observed in the brain. There are marked differences in the spatial distributions of three anticancer drugs within tumor tissue and normal tissues over time, with greater exposure to most normal tissues and limited drug distribution to many cells in tumors. Studies of the spatial distribution of drugs are required to complement pharmacokinetic data in order to better understand and predict drug effects and toxicities.

  16. Concentrating Radioactivity

    Science.gov (United States)

    Herrmann, Richard A.

    1974-01-01

    By concentrating radioactivity contained on luminous dials, a teacher can make a high reading source for classroom experiments on radiation. The preparation of the source and its uses are described. (DT)

  17. Grapefruit and drug interactions.

    Science.gov (United States)

    2012-12-01

    Since the late 1980s, grapefruit juice has been known to affect the metabolism of certain drugs. Several serious adverse effects involving drug interactions with grapefruit juice have been published in detail. The components of grapefruit juice vary considerably depending on the variety, maturity and origin of the fruit, local climatic conditions, and the manufacturing process. No single component accounts for all observed interactions. Other grapefruit products are also occasionally implicated, including preserves, lyophylised grapefruit juice, powdered whole grapefruit, grapefruit seed extract, and zest. Clinical reports of drug interactions with grapefruit juice are supported by pharmacokinetic studies, each usually involving about 10 healthy volunteers, in which the probable clinical consequences were extrapolated from the observed plasma concentrations. Grapefruit juice inhibits CYP3A4, the cytochrome P450 isoenzyme most often involved in drug metabolism. This increases plasma concentrations of the drugs concerned, creating a risk of overdose and dose-dependent adverse effects. Grapefruit juice also inhibits several other cytochrome P450 isoenzymes, but they are less frequently implicated in interactions with clinical consequences. Drugs interacting with grapefruit and inducing serious clinical consequences (confirmed or very probable) include: immunosuppressants, some statins, benzodiazepines, most calcium channel blockers, indinavir and carbamazepine. There are large inter-individual differences in enzyme efficiency. Along with the variable composition of grapefruit juice, this makes it difficult to predict the magnitude and clinical consequences of drug interactions with grapefruit juice in a given patient. There is increasing evidence that transporter proteins such as organic anion transporters and P-glycoprotein are involved in interactions between drugs and grapefruit juice. In practice, numerous drugs interact with grapefruit juice. Although only a few

  18. Microencapsulation of protein drugs for drug delivery: strategy, preparation, and applications.

    Science.gov (United States)

    Ma, Guanghui

    2014-11-10

    Bio-degradable poly(lactide) (PLA)/poly(lactide-glycolide) (PLGA) and chitosan microspheres (or microcapsules) have important applications in Drug Delivery Systems (DDS) of protein/peptide drugs. By encapsulating protein/peptide drugs in the microspheres, the serum drug concentration can be maintained at a higher constant value for a prolonged time, or injection formulation can be changed to orally or mucosally administered formulation. PLA/PLGA and chitosan are most often used in injection formulation and oral formulation. However, in the preparation and applications of PLA/PLGA and chitosan microspheres containing protein/peptide drugs, the problems of broad size distribution and poor reproducibility of microspheres, and deactivation of protein during the preparation, storage and release, are still big challenges. In this article, the techniques for control of the diameter of microspheres and microcapsules will be introduced at first, then the strategies about how to maintain the bioactivity of protein drugs during preparation and drug release will be reviewed and developed in our research group. The membrane emulsification techniques including direct membrane emulsification and rapid membrane emulsification processes were developed to prepare uniform-sized microspheres, the diameter of microspheres can be controlled from submicron to 100μm by these two processes, and the reproducibility of products can be guaranteed. Furthermore, compared with conventional stirring method, the big advantages of membrane emulsification process were that the uniform microspheres with much higher encapsulation efficiency can be obtained, and the release behavior can be adjusted by selecting microsphere size. Mild membrane emulsification condition also can prevent the deactivation of proteins, which frequently occurred under high shear force in mechanical stirring, sonification, and homogenization methods. The strategies for maintaining the bioactivity of protein drug were

  19. Label-free recognition of drug resistance via impedimetric screening of breast cancer cells.

    Directory of Open Access Journals (Sweden)

    Bilge Eker

    Full Text Available We present a novel study on label-free recognition and distinction of drug resistant breast cancer cells (MCF-7 DOX from their parental cells (MCF-7 WT via impedimetric measurements. Drug resistant cells exhibited significant differences in their dielectric properties compared to wild-type cells, exerting much higher extracellular resistance (Rextra . Immunostaining revealed that MCF-7 DOX cells gained a much denser F-actin network upon acquiring drug resistance indicating that remodeling of actin cytoskeleton is probably the reason behind higher Rextra , providing stronger cell architecture. Moreover, having exposed both cell types to doxorubicin, we were able to distinguish these two phenotypes based on their substantially different drug response. Interestingly, impedimetric measurements identified a concentration-dependent and reversible increase in cell stiffness in the presence of low non-lethal drug doses. Combined with a profound frequency analysis, these findings enabled distinguishing distinct cellular responses during drug exposure within four concentration ranges without using any labeling. Overall, this study highlights the possibility to differentiate drug resistant phenotypes from their parental cells and to assess their drug response by using microelectrodes, offering direct, real-time and noninvasive measurements of cell dependent parameters under drug exposure, hence providing a promising step for personalized medicine applications such as evaluation of the disease progress and optimization of the drug treatment of a patient during chemotherapy.

  20. A REVIEW ON OSMOTIC DRUG DELIVERY SYSTEM

    OpenAIRE

    Harnish Patel; Upendra Patel; Hiren Kadikar; Bhavin Bhimani; Dhiren Daslaniya; Ghanshyam Patel

    2012-01-01

    Conventional oral drug delivery systems supply an instantaneous release of drug, which cannot control the release of the drug and effective concentration at the target site. This kind of dosing pattern may result in constantly changing, unpredictable plasma concentrations. Drugs can be delivered in a controlled pattern over a long period of time by the process of osmosis. Osmotic devices are the most promising strategy based systems for controlled drug delivery. They are the most reliable con...

  1. Vaginal drug distribution modeling.

    Science.gov (United States)

    Katz, David F; Yuan, Andrew; Gao, Yajing

    2015-09-15

    This review presents and applies fundamental mass transport theory describing the diffusion and convection driven mass transport of drugs to the vaginal environment. It considers sources of variability in the predictions of the models. It illustrates use of model predictions of microbicide drug concentration distribution (pharmacokinetics) to gain insights about drug effectiveness in preventing HIV infection (pharmacodynamics). The modeling compares vaginal drug distributions after different gel dosage regimens, and it evaluates consequences of changes in gel viscosity due to aging. It compares vaginal mucosal concentration distributions of drugs delivered by gels vs. intravaginal rings. Finally, the modeling approach is used to compare vaginal drug distributions across species with differing vaginal dimensions. Deterministic models of drug mass transport into and throughout the vaginal environment can provide critical insights about the mechanisms and determinants of such transport. This knowledge, and the methodology that obtains it, can be applied and translated to multiple applications, involving the scientific underpinnings of vaginal drug distribution and the performance evaluation and design of products, and their dosage regimens, that achieve it. Copyright © 2015 Elsevier B.V. All rights reserved.

  2. Role of drug transporters and drug accumulation in the temporal acquisition of drug resistance

    International Nuclear Information System (INIS)

    Hembruff, Stacey L; Laberge, Monique L; Villeneuve, David J; Guo, Baoqing; Veitch, Zachary; Cecchetto, Melanie; Parissenti, Amadeo M

    2008-01-01

    Anthracyclines and taxanes are commonly used in the treatment of breast cancer. However, tumor resistance to these drugs often develops, possibly due to overexpression of drug transporters. It remains unclear whether drug resistance in vitro occurs at clinically relevant doses of chemotherapy drugs and whether both the onset and magnitude of drug resistance can be temporally and causally correlated with the enhanced expression and activity of specific drug transporters. To address these issues, MCF-7 cells were selected for survival in increasing concentrations of doxorubicin (MCF-7 DOX-2 ), epirubicin (MCF-7 EPI ), paclitaxel (MCF-7 TAX-2 ), or docetaxel (MCF-7 TXT ). During selection cells were assessed for drug sensitivity, drug uptake, and the expression of various drug transporters. In all cases, resistance was only achieved when selection reached a specific threshold dose, which was well within the clinical range. A reduction in drug uptake was temporally correlated with the acquisition of drug resistance for all cell lines, but further increases in drug resistance at doses above threshold were unrelated to changes in cellular drug uptake. Elevated expression of one or more drug transporters was seen at or above the threshold dose, but the identity, number, and temporal pattern of drug transporter induction varied with the drug used as selection agent. The pan drug transporter inhibitor cyclosporin A was able to partially or completely restore drug accumulation in the drug-resistant cell lines, but had only partial to no effect on drug sensitivity. The inability of cyclosporin A to restore drug sensitivity suggests the presence of additional mechanisms of drug resistance. This study indicates that drug resistance is achieved in breast tumour cells only upon exposure to concentrations of drug at or above a specific selection dose. While changes in drug accumulation and the expression of drug transporters does occur at the threshold dose, the magnitude of

  3. Drug Facts

    Medline Plus

    Full Text Available ... Drug Use Hurts Brains Drug Use and Mental Health Problems Often Happen Together The Link Between Drug Use and HIV/AIDS Treatment & Recovery Why Does a Person Need Treatment? Does Drug Treatment Work? What Are the Treatment Options? What Is Recovery? ...

  4. Drug Facts

    Medline Plus

    Full Text Available ... 4357) at any time to find drug treatment centers near you. I want my daughter to avoid drugs. "Debbie" has been drug-free for years. She wants her daughter to stay away from drugs. But she's afraid ...

  5. 21 CFR 131.115 - Concentrated milk.

    Science.gov (United States)

    2010-04-01

    ... 21 Food and Drugs 2 2010-04-01 2010-04-01 false Concentrated milk. 131.115 Section 131.115 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) FOOD FOR HUMAN CONSUMPTION MILK AND CREAM Requirements for Specific Standardized Milk and Cream § 131.115...

  6. Severe overdosage with the antiepileptic drug oxcarbazepine

    Science.gov (United States)

    van Opstal, J M; Janknegt, R; Cilissen, J; L’Ortije, W H V M; Nel, J E; De Heer, F

    2004-01-01

    Few published human data are available concerning the acute toxicity of the new antiepileptic drug oxcarbazepine of which the metabolite 10- monohydroxy derivate (MHD) is the pharmacologically effective compound. Two hours after a documented overdosage of more than 100 tablets oxcarbazepine, the serum level of the parent compound was 10-fold higher than the therapeutic dosage (31.6 mg l−1). However, the concentration of MHD, which peaked 7 h after intake, was only twofold higher (59.0 mg l−1). No life-threatening situations occurred and the patient fully recovered. The fact that oxcarbazepine is a prodrug and that the formation of the active MHD metabolite is a rate-limiting process may contribute to the relative low toxicity of the drug in overdose. PMID:15327594

  7. Entry time effects and follow-on drug competition.

    Science.gov (United States)

    Andrade, Luiz Flavio; Sermet, Catherine; Pichetti, Sylvain

    2016-01-01

    Pharmaceutical firms have been criticized for concentrating efforts of R&D on the so-called me-too or follow-on drugs. There have been many comments for and against the dissemination of these incremental innovations but few papers have broached the subject from an econometric point of view, possibly because identification of me-too or follow-on drugs is not so obvious. This paper focuses on the impact of entry order on follow-on drug competition in the French market between the years 2001 and 2007. More precisely, this study examines the effects on market share of first entrants in the follow-on drug market and how this possible competitive advantage changes over time. First results are coherent with theoretical microeconomic issues concerning the importance of being first. We find evidence that first movers in the follow-on drug market have the ability to capture and maintain greater market share for a long period of time. The hierarchical market position of follow-on drugs does not seem to be affected by generic drug emergence. From a dynamic perspective, our analysis shows that market share is positively correlated with the ability of follow-on drugs to set prices higher than the average follow-on drug prices in a specific therapeutic class, which means that market power remains considerably important for first movers. Moreover, we found that the optimum level of innovation to maximize market share is the highest one.

  8. Dexamethasone levels and base to apex concentration gradients in scala tympani perilymph following intracochlear delivery in the guinea pig

    Science.gov (United States)

    Hahn, Hartmut; Salt, Alec N.; Biegner, Thorsten; Kammerer, Bernd; Delabar, Ursular; Hartsock, Jared; Plontke, Stefan K.

    2012-01-01

    Hypothesis To determine whether intracochlearly applied dexamethasone will lead to better control of drug levels, higher peak concentrations and lower base-to apex concentration gradients in scala tympani (ST) of the guinea pig than after intratympanic (round window, RW) application. Background Local application of drugs to the RW results in substantial variation of intracochlear drug levels and significant base-to apex concentration gradients in ST. Methods Two μL of dexamethasone-phosphate (10 mg/mL) were injected into ST either through the RW membrane which was covered with 1% sodium hyaluronate gel or through a cochleostomy with a fluid tight seal of the micropipette. Perilymph was sequentially sampled from the apex at a single time point for each animal, at 20, 80, or 200 min after the injection ended. Results were mathematically interpreted by the means of an established computer model and compared with prior experiments performed by our group with the same experimental techniques but using intratympanic applications. Results Single intracochlear injections over 20 min resulted in approximately ten times higher peak concentrations (on average) than 2-3 hours of intratympanic application to the round window niche. Intracochlear drug levels were less variable and could be measured for at least up to 220 min. Concentration gradients along scala tympani were less pronounced. The remaining variability in intracochlear drug levels was attributable to perilymph and drug leak from the injection site. Conclusion With significantly higher, less variable drug levels and smaller base-to apex concentration gradients, intracochlear applications have advantages to intratympanic injections. For further development of this technique, it is of importance to control leaks of perilymph and drug from the injection site and to evaluate its clinical feasibility and associated risks. PMID:22588238

  9. Substance use - prescription drugs

    Science.gov (United States)

    Substance use disorder - prescription drugs; Substance abuse - prescription drugs; Drug abuse - prescription drugs; Drug use - prescription drugs; Narcotics - substance use; Opioid - substance use; Sedative - substance ...

  10. Herb-drug interactions.

    Science.gov (United States)

    Fugh-Berman, A

    2000-01-08

    Concurrent use of herbs may mimic, magnify, or oppose the effect of drugs. Plausible cases of herb-drug interactions include: bleeding when warfarin is combined with ginkgo (Ginkgo biloba), garlic (Allium sativum), dong quai (Angelica sinensis), or danshen (Salvia miltiorrhiza); mild serotonin syndrome in patients who mix St John's wort (Hypericum perforatum) with serotonin-reuptake inhibitors; decreased bioavailability of digoxin, theophylline, cyclosporin, and phenprocoumon when these drugs are combined with St John's wort; induction of mania in depressed patients who mix antidepressants and Panax ginseng; exacerbation of extrapyramidal effects with neuroleptic drugs and betel nut (Areca catechu); increased risk of hypertension when tricyclic antidepressants are combined with yohimbine (Pausinystalia yohimbe); potentiation of oral and topical corticosteroids by liquorice (Glycyrrhiza glabra); decreased blood concentrations of prednisolone when taken with the Chinese herbal product xaio chai hu tang (sho-salko-to); and decreased concentrations of phenytoin when combined with the Ayurvedic syrup shankhapushpi. Anthranoid-containing plants (including senna [Cassia senna] and cascara [Rhamnus purshiana]) and soluble fibres (including guar gum and psyllium) can decrease the absorption of drugs. Many reports of herb-drug interactions are sketchy and lack laboratory analysis of suspect preparations. Health-care practitioners should caution patients against mixing herbs and pharmaceutical drugs.

  11. Dissolution rate enhancement of the poorly water-soluble drug Tibolone using PVP, SiO2, and their nanocomposites as appropriate drug carriers.

    Science.gov (United States)

    Papadimitriou, Sofia; Bikiaris, Dimitrios

    2009-09-01

    Creation of immediate release formulations for the poorly water-soluble drug Tibolone through the use of solid dispersions (SDs). SD systems of Tibolone (Tibo) with poly(vinylpyrrolidone) (PVP), fumed SiO(2) nanoparticles, and their corresponding ternary systems (PVP/SiO(2)/Tibo) were prepared and studied in order to produce formulations with enhanced drug dissolution rates. The prepared SDs were characterized by the use of differential scanning calorimetry and wide-angle X-ray diffractometry techniques. Also dissolution experiments were performed. From the results it was concluded that PVP as well as SiO(2) can be used as appropriate carriers for the amorphization of Tibo, even when the drug is used at high concentrations (20-30%, w/w). This is due to the evolved interactions taking place between the drug and the used carriers, as was verified by Fourier transform infrared spectroscopy. At higher concentrations the drug was recrystallized. Similar are the observations on the ternary PVP/SiO(2)/Tibo SDs. The dissolution profiles of the drug in PVP/Tibo and SiO(2)/Tibo SDs are directly dependent on the physical state of the drug. Immediately release rates are observed in SD with low drug concentrations, in which Tibo was in amorphous state. However, these release profiles are drastically changed in the ternary PVP/SiO(2)/Tibo SDs. An immediate release profile is observed for low drug concentrations and an almost sustained release as the concentration of Tibo increases. This is due to the weak interactions that take place between PVP and SiO(2), which result in alterations of the characteristics of the carrier (PVP/SiO(2) nanocomposites). Immediate release formulation was created for Tibolone as well as new nanocomposite matrices of PVP/SiO((2)), which drastically change the release profile of the drug to a sustained delivery.

  12. Hybrid nanostructured drug carrier with tunable and controlled drug release

    International Nuclear Information System (INIS)

    Depan, D.; Misra, R.D.K.

    2012-01-01

    We describe here a transformative approach to synthesize a hybrid nanostructured drug carrier that exhibits the characteristics of controlled drug release. The synthesis of the nanohybrid architecture involved two steps. The first step involved direct crystallization of biocompatible copolymer along the long axis of the carbon nanotubes (CNTs), followed by the second step of attachment of drug molecule to the polymer via hydrogen bonding. The extraordinary inorganic–organic hybrid architecture exhibited high drug loading ability and is physically stable even under extreme conditions of acidic media and ultrasonic irradiation. The temperature and pH sensitive characteristics of the hybrid drug carrier and high drug loading ability merit its consideration as a promising carrier and utilization of the fundamental aspects used for synthesis of other promising drug carriers. The higher drug release response during the application of ultrasonic frequency is ascribed to a cavitation-type process in which the acoustic bubbles nucleate and collapse releasing the drug. Furthermore, the study underscores the potential of uniquely combining CNTs and biopolymers for drug delivery. - Graphical abstract: Block-copolymer crystallized on carbon nanotubes (CNTs). Nanohybrid drug carrier synthesized by attaching doxorubicin (DOX) to polymer crystallized CNTs. Crystallized polymer on CNTs provide mechanical stability. Triggered release of DOX. Highlights: ► The novel synthesis of a hybrid nanostructured drug carrier is described. ► The drug carrier exhibits high drug loading ability and is physically stable. ► The high drug release is ascribed to a cavitation-type process.

  13. Ownership concentration and bank profitability

    Directory of Open Access Journals (Sweden)

    Peterson Kitakogelu Ozili

    2017-12-01

    Full Text Available We investigate whether ownership concentration influences bank profitability in a developing country context. We focus on bank ownership concentration measured as the amount of direct equity held by a majority shareholder categorised into: high ownership concentration, moderate ownership concentration and disperse ownership. We find that banks with high ownership concentration have higher return on assets, higher net interest margin and higher recurring earning power while banks with dispersed ownership have lower return on assets but have higher return on equity. Also, higher cost efficiency improves the return on assets of widely-held banks and the return on equity of banks with moderate ownership. The findings have implications. JEL: Code: G3, G34, G31, Keywords: Corporate governance, Ownership structure, Agency theory, Profitability, Firm performance, Banks, Return on asset, Return on equity

  14. Measured density and calculated baricity of custom-compounded drugs for chronic intrathecal infusion.

    Science.gov (United States)

    Hejtmanek, Michael R; Harvey, Tracy D; Bernards, Christopher M

    2011-01-01

    To minimize the frequency that intrathecal pumps require refilling, drugs are custom compounded at very high concentrations. Unfortunately, the baricity of these custom solutions is unknown, which is problematic, given baricity's importance in determining the spread of intrathecally administered drugs. Consequently, we measured the density and calculated the baricity of clinically relevant concentrations of multiple drugs used for intrathecal infusion. Morphine, clonidine, bupivacaine, and baclofen were weighed to within 0.0001 g and diluted in volumetric flasks to produce solutions of known concentrations (morphine 1, 10, 25, and 50 mg/mL; clonidine 0.05, 0.5, 1, and 3 mg/mL; bupivacaine 2.5, 5, 10, and 20 mg/mL; baclofen 1, 1.5, 2, and 4 mg/mL). The densities of the solutions were measured at 37°C using the mechanical oscillation method. A "best-fit" curve was calculated for plots of concentration versus density for each drug. All prepared solutions of clonidine and baclofen were hypobaric. Higher concentrations of morphine and bupivacaine were hyperbaric, whereas lower concentrations were hypobaric. The relationship between concentration and density is linear for morphine (r > 0.99) and bupivacaine (r > 0.99) and logarithmic for baclofen (r = 0.96) and clonidine (r = 0.98). This is the first study to examine the relationship between concentration and density for custom drug concentrations commonly used in implanted intrathecal pumps. We calculated an equation that defines the relationship between concentration and density for each drug. Using these equations, clinicians can calculate the density of any solution made from the drugs studied here.

  15. Drug Facts

    Medline Plus

    Full Text Available ... abuse, addiction, and treatment. Watch Videos Information About Drugs Alcohol Bath Salts Cocaine Heroin Marijuana MDMA Meth Pain Medicines Spice (K2) Tobacco/Nicotine Other Drugs You can ...

  16. Prescription Drugs

    Science.gov (United States)

    ... different competition is going on: the National Football League (NFL) vs. drug use. Read More » 92 Comments ... Future survey highlights drug use trends among the Nation’s youth for marijuana, alcohol, cigarettes, e-cigarettes (e- ...

  17. Drug Facts

    Medline Plus

    Full Text Available ... abuse, addiction, and treatment. Watch Videos Information About Drugs Alcohol Bath Salts Cocaine Heroin Marijuana MDMA Meth ... 662-HELP (4357) at any time to find drug treatment centers near you. I want my daughter ...

  18. Drug Facts

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    Full Text Available ... form Search Menu Home Drugs That People Abuse Alcohol Facts Bath Salts Facts Cocaine (Coke, Crack) Facts ... addiction, and treatment. Watch Videos Information About Drugs Alcohol Bath Salts Cocaine Heroin Marijuana MDMA Meth Pain ...

  19. Drug Facts

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    Full Text Available ... Ice) Facts Pain Medicine (Oxy, Vike) Facts Spice (K2) Facts Tobacco and Nicotine Facts Other Drugs of ... Cocaine Heroin Marijuana MDMA Meth Pain Medicines Spice (K2) Tobacco/Nicotine Other Drugs You can call 1- ...

  20. Drug Control

    Science.gov (United States)

    Leviton, Harvey S.

    1975-01-01

    This article attempts to assemble pertinent information about the drug problem, particularily marihuana. It also focuses on the need for an educational program for drug control with the public schools as the main arena. (Author/HMV)

  1. Drug Facts

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    Full Text Available ... Crank, Ice) Facts Pain Medicine (Oxy, Vike) Facts Spice (K2) Facts Tobacco and Nicotine Facts Other Drugs ... Salts Cocaine Heroin Marijuana MDMA Meth Pain Medicines Spice (K2) Tobacco/Nicotine Other Drugs You can call ...

  2. Drug Facts

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    Full Text Available ... Nicotine Facts Other Drugs of Abuse What is Addiction? What are some signs and symptoms of someone ... use problem? How Does Drug Use Become an Addiction? What Makes Someone More Likely to Get Addicted ...

  3. Drug Facts

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    Full Text Available ... Numbers and Websites Search Share Listen English Español Information about this page Click on the button that ... about drug abuse, addiction, and treatment. Watch Videos Information About Drugs Alcohol Bath Salts Cocaine Heroin Marijuana ...

  4. Drug Facts

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    Full Text Available ... Home Drugs That People Abuse Alcohol Facts Bath Salts Facts Cocaine (Coke, Crack) Facts Heroin (Smack, Junk) ... treatment. Watch Videos Information About Drugs Alcohol Bath Salts Cocaine Heroin Marijuana MDMA Meth Pain Medicines Spice ( ...

  5. Drug Facts

    Medline Plus

    Full Text Available ... call 1-800-662-HELP (4357) at any time to find drug treatment centers near you. I ... The National Institute on Drug Abuse (NIDA) is part of the National Institutes of Health (NIH) , the ...

  6. Effect of cell culture medium components on color of formulated monoclonal antibody drug substance.

    Science.gov (United States)

    Vijayasankaran, Natarajan; Varma, Sharat; Yang, Yi; Mun, Melissa; Arevalo, Silvana; Gawlitzek, Martin; Swartz, Trevor; Lim, Amy; Li, Feng; Zhang, Boyan; Meier, Steve; Kiss, Robert

    2013-01-01

    As the industry moves toward subcutaneous delivery as a preferred route of drug administration, high drug substance concentrations are becoming the norm for monoclonal antibodies. At such high concentrations, the drug substance may display a more intense color than at the historically lower concentrations. The effect of process conditions and/or changes on color is more readily observed in the higher color, high concentration formulations. Since color is a product quality attribute that needs to be controlled, it is useful to study the impact of process conditions and/or modifications on color. This manuscript summarizes cell culture experiments and reports on findings regarding the effect of various media components that contribute to drug substance color for a specific monoclonal antibody. In this work, lower drug substance color was achieved via optimization of the cell culture medium. Specifically, lowering the concentrations of B-vitamins in the cell culture medium has the effect of reducing color intensity by as much as 25%. In addition, decreasing concentration of iron was also directly correlated color intensity decrease of as much as 37%. It was also shown that the color of the drug substance directly correlates with increased acidic variants, especially when increased iron levels cause increased color. Potential mechanisms that could lead to antibody coloration are briefly discussed. © 2013 American Institute of Chemical Engineers.

  7. Orphan drugs

    OpenAIRE

    Goločorbin-Kon, Svetlana; Vojinović, Aleksandra; Lalić-Popović, Mladena; Pavlović, Nebojša; Mikov, Momir

    2013-01-01

    Introduction. Drugs used for treatment of rare diseases are known worldwide under the term of orphan drugs because pharmaceutical companies have not been interested in ”adopting” them, that is in investing in research, developing and producing these drugs. This kind of policy has been justified by the fact that these drugs are targeted for small markets, that only a small number of patients is available for clinical trials, and that large investments are required for the development of ...

  8. Target concentration intervention: beyond Y2K.

    Science.gov (United States)

    Holford, N H

    2001-01-01

    Target concentration intervention (TCI) is proposed as an alternative conceptual strategy to therapeutic drug monitoring (TDM). It is argued that the idea of a therapeutic range has limited the interpretation of measured drug concentrations and diminished the anticipated clinical benefit to patients by use of an oversimplified pharmacodynamic model. TCI on the other hand embraces pharmacokinetic and pharmacodynamic concepts and uses the idea of a target effect and associated target concentration to make rational individual dose decisions.

  9. Drug Testing

    Science.gov (United States)

    ... testing, substance abuse testing, toxicology screen, tox screen, sports doping tests What is it used for? Drug screening is used to find out whether or not a person has taken a certain drug or drugs. It ... Sports organizations. Professional and collegiate athletes usually need to ...

  10. Drug Facts

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    Full Text Available ... to main content Easy-to-Read Drug Facts Search form Search Menu Home Drugs That People Abuse Alcohol Facts ... Past Drug Use Prevention Phone Numbers and Websites Search Share Listen English Español Information about this page ...

  11. Drug Facts

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    Full Text Available ... can call 1-800-662-HELP (4357) at any time to find drug treatment centers near you. I want my daughter to avoid drugs. "Debbie" has been drug-free for years. She wants her daughter to stay away from ...

  12. Drug Facts

    Medline Plus

    Full Text Available ... the computer will read the text to you. This website talks about drug abuse, addiction, and treatment. Watch Videos ... I want my daughter to avoid drugs. "Debbie" has been drug-free for years. She wants her daughter to stay away from ...

  13. Drug Facts

    Medline Plus

    Full Text Available ... the text to you. This website talks about drug abuse, addiction, and treatment. Watch Videos Information About Drugs ... adicción. English Español About the National Institute on Drug Abuse (NIDA) | About This Website Tools and Resources | Contact ...

  14. Drug Facts

    Medline Plus

    Full Text Available ... Drug Use and Mental Health Problems Often Happen Together The Link Between Drug Use and HIV/AIDS Treatment & Recovery Why Does a Person Need Treatment? Does Drug Treatment Work? What Are the Treatment Options? What Is Recovery? ...

  15. Drug Facts

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    Full Text Available ... Makes Someone More Likely to Get Addicted to Drugs? Does Addiction Run in Families? Why Is It So Hard ... the text to you. This website talks about drug abuse, addiction, and treatment. Watch Videos Information About Drugs Alcohol ...

  16. Assessing Cyberbullying in Higher Education

    Science.gov (United States)

    Kamali, Ali

    2015-01-01

    This project aims to expose information educators to various aspects of cyberbullying for the purpose of policy development in an environment of higher education. The preponderance of nation-wide research on cyberbullying is concentrated on adolescents; such efforts in college campuses are limited to individual endeavors. Cyberbullying research on…

  17. Therapeutic drug monitoring of aminoglycosides in neonates

    NARCIS (Netherlands)

    Touw, Daniël J; Westerman, Elsbeth M; Sprij, Arwen J

    2009-01-01

    The efficacy and toxicity of aminoglycosides show a strong direct positive relationship with blood drug concentrations, therefore, therapy with aminoglycosides in adults is usually guided by therapeutic drug monitoring. Dosing regimens in adults have evolved from multiple daily dosing to

  18. Photovoltaic static concentrator analysis

    Science.gov (United States)

    Almonacid, G.; Luque, A.; Molledo, A. G.

    1984-12-01

    Ray tracing is the basis of the present analysis of truncated bifacial compound parabolic concentrators filled with a dielectric substance, which are of interest in photovoltaic applications where the bifacial cells allow higher static concentrations to be achieved. Among the figures of merit for this type of concentrator, the directional intercept factor plays a major role and is defined as the ratio of the power of the collector to that at the entry aperture, in a lossless concentrator illuminated by light arriving from a given direction. A procedure for measuring outdoor, full size panels has been developed, and a correction method for avoiding the effect of unwanted diffuse radiation during the measurements is presented.

  19. Therapeutic drug monitoring of atypical antipsychotic drugs

    Directory of Open Access Journals (Sweden)

    Grundmann Milan

    2014-12-01

    Full Text Available Schizophrenia is a severe psychiatric disorder often associated with cognitive impairment and affective, mainly depressive, symptoms. Antipsychotic medication is the primary intervention for stabilization of acute psychotic episodes and prevention of recurrences and relapses in patients with schizophrenia. Typical antipsychotics, the older class of antipsychotic agents, are currently used much less frequently than newer atypical antipsychotics. Therapeutic drug monitoring (TDM of antipsychotic drugs is the specific method of clinical pharmacology, which involves measurement of drug serum concentrations followed by interpretation and good cooperation with the clinician. TDM is a powerful tool that allows tailor-made treatment for the specific needs of individual patients. It can help in monitoring adherence, dose adjustment, minimizing the risk of toxicity and in cost-effectiveness in the treatment of psychiatric disorders. The review provides complex knowledge indispensable to clinical pharmacologists, pharmacists and clinicians for interpretation of TDM results.

  20. WAr on DrugS

    African Journals Online (AJOL)

    2009-04-12

    Apr 12, 2009 ... ABStrAct. Since drugs became both a public and social issue in Nigeria, fear about both the real and .... drugs as being morally reprehensible, and ..... tice system (see for instance, Shaw, 1995; ..... A cut throat business:.

  1. A new approach in gastroretentive drug delivery system using cholestyramine.

    Science.gov (United States)

    Umamaheshwari, R B; Jain, Subheet; Jain, N K

    2003-01-01

    We prepared cellulose acetate butyrate (CAB)-coated cholestyramine microcapsules as a intragastric floating drug delivery system endowed with floating ability due to the carbon dioxide generation when exposed to the gastric fluid. The microcapsules also have a mucoadhesive property. Ion-exchange resin particles can be loaded with bicarbonate followed by acetohydroxamic acid (AHA) and coated with CAB by emulsion solvent evaporation method. The drug concentration was monitored to maintain the floating property and minimum effective concentration. The effect of CAB: drug-resin ratio (2:1, 4:1, 6:1 w/w) on the particle size, floating time, and drug release was determined. Cholestyramine microcapsules were characterized for shape, surface characteristics, and size distribution; cholestyramine/acetohydroxamic acid interactions inside microcapsules were investigated by X-ray diffractometry. The buoyancy time of CAB-coated formulations was better than that of uncoated resin particles. Also, a longer floating time was observed with a higher polymer:drug resin complex ratio (6:1). With increasing coating thickness the particle size was increased but drug release rate was decreased. The drug release rate was higher in simulated gastric fluid (SGF) than in simulated intestinal fluid (SIF). The in vivo mucoadhesion studies were performed with rhodamine-isothiocyanate (RITC) by fluorescent probe method. The amount of CAB-coated cholestyramine microcapsules that remained in the stomach was slightly lower than that of uncoated resin particles. Cholestyramine microcapsules were distributed throughout the stomach and exhibited prolonged gastric residence via mucoadhesion. These results suggest that CAB-coated microcapsules could be a floating as well as a mucoadhesive drug delivery system. Thus, it has promise in the treatment of Helicobacter pylori.

  2. Effect of the surfactant on the availability of piroxicam as a poorly hydrosoluble drug from suppositories.

    Science.gov (United States)

    Dal Zorro, M; Franceschinis, E; Punchina, A; Realdon, N

    2012-01-01

    The use of surfactants in suppository formulations has been suggested to improve availability of poorly soluble drugs. In the present study, different kinds of surfactants have been investigated to clarify the influence on piroxicam release from suppositories formulated with both lipophilic and hydrophilic bases. Two hydrophilic glucose-derivate surfactants, and a polyoxylglyceride amphiphilic surfactant, all with high HLB values, were investigated for their use in improving drug availability. The two glucose derivate surfactants reduced drug availability from both lipophilic suppositories and hydrophilic formulations, according to longer disintegration times and drug micellization. The more complex surfactant, a lauroyl macrogolglyceride, showed an increase in piroxicam availability from lipophilic suppositories at the higher tested concentrations (15% and 20%). Otherwise, when used in hydrophilic formulations, it was less effective in promoting drug release and even reduced drug availability.

  3. Therapeutic drug management of linezolid: a missed opportunity for clinicians?

    Science.gov (United States)

    Cattaneo, Dario; Gervasoni, Cristina; Cozzi, Valeria; Castoldi, Simone; Baldelli, Sara; Clementi, Emilio

    2016-12-01

    Some studies have shown that adjustments to the linezolid dose guided by therapeutic drug monitoring (TDM) can reduce interindividual variability in drug exposure and improve linezolid tolerability. In this study, 6 years of linezolid TDM, a diagnostic service for our hospital and others in the Milan (Italy) area, is described. Samples were collected immediately before the morning dose intake (trough concentrations) in steady-state conditions. Linezolid concentrations were quantified by a validated high-performance liquid chromatography (HPLC) method. Four hundred linezolid trough concentrations from 220 patients were collected. A 20-fold variability in linezolid levels was observed. Positive and significant correlations between linezolid trough concentrations and patient age (r = 0.325, P linezolid concentrations with time was observed in a subgroup of patients with more than one TDM assessment. Elderly patients, especially those aged >80 years and with impaired renal function, are at a higher risk of overexposure to linezolid. Despite the observed progressive increase in linezolid concentrations over time, most physicians did not change the drug dose according to the TDM results, even in the presence of frank overexposure to linezolid. Copyright © 2016 Elsevier B.V. and International Society of Chemotherapy. All rights reserved.

  4. COPD - control drugs

    Science.gov (United States)

    Chronic obstructive pulmonary disease - control drugs; Bronchodilators - COPD - control drugs; Beta agonist inhaler - COPD - control drugs; Anticholinergic inhaler - COPD - control drugs; Long-acting inhaler - COPD - control drugs; ...

  5. [Orphan drugs].

    Science.gov (United States)

    Golocorbin Kon, Svetlana; Vojinović, Aleksandra; Lalić-Popović, Mladena; Pavlović, Nebojsa; Mikov, Momir

    2013-01-01

    Drugs used for treatment of rare diseases are known worldwide under the term of orphan drugs because pharmaceutical companies have not been interested in "adopting" them, that is in investing in research, developing and producing these drugs. This kind of policy has been justified by the fact that these drugs are targeted for small markets, that only a small number of patients is available for clinical trials, and that large investments are required for the development of drugs meant to treat diseases whose pathogenesis has not yet been clarified in majority of cases. The aim of this paper is to present previous and present status of orphan drugs in Serbia and other countries. THE BEGINNING OF ORPHAN DRUGS DEVELOPMENT: This problem was first recognized by Congress of the United States of America in January 1983, and when the "Orphan Drug Act" was passed, it was a turning point in the development of orphan drugs. This law provides pharmaceutical companies with a series of reliefs, both financial ones that allow them to regain funds invested into the research and development and regulatory ones. Seven years of marketing exclusivity, as a type of patent monopoly, is the most important relief that enables companies to make large profits. There are no sufficient funds and institutions to give financial support to the patients. It is therefore necessary to make health professionals much more aware of rare diseases in order to avoid time loss in making the right diagnosis and thus to gain more time to treat rare diseases. The importance of discovery, development and production of orphan drugs lies in the number of patients whose life quality can be improved significantly by administration of these drugs as well as in the number of potential survivals resulting from the treatment with these drugs.

  6. AIDSinfo Drug Database

    Science.gov (United States)

    ... AIDS Drugs Clinical Trials Apps skip to content Drugs Home Drugs Find information on FDA-approved HIV/ ... infection drugs and investigational HIV/AIDS drugs. Search Drugs Search drug Search Icon What's this? Close Popup ...

  7. Influence of molar mass, dispersity, and type and location of hydrophobic side chain moieties on the critical micellar concentration and stability of amphiphilic HPMA-based polymer drug carriers

    Czech Academy of Sciences Publication Activity Database

    Filippov, Sergey K.; Vishnevetskaya, N. S.; Niebuur, B.-J.; Koziolová, Eva; Lomkova, Ekaterina A.; Chytil, Petr; Etrych, Tomáš; Papadakis, C. M.

    2017-01-01

    Roč. 295, č. 8 (2017), s. 1313-1325 ISSN 0303-402X R&D Projects: GA MZd(CZ) NV16-28600A; GA ČR(CZ) GC15-10527J Institutional support: RVO:61389013 Keywords : drug delivery * HPMA copolymers * fluorescence correlation spectroscopy Subject RIV: CD - Macromolecular Chemistry OBOR OECD: Polymer science Impact factor: 1.723, year: 2016

  8. A paradigm shift in pharmacokinetic-pharmacodynamic (PKPD) modeling: rule of thumb for estimating free drug level in tissue compared with plasma to guide drug design.

    Science.gov (United States)

    Poulin, Patrick

    2015-07-01

    A basic assumption in pharmacokinetics-pharmacodynamics research is that the free drug concentration is similar in plasma and tissue, and, hence, in vitro plasma data can be used to estimate the in vivo condition in tissue. However, in a companion manuscript, it has been demonstrated that this assumption is violated for the ionized drugs. Nonetheless, these observations focus on in vitro static environments and do not challenge data with an in vivo dynamic system. Therefore, an extension from an in vitro to an in vivo system becomes the necessary next step. The objective of this study was to perform theoretical simulations of the free drug concentration in tissue and plasma by using a physiologically based pharmacokinetics (PBPK) model reproducing the in vivo conditions in human. Therefore, the effects of drug ionization, lipophilicity, and clearance have been taken into account in a dynamic system. This modeling exercise was performed as a proof of concept to demonstrate that free drug concentration in tissue and plasma may also differ in a dynamic system for passively permeable drugs that are ionized at the physiological pH. The PBPK model simulations indicated that free drug concentrations in tissue cells and plasma significantly differ for the ionized drugs because of the pH gradient effect between cells and interstitial space. Hence, a rule of thumb for potentially performing more accurate PBPK/PD modeling is suggested, which states that the free drug concentration in tissue and plasma will differ for the ionizable drugs in contrast to the neutral drugs. In addition to the pH gradient effect for the ionizable drugs, lipophilicity and clearance effects will increase or decrease the free drug concentration in tissue and plasma for each class of drugs; thus, higher will be the drug lipophilicity and clearance, lower would be the free drug concentration in plasma, and, hence, in tissue, in a dynamic in vivo system. Therefore, only considering the value of free

  9. Drug Facts

    Medline Plus

    Full Text Available ... Pain Medicine (Oxy, Vike) Facts Spice (K2) Facts Tobacco and Nicotine Facts Other Drugs of Abuse What ... Heroin Marijuana MDMA Meth Pain Medicines Spice (K2) Tobacco/Nicotine Other Drugs You can call 1-800- ...

  10. Drug Facts

    Medline Plus

    Full Text Available ... Oxy, Vike) Facts Spice (K2) Facts Tobacco and Nicotine Facts Other Drugs of Abuse What is Addiction? ... Marijuana MDMA Meth Pain Medicines Spice (K2) Tobacco/Nicotine Other Drugs You can call 1-800-662- ...

  11. Antineoplastic Drugs

    Science.gov (United States)

    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).

  12. Drugged Driving

    Science.gov (United States)

    ... Survey Results Synthetic Cannabinoids (K2/Spice) Unpredictable Danger Drug and Alcohol Use in College-Age Adults in 2016 Monitoring the Future 2016 Survey Results Drug and Alcohol Use in College-Age Adults in 2015 View All NIDA Home ...

  13. Dexamethasone levels and base-to-apex concentration gradients in the scala tympani perilymph after intracochlear delivery in the guinea pig.

    Science.gov (United States)

    Hahn, Hartmut; Salt, Alec N; Biegner, Thorsten; Kammerer, Bernd; Delabar, Ursular; Hartsock, Jared J; Plontke, Stefan K

    2012-06-01

    To determine whether intracochlearly applied dexamethasone will lead to better control of drug levels, higher peak concentrations, and lower base-to-apex concentration gradients in the scala tympani (ST) of the guinea pig than after intratympanic (round window [RW]) application. Local application of drugs to the RW results in substantial variation of intracochlear drug levels and significant base-to-apex concentration gradients in ST. Two microliters of dexamethasone-phosphate (10 mg/ml) were injected into ST either through the RW membrane, which was covered with 1% sodium hyaluronate gel or through a cochleostomy with a fluid tight seal of the micropipette. Perilymph was sequentially sampled from the apex at a single time point for each animal, at 20, 80, or 200 min after the injection ended. Results were mathematically interpreted by means of an established computer model and compared with previous experiments performed by our group with the same experimental techniques but using intratympanic applications. Single intracochlear injections of 20 minutes resulted in approximately 10 times higher peak concentrations (on average) than 2 to 3 hours of intratympanic application to the RW niche. Intracochlear drug levels were less variable and could be measured for over 220 minutes. Concentration gradients along the scala tympani were less pronounced. The remaining variability in intracochlear drug levels was attributable to perilymph and drug leak from the injection site. With significantly higher, less variable drug levels and smaller base-to-apex concentration gradients, intracochlear applications have advantages to intratympanic injections. For further development of this technique, it is of importance to control leaks of perilymph and drug from the injection site and to evaluate its clinical feasibility and associated risks.

  14. Selective serotonin reuptake inhibitors and venlafaxine in pregnancy: Changes in drug disposition.

    Directory of Open Access Journals (Sweden)

    Andreas Austgulen Westin

    Full Text Available Pregnancy may cause changes in drug disposition. The clinical consequences may be profound and even counterintuitive; in some cases pregnant women may need more than twice their usual drug dose in order to maintain therapeutic drug levels. For antidepressants, evidence on drug disposition in pregnancy is scarce. The aim of this study was to determine the effects of pregnancy on serum levels of selective serotonin reuptake inhibitors (SSRIs and venlafaxine in a large and naturalistic patient material, in order to provide tentative dose recommendations for pregnant women.Using patient data from two routine therapeutic drug monitoring (TDM services in Norway with linkage to the national birth registry, dose-adjusted serum drug concentrations of SSRIs and venlafaxine during pregnancy were compared to the women's own baseline (non-pregnant values, using a linear mixed model.Overall, the TDM databases contained 196,726 serum concentration measurements from 54,393 women. After data linkage and drug selection (SSRIs or venlafaxine only, we identified 367 analyses obtained from a total of 290 pregnancies in 281 women, and 420 baseline observations from the same women. Serum concentrations in the third trimester were significantly lower than baseline for paroxetine (-51%; 95% confidence interval [CI], -66%, -30%; p<0.001, fluvoxamine (-56%; CI, -75%, -23%; p = 0.004 and citalopram (-24%; CI, -38%, -7%; p = 0,007, and higher than baseline for sertraline (+68%; CI, +37%, +106%; p<0.001. For escitalopram, fluoxetine and venlafaxine concentrations did not change significantly.For paroxetine and fluvoxamine the pronounced decline in maternal drug serum concentrations in pregnancy may necessitate a dose increase of about 100% during the third trimester in order to maintain stable concentrations. For fluoxetine, venlafaxine, citalopram, escitalopram and sertraline, the present study indicates that dose adjustments are generally not necessary during pregnancy.

  15. Drug repurposing based on drug-drug interaction.

    Science.gov (United States)

    Zhou, Bin; Wang, Rong; Wu, Ping; Kong, De-Xin

    2015-02-01

    Given the high risk and lengthy procedure of traditional drug development, drug repurposing is gaining more and more attention. Although many types of drug information have been used to repurpose drugs, drug-drug interaction data, which imply possible physiological effects or targets of drugs, remain unexploited. In this work, similarity of drug interaction was employed to infer similarity of the physiological effects or targets for the drugs. We collected 10,835 drug-drug interactions concerning 1074 drugs, and for 700 of them, drug similarity scores based on drug interaction profiles were computed and rendered using a drug association network with 589 nodes (drugs) and 2375 edges (drug similarity scores). The 589 drugs were clustered into 98 groups with Markov Clustering Algorithm, most of which were significantly correlated with certain drug functions. This indicates that the network can be used to infer the physiological effects of drugs. Furthermore, we evaluated the ability of this drug association network to predict drug targets. The results show that the method is effective for 317 of 561 drugs that have known targets. Comparison of this method with the structure-based approach shows that they are complementary. In summary, this study demonstrates the feasibility of drug repurposing based on drug-drug interaction data. © 2014 John Wiley & Sons A/S.

  16. [Club drugs].

    Science.gov (United States)

    Guerreiro, Diogo Frasquilho; Carmo, Ana Lisa; da Silva, Joaquim Alves; Navarro, Rita; Góis, Carlos

    2011-01-01

    Club drugs are the following substances: Methylenedioxymethamphetamine (MDMA); Methamphetamine; Lysergic Acid Diethylamide (LSD); Ketamine; Gamma-hydroxybutyrate (GHB) and Flunitrazepam. These substances are mainly used by adolescents and young adults, mostly in recreational settings like dance clubs and rave parties. These drugs have diverse psychotropic effects, are associated with several degrees of toxicity, dependence and long term adverse effects. Some have been used for several decades, while others are relatively recent substances of abuse. They have distinct pharmacodynamic and pharmacokinetic properties, are not easy to detect and, many times, the use of club drugs is under diagnosed. Although the use of these drugs is increasingly common, few health professionals feel comfortable with the diagnosis and treatment. The authors performed a systematic literature review, with the goal of synthesising the existing knowledge about club drugs, namely epidemiology, mechanism of action, detection, adverse reactions and treatment. The purpose of this article is creating in Portuguese language a knowledge data base on club drugs, that health professionals of various specialties can use as a reference when dealing with individual with this kind of drug abuse.

  17. A Review of Moxifloxacin for the Treatment of Drug-Susceptible Tuberculosis.

    Science.gov (United States)

    Naidoo, Anushka; Naidoo, Kogieleum; McIlleron, Helen; Essack, Sabiha; Padayatchi, Nesri

    2017-11-01

    Moxifloxacin, an 8-methoxy quinolone, is an important drug in the treatment of multidrug-resistant tuberculosis and is being investigated in novel drug regimens with pretomanid, bedaquiline, and pyrazinamide, or rifapentine, for the treatment of drug-susceptible tuberculosis. Early results of these studies are promising. Although current evidence does not support the use of moxifloxacin in treatment-shortening regimens for drug-susceptible tuberculosis, it may be recommended in patients unable to tolerate standard first-line drug regimens or for isoniazid monoresistance. Evidence suggests that the standard 400-mg dose of moxifloxacin used in the treatment of tuberculosis may be suboptimal in some patients, leading to worse tuberculosis treatment outcomes and emergence of drug resistance. Furthermore, a drug interaction with the rifamycins results in up to 31% reduced plasma concentrations of moxifloxacin when these are combined for treatment of drug-susceptible tuberculosis, although the clinical relevance of this interaction is unclear. Moxifloxacin exhibits extensive interindividual pharmacokinetic variability. Higher doses of moxifloxacin may be needed to achieve drug exposures required for improved clinical outcomes. Further study is, however, needed to determine the safety of proposed higher doses and clinically validated targets for drug exposure to moxifloxacin associated with improved tuberculosis treatment outcomes. We discuss in this review the evidence for the use of moxifloxacin in drug-susceptible tuberculosis and explore the role of moxifloxacin pharmacokinetics, pharmacodynamics, and drug interactions with rifamycins, on tuberculosis treatment outcomes when used in first-line tuberculosis drug regimens. © 2017, The American College of Clinical Pharmacology.

  18. Emerging Frontiers in Drug Delivery.

    Science.gov (United States)

    Tibbitt, Mark W; Dahlman, James E; Langer, Robert

    2016-01-27

    Medicine relies on the use of pharmacologically active agents (drugs) to manage and treat disease. However, drugs are not inherently effective; the benefit of a drug is directly related to the manner by which it is administered or delivered. Drug delivery can affect drug pharmacokinetics, absorption, distribution, metabolism, duration of therapeutic effect, excretion, and toxicity. As new therapeutics (e.g., biologics) are being developed, there is an accompanying need for improved chemistries and materials to deliver them to the target site in the body, at a therapeutic concentration, and for the required period of time. In this Perspective, we provide an historical overview of drug delivery and controlled release followed by highlights of four emerging areas in the field of drug delivery: systemic RNA delivery, drug delivery for localized therapy, oral drug delivery systems, and biologic drug delivery systems. In each case, we present the barriers to effective drug delivery as well as chemical and materials advances that are enabling the field to overcome these hurdles for clinical impact.

  19. Computational Studies of Drug Release, Transport and Absorption in the Human Intestines

    Science.gov (United States)

    Behafarid, Farhad; Brasseur, J. G.; Vijayakumar, G.; Jayaraman, B.; Wang, Y.

    2016-11-01

    Following disintegration of a drug tablet, a cloud of particles 10-200 μm in diameter enters the small intestine where drug molecules are absorbed into the blood. Drug release rate depends on particle size, solubility and hydrodynamic enhancements driven by gut motility. To quantify the interrelationships among dissolution, transport and wall permeability, we apply lattice Boltzmann method to simulate the drug concentration field in the 3D gut released from polydisperse distributions of drug particles in the "fasting" vs. "fed" motility states. Generalized boundary conditions allow for both solubility and gut wall permeability to be systematically varied. We apply a local 'quasi-steady state' approximation for drug dissolution using a mathematical model generalized for hydrodynamic enhancements and heterogeneity in drug release rate. We observe fundamental differences resulting from the interplay among release, transport and absorption in relationship to particle size distribution, luminal volume, motility, solubility and permeability. For example, whereas smaller volume encourages higher bulk concentrations and reduced release rate, it also encourages higher absorption rate, making it difficult to generalize predictions. Supported by FDA.

  20. Plasma concentrations of misonidazole

    Energy Technology Data Exchange (ETDEWEB)

    Notter, G; Rylander, U; Turesson, I

    1980-10-01

    The plasma concentrations of misonidazole doses between 0.6 and 2.0 g/m/sup 2/ were analyzed in respect to the variation within the same patient and between different patients. Peak plasma levels were observed after 2 hours. The mean plasma levels of misonidazole only at 3 hours were 23.8, 47.0 and 76.5 ..mu..g/ml after misonidazole doses of 0.6, 1.2 g/m/sup 2/, respectively. The half-life of misonidazole only was found to be 8.2 hours for women and 10.5 for men. Good linearity between plasma levels and drug doses was observed after administration of different single doses to the same patient within the dose range 0.6 to 2.0 g/m/sup 2/.

  1. Globalisation and Higher Education

    NARCIS (Netherlands)

    Marginson, Simon; van der Wende, Marijk

    2007-01-01

    Economic and cultural globalisation has ushered in a new era in higher education. Higher education was always more internationally open than most sectors because of its immersion in knowledge, which never showed much respect for juridical boundaries. In global knowledge economies, higher education

  2. The influence of environmental variables on platelet concentration in horse platelet-rich plasma.

    Science.gov (United States)

    Rinnovati, Riccardo; Romagnoli, Noemi; Gentilini, Fabio; Lambertini, Carlotta; Spadari, Alessandro

    2016-07-04

    Platelet-rich plasma (PRP) commonly refers to blood products which contain a higher platelet (PLT) concentration as compared to normal plasma. Autologous PRP has been shown to be safe and effective in promoting the natural processes of soft tissue healing or reconstruction in humans and horses. Variability in PLT concentration has been observed in practice between PRP preparations from different patients or from the same individual under different conditions. A change in PLT concentration could modify PRP efficacy in routine applications. The aim of this study was to test the influence of environmental, individual and agonistic variables on the PLT concentration of PRP in horses. Six healthy Standardbred mares were exposed to six different variables with a one-week washout period between variables, and PRP was subsequently obtained from each horse. The variables were time of withdrawal during the day (morning/evening), hydration status (overhydration/dehydration) treatment with anti-inflammatory drugs and training periods on a treadmill. The platelet concentration was significantly higher in horses treated with a non-steroidal anti-inflammatory drug (P = 0.03). The leukocyte concentration increased 2-9 fold with respect to whole blood in the PRP which was obtained after exposure to all the variable considered. Environmental variation in platelet concentration should be taken into consideration during PRP preparation.

  3. Blood lead concentration and related factors in Korea from the 2008 National Survey for Environmental Pollutants in the Human Body.

    Science.gov (United States)

    Jeong, Seong Wook; Lee, Chae Kwan; Suh, Chun Hui; Kim, Kun Hyung; Son, Byung Chul; Kim, Jeong Ho; Lee, Jong Tae; Lee, Soo Woong; Park, Yeong Beom; Lee, Jong Wha; Yu, Seung-Do; Moon, Chan Seok; Kim, Dae Hwan; Lee, Sang Yoon

    2014-11-01

    This study evaluated blood lead concentrations in the Korean general population and the correlation between various exposure sources using data from the 2008 Korea National Survey for Environmental Pollutants in the Human Body (National Institute of Environmental Research, Korea). The general and occupational characteristics were gathered from 5136 participants who were 20 years of age and older using a structured questionnaire. Blood lead concentrations were analyzed using an atomic absorption spectrophotometer. Statistical analysis was performed using multiple linear regressions of the log lead concentrations to the independent variables such as age, gender, smoke, herbal medication and drug consumption, drinking water, and living area. Geometric mean (GM) blood lead concentrations in Korean adults were 19.7 μg/l. The blood lead concentrations increased with age; the highest concentrations were found in the 50-69-year age group (pdrug consumption were higher than those who did not (plead concentration (plead concentration (plead concentration, but not significantly. For drinking water, the underground water (spring or well water) drinking group had higher concentrations than other types of water drinking groups, but not significantly (p=0.063). The blood lead concentrations by occupation were significant (plead concentrations tended to decrease with increasing delivery times, but not significantly. The blood lead concentration (GM) of the general adult population in Korea has decreased over time from 45.8 μg/l (1999) to 19.7 μg/l (2008). Although it is still higher than in other countries such as the United States and Canada, it is rapidly decreasing. Gender, age, smoking and alcohol drinking status, herbal medication and drug consumption, education level, living area and occupation were significantly related to the blood lead concentrations in Korea. Copyright © 2014. Published by Elsevier GmbH.

  4. Polymeric nanoparticles for increased oral bioavailability and rapid absorption using celecoxib as a model of a low-solubility, high-permeability drug.

    Science.gov (United States)

    Morgen, Michael; Bloom, Corey; Beyerinck, Ron; Bello, Akintunde; Song, Wei; Wilkinson, Karen; Steenwyk, Rick; Shamblin, Sheri

    2012-02-01

    To demonstrate drug/polymer nanoparticles can increase the rate and extent of oral absorption of a low-solubility, high-permeability drug. Amorphous drug/polymer nanoparticles containing celecoxib were prepared using ethyl cellulose and either sodium caseinate or bile salt. Nanoparticles were characterized using dynamic light scattering, transmission and scanning electron microscopy, and differential scanning calorimetry. Drug release and resuspension studies were performed using high-performance liquid chromatography. Pharmacokinetic studies were performed in dogs and humans. A physical model is presented describing the nanoparticle state of matter and release performance. Nanoparticles dosed orally in aqueous suspensions provided higher systemic exposure and faster attainment of peak plasma concentrations than commercial capsules, with median time to maximum drug concentration (Tmax) of 0.75 h in humans for nanoparticles vs. 3 h for commercial capsules. Nanoparticles released celecoxib rapidly and provided higher dissolved-drug concentrations than micronized crystalline drug. Nanoparticle suspensions are stable for several days and can be spray-dried to form dry powders that resuspend in water. Drug/polymer nanoparticles are well suited for providing rapid oral absorption and increased bioavailability of BCS Class II drugs.

  5. Higher Maternal Protein Intake during Pregnancy Is Associated with Lower Cord Blood Concentrations of Insulin-like Growth Factor (IGF)-II, IGF Binding Protein 3, and Insulin, but Not IGF-I, in a Cohort of Women with High Protein Intake.

    Science.gov (United States)

    Switkowski, Karen M; Jacques, Paul F; Must, Aviva; Hivert, Marie-France; Fleisch, Abby; Gillman, Matthew W; Rifas-Shiman, Sheryl; Oken, Emily

    2017-07-01

    Background: Prenatal exposure to dietary protein may program growth-regulating hormones, consequently influencing early-life growth patterns and later risk of associated chronic diseases. The insulin-like growth factor (IGF) axis is of particular interest in this context given its influence on pre- and postnatal growth and its sensitivity to the early nutritional environment. Objective: Our objective was to examine associations of maternal protein intake during pregnancy with cord blood concentrations of IGF-I, IGF-II, IGF binding protein-3 (IGFBP-3), and insulin. Methods: We studied 938 mother-child pairs from early pregnancy through delivery in the Project Viva cohort. Using multivariable linear regression models adjusted for maternal race/ethnicity, education, income, smoking, parity, height, and gestational weight gain and for child sex, we examined associations of second-trimester maternal protein intake [grams per kilogram (weight before pregnancy) per day], as reported on a food frequency questionnaire, with IGF-I, IGF-II, IGFBP-3, and insulin concentrations in cord blood. We also examined how these associations may differ by child sex and parity. Results: Mothers were predominantly white (71%), college-educated (64%), and nonsmokers (67%). Mean ± SD protein intake was 1.35 ± 0.35 g ⋅ kg -1 ⋅ d -1 Each 1-SD increment in second-trimester protein intake corresponded to a change of -0.50 ng/mL (95% CI: -2.26, 1.26 ng/mL) in IGF-I and -0.91 μU/mL (95% CI: -1.45, -0.37 μU/mL) in insulin. Child sex and parity modified associations of maternal protein intake with IGF-II and IGFBP-3: protein intake was inversely associated with IGF-II in girls ( P -interaction = 0.04) and multiparous mothers ( P -interaction = 0.05), and with IGFBP-3 in multiparous mothers ( P -interaction = 0.04). Conclusions: In a cohort of pregnant women with relatively high mean protein intakes, higher intake was associated with lower concentrations of growth-promoting hormones in cord

  6. Realizing drug repositioning by adapting a recommendation system to handle the process.

    Science.gov (United States)

    Ozsoy, Makbule Guclin; Özyer, Tansel; Polat, Faruk; Alhajj, Reda

    2018-04-12

    Drug repositioning is the process of identifying new targets for known drugs. It can be used to overcome problems associated with traditional drug discovery by adapting existing drugs to treat new discovered diseases. Thus, it may reduce associated risk, cost and time required to identify and verify new drugs. Nowadays, drug repositioning has received more attention from industry and academia. To tackle this problem, researchers have applied many different computational methods and have used various features of drugs and diseases. In this study, we contribute to the ongoing research efforts by combining multiple features, namely chemical structures, protein interactions and side-effects to predict new indications of target drugs. To achieve our target, we realize drug repositioning as a recommendation process and this leads to a new perspective in tackling the problem. The utilized recommendation method is based on Pareto dominance and collaborative filtering. It can also integrate multiple data-sources and multiple features. For the computation part, we applied several settings and we compared their performance. Evaluation results show that the proposed method can achieve more concentrated predictions with high precision, where nearly half of the predictions are true. Compared to other state of the art methods described in the literature, the proposed method is better at making right predictions by having higher precision. The reported results demonstrate the applicability and effectiveness of recommendation methods for drug repositioning.

  7. A heuristic model to quantify the impact of excess cyclodextrin on oral drug absorption from aqueous solution

    DEFF Research Database (Denmark)

    Olesen, Niels Erik; Westh, Peter; Holm, René

    2016-01-01

    , the cyclodextrin concentration in the drug product must be higher than the amount needed to solubilise the compound, due to the displacement of the drug from the cyclodextrin cavity by bile salts in the intestinal lumen. On the other hand, dosing cyclodextrin at View the MathML source>DtotSC is expected to result...... the implication of having excess cyclodextrin in an oral solution....

  8. Drug Facts

    Medline Plus

    Full Text Available ... MDMA (Ecstasy, Molly) Facts Meth (Crank, Ice) Facts Pain Medicine (Oxy, Vike) Facts Spice (K2) Facts Tobacco ... Alcohol Bath Salts Cocaine Heroin Marijuana MDMA Meth Pain Medicines Spice (K2) Tobacco/Nicotine Other Drugs You ...

  9. Drug Facts

    Medline Plus

    Full Text Available ... Facts Bath Salts Facts Cocaine (Coke, Crack) Facts Heroin (Smack, Junk) Facts Marijuana (Weed, Pot) Facts MDMA ( ... Videos Information About Drugs Alcohol Bath Salts Cocaine Heroin Marijuana MDMA Meth Pain Medicines Spice (K2) Tobacco/ ...

  10. Drug Facts

    Medline Plus

    Full Text Available ... Cocaine (Coke, Crack) Facts Heroin (Smack, Junk) Facts Marijuana (Weed, Pot) Facts MDMA (Ecstasy, Molly) Facts Meth ( ... Information About Drugs Alcohol Bath Salts Cocaine Heroin Marijuana MDMA Meth Pain Medicines Spice (K2) Tobacco/Nicotine ...

  11. Drug Facts

    Medline Plus

    Full Text Available ... Heroin (Smack, Junk) Facts Marijuana (Weed, Pot) Facts MDMA (Ecstasy, Molly) Facts Meth (Crank, Ice) Facts Pain ... About Drugs Alcohol Bath Salts Cocaine Heroin Marijuana MDMA Meth Pain Medicines Spice (K2) Tobacco/Nicotine Other ...

  12. Drug Metabolism

    Indian Academy of Sciences (India)

    Home; Journals; Resonance – Journal of Science Education; Volume 19; Issue 3. Drug Metabolism: A Fascinating Link Between Chemistry and Biology. Nikhil Taxak Prasad V Bharatam. General Article Volume 19 Issue 3 March 2014 pp 259-282 ...

  13. Drugged Driving

    Science.gov (United States)

    ... Alcohol Club Drugs Cocaine Fentanyl Hallucinogens Inhalants Heroin Marijuana MDMA (Ecstasy/Molly) Methamphetamine Opioids Over-the-Counter Medicines Prescription Medicines Steroids (Anabolic) Synthetic Cannabinoids (K2/Spice) Synthetic Cathinones (Bath Salts) Tobacco/ ...

  14. Club Drugs

    Science.gov (United States)

    ... Alcohol Club Drugs Cocaine Fentanyl Hallucinogens Inhalants Heroin Marijuana MDMA (Ecstasy/Molly) Methamphetamine Opioids Over-the-Counter Medicines Prescription Medicines Steroids (Anabolic) Synthetic Cannabinoids (K2/Spice) Synthetic Cathinones (Bath Salts) Tobacco/ ...

  15. Drug Metabolism

    Indian Academy of Sciences (India)

    IAS Admin

    behind metabolic reactions, importance, and consequences with several ... required for drug action. ... lism, which is catalyzed by enzymes present in the above-men- ... catalyze the transfer of one atom of oxygen to a substrate produc-.

  16. Drug Facts

    Medline Plus

    Full Text Available ... Ecstasy, Molly) Facts Meth (Crank, Ice) Facts Pain Medicine (Oxy, Vike) Facts Spice (K2) Facts Tobacco and ... Bath Salts Cocaine Heroin Marijuana MDMA Meth Pain Medicines Spice (K2) Tobacco/Nicotine Other Drugs You can ...

  17. Drug Facts

    Medline Plus

    Full Text Available ... 800-662-HELP (4357) at any time to find drug treatment centers near you. I want my ... is making positive changes in her life. She finds support from family and friends who don't ...

  18. Drug Facts

    Medline Plus

    Full Text Available ... That People Abuse Alcohol Facts Bath Salts Facts Cocaine (Coke, Crack) Facts Heroin (Smack, Junk) Facts Marijuana (Weed, ... Watch Videos Information About Drugs Alcohol Bath Salts Cocaine Heroin Marijuana MDMA Meth Pain Medicines Spice (K2) ...

  19. Drug Facts

    Medline Plus

    Full Text Available ... Together The Link Between Drug Use and HIV/AIDS Treatment & Recovery Why Does a Person Need Treatment? ... of Health (NIH) , the principal biomedical and behavioral research agency of the United States Government. NIH is ...

  20. Drug Reactions

    Science.gov (United States)

    ... Kids and Teens Pregnancy and Childbirth Women Men Seniors Your Health Resources Healthcare Management End-of-Life Issues Insurance & Bills Self Care Working With Your Doctor Drugs, Procedures & Devices Over-the- ...

  1. Drug Facts

    Medline Plus

    Full Text Available ... prescription drugs. The addiction slowly took over his life. I need different people around me. To stop ... marijuana, "Cristina" is making positive changes in her life. She finds support from family and friends who ...

  2. Drug Resistance

    Science.gov (United States)

    ... Drug-resistance testing is also recommended for all pregnant women with HIV before starting HIV medicines and also in some pregnant women already taking HIV medicines. Pregnant women will work with their health ...

  3. Drug Facts

    Medline Plus

    Full Text Available ... Cocaine (Coke, Crack) Facts Heroin (Smack, Junk) Facts Marijuana (Weed, Pot) Facts MDMA (Ecstasy, Molly) Facts Meth (Crank, ... Information About Drugs Alcohol Bath Salts Cocaine Heroin Marijuana MDMA Meth Pain Medicines Spice (K2) Tobacco/Nicotine ...

  4. Drug Addiction

    Science.gov (United States)

    ... as hearing colors Impulsive behavior Rapid shifts in emotions Permanent mental changes in perception Rapid heart rate ... Drug use can negatively affect academic performance and motivation to excel in school. Legal issues. Legal problems ...

  5. Drug Facts

    Medline Plus

    Full Text Available ... That People Abuse Alcohol Facts Bath Salts Facts Cocaine (Coke, Crack) Facts Heroin (Smack, Junk) Facts Marijuana ( ... Watch Videos Information About Drugs Alcohol Bath Salts Cocaine Heroin Marijuana MDMA Meth Pain Medicines Spice (K2) ...

  6. Biochemistry of drugs. XXVII

    International Nuclear Information System (INIS)

    Raz, K.; Smolik, S.; Vinarova, M.; Janda, J.; Franc, Z.

    1979-01-01

    The erythro- and threoform of p-hydroxynorephedrine belong to the group of drugs affecting the course of hypertensive disease. For pharmacological studies both forms were labelled with 3 H radionuclide on the benzene ring. 90% of radioactivity was concentrated in the ortho positions with regard to the hydroxyl, 10% in the meta position. After the administration of the labelled drug to rats, rapid absorption occurs and radioactivity is eliminated from the organism, especially in the urine. Three radioactive substances were found in the urine of experimental animals. A substance with properties corresponding to those of the administered drug prevailed. The highest levels of radioactivity in the tissues were found after intravenous administration as early as after 5 minutes after administration, 15 minutes after subcutaneous administration. It was found that p-hydroxynorephedrine significantly restricted the detainment of labelled noradrenaline-7- 3 H in the tissues of premedicated animals. (author)

  7. Toxins and drug discovery.

    Science.gov (United States)

    Harvey, Alan L

    2014-12-15

    Components from venoms have stimulated many drug discovery projects, with some notable successes. These are briefly reviewed, from captopril to ziconotide. However, there have been many more disappointments on the road from toxin discovery to approval of a new medicine. Drug discovery and development is an inherently risky business, and the main causes of failure during development programmes are outlined in order to highlight steps that might be taken to increase the chances of success with toxin-based drug discovery. These include having a clear focus on unmet therapeutic needs, concentrating on targets that are well-validated in terms of their relevance to the disease in question, making use of phenotypic screening rather than molecular-based assays, and working with development partners with the resources required for the long and expensive development process. Copyright © 2014 The Author. Published by Elsevier Ltd.. All rights reserved.

  8. [Ozone concentration distribution of urban].

    Science.gov (United States)

    Yin, Yong-quan; Li, Chang-mei; Ma, Gui-xia; Cui, Zhao-jie

    2004-11-01

    The increase of ozone concentration in urban is one of the most important research topics on environmental science. With the increase of nitrogen oxides and hydrogen-carbon compounds which are exhausted from cars, the ozone concentration in urban is obviously increased on sunlight, and threat of photochemistry smog will be possible. Therefore, it is very important to monitor and study the ozone concentration distribution in urban. The frequency-distribution, diurnal variation and monthly variation of ozone concentration were studied on the campus of Shandong University during six months monitoring. The influence of solar radiation and weather conditions on ozone concentration were discussed. The frequency of ozone concentration less than 200 microg/m3 is 96.88%. The ozone concentration has an obvious diurnal variation. The ozone concentration in the afternoon is higher than in the morning and in the evening. The maximum appears in June, when it is the strong solar radiation and high air-temperature. The weather conditions also influence the ozone concentration. The ozone concentration in clear day is higher than in rainy and cloudy day.

  9. Enhanced drug delivery capabilities from stents coated with absorbable polymer and crystalline drug

    OpenAIRE

    Carlyle, Wenda C.; McClain, James B.; Tzafriri, Abraham R.; Bailey, Lynn; Zani, Brett G.; Markham, Peter M.; Stanley, James R.L.; Edelman, Elazer R.

    2012-01-01

    Current drug eluting stent (DES) technology is not optimized with regard to the pharmacokinetics of drug delivery. A novel, absorbable-coating sirolimus-eluting stent (AC-SES) was evaluated for its capacity to deliver drug more evenly within the intimal area rather than concentrating drug around the stent struts and for its ability to match coating erosion with drug release. The coating consisted of absorbable poly-lactide-co-glycolic acid (PLGA) and crystalline sirolimus deposited by a dry-p...

  10. Intra-cystic concentrations of albendazole-sulphoxide in human cystic echinococcosis: a systematic review and analysis of individual patient data.

    Science.gov (United States)

    Lötsch, Felix; Naderer, Judith; Skuhala, Tomislava; Groger, Mirjam; Auer, Herbert; Kaczirek, Klaus; Waneck, Fredrik; Ramharter, Michael

    2016-08-01

    Cystic echinococcosis (CE) is a widespread zoonosis caused by the species complex Echinococcus granulosus. Albendazole (ABZ)-the first-line anthelminthic drug for medical treatment of CE-is metabolized in vivo to the active derivative ABZ-sulphoxide (ABZ-SO). Target-site ABZ-SO concentrations in the hydatid cyst mediate the anthelminthic effect in CE. Primary outcome of this systematic review of individual patient data was the intra-cystic ABZ-SO concentration stratified by cyst size, location, calcification status and use of praziquantel. Studies reporting intra-cystic ABZ-SO concentrations in humans were identified by a systematic search. A pooled analysis of individual patient data was performed to assess intra-cystic concentrations. Pharmacokinetic data of 121 individual cysts were analysed. There was no correlation between plasma and intra-cystic ABZ-SO concentrations (rho = -0.03, p = 0.76). Intra-cystic drug concentrations were also not associated with sex and treatment duration. Use of praziquantel in combination with ABZ was associated with higher plasma (median 540 vs. 240 μg/L; p = 0.04) but not intra-cystic ABZ-SO concentrations (median 220 vs. 199 μg/L; p = 0.36). Relative drug concentrations in hepatic cysts were higher than in other cysts (0.8 vs. 0.4; p = 0.05). Intra-cystic concentrations were higher in calcified than non-calcified cysts (median 897 vs. 245 μg/L; p = 0.03). There was a trend towards higher intra-cystic concentrations in smaller sized cysts (β = -17.2 μg/L/cm; 95th CI, -35.9 to 1.6; p = 0.07). This study demonstrates that mean intra-cystic drug concentrations are similar to plasma concentrations on a population level. However, in individual patients plasma concentrations are not directly predictive for intra-cystic concentrations. The use of booster drugs was not associated with higher intra-cystic ABZ-SO concentrations in this analysis.

  11. Construction of a novel pH-sensitive drug release system from mesoporous silica tablets coated with Eudragit

    Science.gov (United States)

    Xu, Yingpu; Qu, Fengyu; Wang, Yu; Lin, Huiming; Wu, Xiang; Jin, Yingxue

    2011-03-01

    A novel pH-sensitive drug release system has been established by coating Eudragit (Eud) on drug-loaded mesoporous silica (MS) tablets. The release rate of ibuprofen (IBU) from the MS was retarded by coating with Eudragit S-100, and the higher retardation was due to the increase of coating concentration and the coating layers. The target position of the release depended on the pH of the release medium, which was confirmed by the drug release from IBU/MS/Eud increasing rapidly with the change of medium pH from 1.2 to 7.4. This drug delivery system could prohibit irritant drug from leaking in the stomach and make it only release in the intestine. The loaded and unloaded drug samples were characterized by powder X-ray diffraction (XRD), Fourier transform infrared spectrometer (FTIR), N 2 adsorption/desorption, scanning electron microscopy (SEM), and transmission electron microscopy (TEM).

  12. Interactions between a poorly soluble cationic drug and sodium dodecyl sulfate in dissolution medium and their impact on in vitro dissolution behavior.

    Science.gov (United States)

    Huang, Zongyun; Parikh, Shuchi; Fish, William P

    2018-01-15

    In the pharmaceutical industry, in vitro dissolution testing ofsolid oral dosage forms is a very important tool for drug development and quality control. However, ion-pairing interaction between the ionic drugand surfactants in dissolution medium often occurs, resulting in inconsistent and incomplete drug release. The aim of this study is toevaluate the effects ofsodium dodecyl sulfate (SDS) mediated medium onthe dissolution behaviors of a poorly soluble cationic drug (Drug B). The study was carried out by measuring solubility of Drug B substance and dissolution rate of Drug B product in media containing SDS.Desolubilization of Drug B substance was observed at pH 4.5 in the presence of SDS at concentrations below critical micelle concentration (CMC) which is attributed to the formation of an insoluble di-dodecyl sulfate salt between SDS and Drug B. This ion-pairing effect is less significant with increasing medium pH where Drug B is less ionized and CMC of SDS is lower. In medium at pH 4.5, dissolution of Drug B product was found incomplete with SDS concentration below CMC due to the desolubilization of Drug B substance. In media with SDS level above CMC, the dissolution rate is rather slower with higher inter-vessel variations compared to that obtained in pH 4.5 medium without SDS. The dissolution results demonstrate that the presence of SDS in medium generates unexpected irregular dissolution profiles for Drug B which are attributed to incompatible dissolution medium for this particular drug. Therefore, non-ionic surfactant was selected for Drug B product dissolution method and ion-pairing effect in SDS mediated medium should be evaluated when developing a dissolution method for any poorly soluble cationic drugs. Copyright © 2017 Elsevier B.V. All rights reserved.

  13. Postmortem Femoral Blood Concentrations of Risperidone

    DEFF Research Database (Denmark)

    Linnet, Kristian; Johansen, Sys Stybe

    2014-01-01

    Postmortem femoral blood concentrations of the antipsychotic drug risperidone and the active metabolite 9-hydroxyrisperidone were determined by an achiral LC-MS/MS method in 38 cases. The cause of death was classified as unrelated to risperidone in 30 cases, in which the sum of the concentration ...

  14. Higher Education and Inequality

    Science.gov (United States)

    Brown, Roger

    2018-01-01

    After climate change, rising economic inequality is the greatest challenge facing the advanced Western societies. Higher education has traditionally been seen as a means to greater equality through its role in promoting social mobility. But with increased marketisation higher education now not only reflects the forces making for greater inequality…

  15. Higher Education in California

    Science.gov (United States)

    Public Policy Institute of California, 2016

    2016-01-01

    Higher education enhances Californians' lives and contributes to the state's economic growth. But population and education trends suggest that California is facing a large shortfall of college graduates. Addressing this short­fall will require strong gains for groups that have been historically under­represented in higher education. Substantial…

  16. Reimagining Christian Higher Education

    Science.gov (United States)

    Hulme, E. Eileen; Groom, David E., Jr.; Heltzel, Joseph M.

    2016-01-01

    The challenges facing higher education continue to mount. The shifting of the U.S. ethnic and racial demographics, the proliferation of advanced digital technologies and data, and the move from traditional degrees to continuous learning platforms have created an unstable environment to which Christian higher education must adapt in order to remain…

  17. Happiness in Higher Education

    Science.gov (United States)

    Elwick, Alex; Cannizzaro, Sara

    2017-01-01

    This paper investigates the higher education literature surrounding happiness and related notions: satisfaction, despair, flourishing and well-being. It finds that there is a real dearth of literature relating to profound happiness in higher education: much of the literature using the terms happiness and satisfaction interchangeably as if one were…

  18. Gender and Higher Education

    Science.gov (United States)

    Bank, Barbara J., Ed.

    2011-01-01

    This comprehensive, encyclopedic review explores gender and its impact on American higher education across historical and cultural contexts. Challenging recent claims that gender inequities in U.S. higher education no longer exist, the contributors--leading experts in the field--reveal the many ways in which gender is embedded in the educational…

  19. Lapatinib Plasma and Tumor Concentrations and Effects on HER Receptor Phosphorylation in Tumor.

    Directory of Open Access Journals (Sweden)

    Neil L Spector

    Full Text Available The paradigm shift in cancer treatment from cytotoxic drugs to tumor targeted therapies poses new challenges, including optimization of dose and schedule based on a biologically effective dose, rather than the historical maximum tolerated dose. Optimal dosing is currently determined using concentrations of tyrosine kinase inhibitors in plasma as a surrogate for tumor concentrations. To examine this plasma-tumor relationship, we explored the association between lapatinib levels in tumor and plasma in mice and humans, and those effects on phosphorylation of human epidermal growth factor receptors (HER in human tumors.Mice bearing BT474 HER2+ human breast cancer xenografts were dosed once or twice daily (BID with lapatinib. Drug concentrations were measured in blood, tumor, liver, and kidney. In a randomized phase I clinical trial, 28 treatment-naïve female patients with early stage HER2+ breast cancer received lapatinib 1000 or 1500 mg once daily (QD or 500 mg BID before evaluating steady-state lapatinib levels in plasma and tumor.In mice, lapatinib levels were 4-fold higher in tumor than blood with a 4-fold longer half-life. Tumor concentrations exceeded the in vitro IC90 (~ 900 nM or 500 ng/mL for inhibition of HER2 phosphorylation throughout the 12-hour dosing interval. In patients, tumor levels were 6- and 10-fold higher with QD and BID dosing, respectively, compared to plasma trough levels. The relationship between tumor and plasma concentration was complex, indicating multiple determinants. HER receptor phosphorylation varied depending upon lapatinib tumor concentrations, suggestive of changes in the repertoire of HER homo- and heterodimers.Plasma lapatinib concentrations underestimated tumor drug levels, suggesting that optimal dosing should be focused on the site of action to avoid to inappropriate dose escalation. Larger clinical trials are required to determine optimal dose and schedule to achieve tumor concentrations that maximally

  20. Legal Drugs Are Good Drugs and Illegal Drugs Are Bad Drugs

    OpenAIRE

    Indrati, Dina; Prasetyo, Herry

    2011-01-01

    ABSTRACT : Labelling drugs are important issue nowadays in a modern society. Although it is generally believed that legal drugs are good drugs and illegal drugs are bad drugs, it is evident that some people do not aware about the side effects of drugs used. Therefore, a key contention of this philosophical essay is that explores harms minimisation policy, discuss whether legal drugs are good drugs and illegal drugs are bad drugs and explores relation of drugs misuse in a psychiatric nursing s...

  1. Quality of Higher Education

    DEFF Research Database (Denmark)

    Zou, Yihuan

    is about constructing a more inclusive understanding of quality in higher education through combining the macro, meso and micro levels, i.e. from the perspectives of national policy, higher education institutions as organizations in society, individual teaching staff and students. It covers both......Quality in higher education was not invented in recent decades – universities have always possessed mechanisms for assuring the quality of their work. The rising concern over quality is closely related to the changes in higher education and its social context. Among others, the most conspicuous...... changes are the massive expansion, diversification and increased cost in higher education, and new mechanisms of accountability initiated by the state. With these changes the traditional internally enacted academic quality-keeping has been given an important external dimension – quality assurance, which...

  2. Drugs@FDA: FDA Approved Drug Products

    Science.gov (United States)

    ... Cosmetics Tobacco Products Home Drug Databases Drugs@FDA Drugs@FDA: FDA Approved Drug Products Share Tweet Linkedin Pin it More sharing ... Download Drugs@FDA Express for free Search by Drug Name, Active Ingredient, or Application Number Enter at ...

  3. Effect of protein binding on unbound atazanavir and darunavir cerebrospinal fluid concentrations.

    Science.gov (United States)

    Delille, Cecile A; Pruett, Sarah T; Marconi, Vincent C; Lennox, Jeffrey L; Armstrong, Wendy S; Arrendale, Richard F; Sheth, Anandi N; Easley, Kirk A; Acosta, Edward P; Vunnava, Aswani; Ofotokun, Ighovwerha

    2014-09-01

    HIV-1 protease inhibitors (PIs) exhibit different protein binding affinities and achieve variable plasma and tissue concentrations. Degree of plasma protein binding may impact central nervous system penetration. This cross-sectional study assessed cerebrospinal fluid (CSF) unbound PI concentrations, HIV-1 RNA, and neopterin levels in subjects receiving either ritonavir-boosted darunavir (DRV), 95% plasma protein bound, or atazanavir (ATV), 86% bound. Unbound PI trough concentrations were measured using rapid equilibrium dialysis and liquid chromatography/tandem mass spectrometry. Plasma and CSF HIV-1 RNA and neopterin were measured by Ampliprep/COBAS® Taqman® 2.0 assay (Roche) and enzyme-linked immunosorbent assay (ALPCO), respectively. CSF/plasma unbound drug concentration ratio was higher for ATV, 0.09 [95% confidence interval (CI) 0.06-0.12] than DRV, 0.04 (95%CI 0.03-0.06). Unbound CSF concentrations were lower than protein adjusted wild-type inhibitory concentration-50 (IC50 ) in all ATV and 1 DRV-treated subjects (P < 0.001). CSF HIV-1 RNA was detected in 2/15 ATV and 4/15 DRV subjects (P = 0.65). CSF neopterin levels were low and similar between arms. ATV relative to DRV had higher CSF/plasma unbound drug ratio. Low CSF HIV-1 RNA and neopterin suggest that both regimens resulted in CSF virologic suppression and controlled inflammation. © 2014, The American College of Clinical Pharmacology.

  4. Study Drugs

    OpenAIRE

    Lam, Stephanie Phuong; Roosta, Natalie; Nielsen, Mikkel Fuhr; Meyer, Maria Holmgaard; Friis, Katrine Birk

    2016-01-01

    In recent years, students around the world, started to use preparations as Ritalin and Modafinil,also known as study drugs, to improve their cognitive abilities1. It is a common use among thestudents in United States of America, but it is a new tendency in Denmark. Our main focus is tolocate whether study drugs needs to be legalized in Denmark or not. To investigate this ourstarting point is to understand central ethical arguments in the debate. We have chosen twoarguments from Nick Bostrom a...

  5. Repurposing salicylanilide anthelmintic drugs to combat drug resistant Staphylococcus aureus.

    Science.gov (United States)

    Rajamuthiah, Rajmohan; Fuchs, Beth Burgwyn; Conery, Annie L; Kim, Wooseong; Jayamani, Elamparithi; Kwon, Bumsup; Ausubel, Frederick M; Mylonakis, Eleftherios

    2015-01-01

    Staphylococcus aureus is a Gram-positive bacterium that has become the leading cause of hospital acquired infections in the US. Repurposing Food and Drug Administration (FDA) approved drugs for antimicrobial therapy involves lower risks and costs compared to de novo development of novel antimicrobial agents. In this study, we examined the antimicrobial properties of two commercially available anthelmintic drugs. The FDA approved drug niclosamide and the veterinary drug oxyclozanide displayed strong in vivo and in vitro activity against methicillin resistant S. aureus (minimum inhibitory concentration (MIC): 0.125 and 0.5 μg/ml respectively; minimum effective concentration: ≤ 0.78 μg/ml for both drugs). The two drugs were also effective against another Gram-positive bacteria Enterococcus faecium (MIC 0.25 and 2 μg/ml respectively), but not against the Gram-negative species Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacter aerogenes. The in vitro antimicrobial activity of niclosamide and oxyclozanide were determined against methicillin, vancomycin, linezolid or daptomycin resistant S. aureus clinical isolates, with MICs at 0.0625-0.5 and 0.125-2 μg/ml for niclosamide and oxyclozanide respectively. A time-kill study demonstrated that niclosamide is bacteriostatic, whereas oxyclozanide is bactericidal. Interestingly, oxyclozanide permeabilized the bacterial membrane but neither of the anthelmintic drugs exhibited demonstrable toxicity to sheep erythrocytes. Oxyclozanide was non-toxic to HepG2 human liver carcinoma cells within the range of its in vitro MICs but niclosamide displayed toxicity even at low concentrations. These data show that the salicylanilide anthelmintic drugs niclosamide and oxyclozanide are suitable candidates for mechanism of action studies and further clinical evaluation for treatment of staphylococcal infections.

  6. Serum concentrations of buprenorphine after oral and parenteral administration in male mice

    DEFF Research Database (Denmark)

    Kalliokoski, Otto; Jacobsen, Kirsten R; Hau, Jann

    2011-01-01

    Buprenorphine is the most commonly used drug for peri-operative pain relief in laboratory rodents. The systemic concentrations of buprenorphine were measured in mice following administration intravenously (IV), subcutaneously (SC), orally by gavage and by voluntary ingestion, to determine the post-administration...... serum concentration of buprenorphine. Voluntarily ingested buprenorphine resulted in long-lasting high serum concentrations, as did oral gavage administration (24h serum concentration: 110ngh/mL for both routes of administration). In contrast, buprenorphine administered parenterally remained...... in the circulation for a substantially shorter time (24h serum concentration for IV and SC were 40ngh/mL and 30ngh/mL, respectively). This marked difference was probably due to the higher dose used for oral administration, which is regarded necessary for sufficient analgesic effect, and to the slower absorption...

  7. SU-D-201-04: Study On the Impact of Tumor Shape and Size On Drug Delivery to Pancreatic Tumors

    International Nuclear Information System (INIS)

    Soltani, M; Bazmara, H; Sefidgar, M; Subramaniam, R; Rahmim, A

    2015-01-01

    Purpose: Drug delivery to solid tumors can be expressed physically using transport phenomena such as convection and diffusion for the drug of interest within extracellular matrices. We aimed to carefully model these phenomena, and to investigate the effect of tumor shape and size on drug delivery to solid tumors in the pancreas. Methods: In this study, multiple tumor geometries as obtained from clinical PET/CT images were considered. An advanced numerical method was used to simultaneously solve fluid flow and solute transport equations. Data from n=45 pancreatic cancer patients with non-resectable locoregional disease were analyzed, and geometrical information from the tumors including size, shape, and aspect ratios were classified. To investigate effect of tumor shape, tumors with similar size but different shapes were selected and analyzed. Moreover, to investigate effect of tumor size, tumors with similar shapes but different sizes, ranging from 1 to 77 cm 3 , were selected and analyzed. A hypothetical tumor similar to one of the analyzed tumors, but scaled to reduce its size below 0.2 cm 3 , was also analyzed. Results: The results showed relatively similar average drug concentration profiles in tumors with different sizes. Generally, smaller tumors had higher absolute drug concentration. In the hypothetical tumor, with volume less than 0.2 cm 3 , the average drug concentration was 20% higher in comparison to its counterparts. For the various real tumor geometries, however, the maximum difference between average drug concentrations was 10% for the smallest and largest tumors. Moreover, the results demonstrated that for pancreatic tumors the shape is not significant. The negligible difference of drug concentration in different tumor shapes was due to the minimum effect of convection in pancreatic tumors. Conclusion: In tumors with different sizes, smaller tumors have higher drug delivery; however, the impact of tumor shape in the case of pancreatic tumors is not

  8. SU-D-201-04: Study On the Impact of Tumor Shape and Size On Drug Delivery to Pancreatic Tumors

    Energy Technology Data Exchange (ETDEWEB)

    Soltani, M [ohns Hopkins University School of Medicine, Baltimore, Maryland, and KNT university, Tehran (Iran, Islamic Republic of); Bazmara, H [KNT university, Tehran (Iran, Islamic Republic of); Sefidgar, M [IKI University, Qazvin (Iran, Islamic Republic of); Subramaniam, R; Rahmim, A [Johns Hopkins University School of Medicine, Baltimore, MD (United States)

    2015-06-15

    Purpose: Drug delivery to solid tumors can be expressed physically using transport phenomena such as convection and diffusion for the drug of interest within extracellular matrices. We aimed to carefully model these phenomena, and to investigate the effect of tumor shape and size on drug delivery to solid tumors in the pancreas. Methods: In this study, multiple tumor geometries as obtained from clinical PET/CT images were considered. An advanced numerical method was used to simultaneously solve fluid flow and solute transport equations. Data from n=45 pancreatic cancer patients with non-resectable locoregional disease were analyzed, and geometrical information from the tumors including size, shape, and aspect ratios were classified. To investigate effect of tumor shape, tumors with similar size but different shapes were selected and analyzed. Moreover, to investigate effect of tumor size, tumors with similar shapes but different sizes, ranging from 1 to 77 cm{sup 3}, were selected and analyzed. A hypothetical tumor similar to one of the analyzed tumors, but scaled to reduce its size below 0.2 cm{sup 3}, was also analyzed. Results: The results showed relatively similar average drug concentration profiles in tumors with different sizes. Generally, smaller tumors had higher absolute drug concentration. In the hypothetical tumor, with volume less than 0.2 cm{sup 3}, the average drug concentration was 20% higher in comparison to its counterparts. For the various real tumor geometries, however, the maximum difference between average drug concentrations was 10% for the smallest and largest tumors. Moreover, the results demonstrated that for pancreatic tumors the shape is not significant. The negligible difference of drug concentration in different tumor shapes was due to the minimum effect of convection in pancreatic tumors. Conclusion: In tumors with different sizes, smaller tumors have higher drug delivery; however, the impact of tumor shape in the case of pancreatic

  9. Neuropharmacological Consequences of Variant Drugs

    Directory of Open Access Journals (Sweden)

    Mahnoor Amjad Butt

    2017-11-01

    Full Text Available Neuropharmacological effects deals with the influence of drugs on nervous system which harvest the changes in mood, behavioral action of an individual. The drugs are characterized by the chemical substances that communicate with the neurons which have different impacts on nervous system. It may either conducts the abusive or pleasure response which depends on the neural chemicals activity and concerns with the licit and illicit drugs. The elucidation of drugs via LC/MS shows its exertion on the brain components. The computational model helps in the identification of signaling pathways that trigger or inhibit the neurotransmitters. The licit drugs have indisputable responses on CNS. It imparts neuroprotection by either stimulating or inhibiting the receptor, by down regulation yield antinociceptors. However, the illicit drugs have negative acknowledgment on the body as in nicotine the fewer amounts provides benefits but in higher amount mimics the activity of brain receptors and replaces it. Many other drugs induce neurodegenerative disorders. Due to advances in field of neuropharmacology innumerable drugs are available for feasible treatment. The main objective of this review is neuropharmacological consequences in correlation to licit and illicit drugs that what type of responses generated by using these drugs, the neurodegenerative disorders, and their restoration via current treatment.

  10. Higher English for CFE

    CERN Document Server

    Bridges, Ann; Mitchell, John

    2015-01-01

    A brand new edition of the former Higher English: Close Reading , completely revised and updated for the new Higher element (Reading for Understanding, Analysis and Evaluation) - worth 30% of marks in the final exam!. We are working with SQA to secure endorsement for this title. Written by two highly experienced authors this book shows you how to practice for the Reading for Understanding, Analysis and Evaluation section of the new Higher English exam. This book introduces the terms and concepts that lie behind success and offers guidance on the interpretation of questions and targeting answer

  11. Topical Drugs for Pain Relief

    Directory of Open Access Journals (Sweden)

    Anjali Srinivasan

    2015-03-01

    Full Text Available Topical therapy helps patients with oral and perioral pain problems such as ulcers, burning mouth syndrome, temporomandibular disorders, neuromas, neuropathies and neuralgias. Topical drugs used in the field of dentistry are topical anaesthetics, topical analgesics, topical antibiotics and topical corticosteroids. It provides symptomatic/curative effect. Topical drugs are easy to apply, avoids hepatic first pass metabolism and more sites specific. But it can only be used for medications that require low plasma concentrations to achieve a therapeutic effect.

  12. Drugs and taste aversion

    International Nuclear Information System (INIS)

    Rondeau, D.B.; Jolicoeur, F.B.; Merkel, A.D.; Wayner, M.J.

    1981-01-01

    The literature on the effects of drugs on the acquisition and the magnitude of taste aversion is reviewed and discussed. Then, the results of a series of experiments on the effects of phenobarbital and related drugs on taste aversion are reported. A standard taste aversion model was used in all experiments; test drugs were injected prior to drinking in a one bottle situation on the first test day following the taste aversion treatment. Phenobarbital in doses ranging from 20 to 80 mg/kg significantly attenuated taste aversion induced by lithium chloride (LiCl) and x-radiation, the maximal effect occurred with the 60 mg/kg dose. The attenuating effect was found to be dependent upon the magnitude of the aversion to the sapid solution. Phenobarbital completely abolished aversion produced by 0.375 mEq LiCl while the attenuation effect decreased linearly with higher doses of LiCl. Results also indicate that phenobarbital's attenuating effect cannot be solely attributed to its dipsogenic characteristic or to its state dependent learning effect. Attenuation of LiCl aversion to a saccharin solution was also observed following single doses of amobarbital, 30 mg/kg, pentobarbital, 15 mg/kg, and chloropromazine, 0.75 mg/kg. Taste aversion was not affected by other doses of those drugs or by hexobarbital, barbital, and chlordiazepoxide. Phenobarbital's attenuating effect on taste aversion is discussed in relation to other known behavioral and neurophysiological effects of the drug

  13. Drug Facts

    Medline Plus

    Full Text Available ... Phone Numbers and Websites Search Share Listen English Español Information about this page Click on the button ... sobre el abuso de drogas, y adicción. English Español About the National Institute on Drug Abuse (NIDA) | ...

  14. Drugs reviews

    African Journals Online (AJOL)

    Angel_D

    tests (LFTs) to monitor hepatotoxicity (liver [hepatic] damage) is uncommon in many resource-poor ... cholesterol ester storage disease. ... The problem with many patients is that they are taking several drugs often ... Urine, saliva and other body fluids may be coloured orange-red: this can be very alarming to patients.

  15. Drug resistance

    NARCIS (Netherlands)

    Gorter, J.A.; Potschka, H.; Noebels, J.L.; Avoli, M.; Rogawski, M.A.; Olsen, R.W.; Delgado-Escueta, A.V.

    2012-01-01

    Drug resistance remains to be one of the major challenges in epilepsy therapy. Identification of factors that contribute to therapeutic failure is crucial for future development of novel therapeutic strategies for difficult-to-treat epilepsies. Several clinical studies have shown that high seizure

  16. Capping Drugs

    Indian Academy of Sciences (India)

    preventing disease in human beings or in animals. In the process ... of requirement. In the process, they may cause toxic side effects. .... the liver to release the physiologically active drug. Similarly ... patients addicted to alcohol. However, it is a ...

  17. Drug Facts

    Medline Plus

    Full Text Available ... Prevention Phone Numbers and Websites Search Share Listen English Español Information about this page Click on the ... información sobre el abuso de drogas, y adicción. English Español About the National Institute on Drug Abuse ( ...

  18. Planning for Higher Education.

    Science.gov (United States)

    Lindstrom, Caj-Gunnar

    1984-01-01

    Decision processes for strategic planning for higher education institutions are outlined using these parameters: institutional goals and power structure, organizational climate, leadership attitudes, specific problem type, and problem-solving conditions and alternatives. (MSE)

  19. Advert for higher education

    OpenAIRE

    N.V. Provozin; А.S. Teletov

    2011-01-01

    The article discusses the features advertising higher education institution. The analysis results of marketing research students for their choice of institutions and further study. Principles of the advertising campaign on three levels: the university, the faculty, the separate department.

  20. On higher derivative gravity

    International Nuclear Information System (INIS)

    Accioly, A.J.

    1987-01-01

    A possible classical route conducting towards a general relativity theory with higher-derivatives starting, in a sense, from first principles, is analysed. A completely causal vacuum solution with the symmetries of the Goedel universe is obtained in the framework of this higher-derivative gravity. This very peculiar and rare result is the first known vcuum solution of the fourth-order gravity theory that is not a solution of the corresponding Einstein's equations.(Author) [pt

  1. Higher Spins & Strings

    CERN Multimedia

    CERN. Geneva

    2014-01-01

    The conjectured relation between higher spin theories on anti de-Sitter (AdS) spaces and weakly coupled conformal field theories is reviewed. I shall then outline the evidence in favour of a concrete duality of this kind, relating a specific higher spin theory on AdS3 to a family of 2d minimal model CFTs. Finally, I shall explain how this relation fits into the framework of the familiar stringy AdS/CFT correspondence.

  2. Drug abuse first aid

    Science.gov (United States)

    ... use of these drugs is a form of drug abuse. Medicines that are for treating a health problem ... about local resources. Alternative Names Overdose from drugs; Drug abuse first aid References Myck MB. Hallucinogens and drugs ...

  3. Bioresponsive matrices in drug delivery

    Directory of Open Access Journals (Sweden)

    Ye George JC

    2010-11-01

    Full Text Available Abstract For years, the field of drug delivery has focused on (1 controlling the release of a therapeutic and (2 targeting the therapeutic to a specific cell type. These research endeavors have concentrated mainly on the development of new degradable polymers and molecule-labeled drug delivery vehicles. Recent interest in biomaterials that respond to their environment have opened new methods to trigger the release of drugs and localize the therapeutic within a particular site. These novel biomaterials, usually termed "smart" or "intelligent", are able to deliver a therapeutic agent based on either environmental cues or a remote stimulus. Stimuli-responsive materials could potentially elicit a therapeutically effective dose without adverse side effects. Polymers responding to different stimuli, such as pH, light, temperature, ultrasound, magnetism, or biomolecules have been investigated as potential drug delivery vehicles. This review describes the most recent advances in "smart" drug delivery systems that respond to one or multiple stimuli.

  4. Detection and aggregation of the antitumoral drug parietin in ethanol/water mixture and on plasmonic metal nanoparticles studied by surface-enhanced optical spectroscopy: Effect of pH and ethanol concentration

    Science.gov (United States)

    Lopez-Tobar, Eduardo; Verebova, Valeria; Blascakova, Ludmila; Jancura, Daniel; Fabriciova, Gabriela; Sanchez-Cortes, Santiago

    2016-04-01

    In the present paper, we have investigated the effect of ethanol in aqueous media, the pH and the presence of Ag nanoparticles (NPs) on the aggregation processes of the antitumoral anthraquinone parietin in aqueous media and on the metal surface. UV-visible absorption, fluorescence and Raman spectra of parietin were used for such purpose. The present study provides information about the deprotonation and molecular aggregation processes occurring in parietin under different environments: ethanol/water mixture and when adsorbed onto Ag nanoparticles. The effect of ethanol on the optical properties of parietin in alcohol-water mixtures was also investigated at different ethanol concentrations with the time. For the case of the adsorption and organization of parietin molecules on the surface of Ag NPs, special attention was paid to the use of surface-enhanced optical techniques, SEF (surface-enhanced fluorescence) and SERS (surface-enhanced Raman scattering), for the characterization of the parietin aggregates and the ionization of the molecule on the surface. In particular, we have studied the variation of the SEF signal with the pH, which depends on the molecular organization of the molecule on the surface. Furthermore, a detailed analysis of the SERS spectra at different pH was accomplished and the main Raman bands of the protonated, mono-deprotonated and di-deprotonated parietin were identified. Finally, the second ionization pK of parietin on metal NPs was deduced from the SERS spectra.

  5. 21 CFR 169.176 - Concentrated vanilla extract.

    Science.gov (United States)

    2010-04-01

    ... content of ethyl alcohol is not less than 35 percent by volume. (b) The specified name of the food is... 21 Food and Drugs 2 2010-04-01 2010-04-01 false Concentrated vanilla extract. 169.176 Section 169.176 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED...

  6. Multiple sclerosis influences on the augmentation of serum Klotho concentration

    DEFF Research Database (Denmark)

    Ahmadi, Mona; Aleagha, Mohammad Sajad Emami; Harirchian, Mohammad Hossein

    2016-01-01

    We have already shown that the concentration of secreted form of Klotho decreases in the cerebrospinal fluid of patients with relapsing–remitting multiple sclerosis (RRMS). The current study aimed at assessing possible changes in the serum Klotho concentration of MS patients. Participants involved...... 15 new cases of RRMS patients in the relapse phase, 15 RRMS patients who had been suffering from the disease for more than three years and were under regular treatments (interferon beta-1a) and, finally, 15 non-MS patients who constituted the control group. Beside thorough neurological examinations...... to be higher in MS patients when compared to control group. This finding might be attributed to treatment of MS patients with immunomodulatory drugs or a compensatory response to enhance CNS regeneration and/or vitamin D biosynthesis. Further studies are required to elucidate the role of Klotho in MS...

  7. 21 CFR 146.145 - Orange juice from concentrate.

    Science.gov (United States)

    2010-04-01

    ... 21 Food and Drugs 2 2010-04-01 2010-04-01 false Orange juice from concentrate. 146.145 Section 146... Juices and Beverages § 146.145 Orange juice from concentrate. (a) Orange juice from concentrate is the food prepared by mixing water with frozen concentrated orange juice as defined in § 146.146 or with...

  8. 21 CFR 146.150 - Canned concentrated orange juice.

    Science.gov (United States)

    2010-04-01

    ... 21 Food and Drugs 2 2010-04-01 2010-04-01 false Canned concentrated orange juice. 146.150 Section... Fruit Juices and Beverages § 146.150 Canned concentrated orange juice. (a) Canned concentrated orange... labeling of ingredients prescribed for frozen concentrated orange juice by § 146.146, except that it is not...

  9. Mathematical Modeling and Experimental Validation of Nanoemulsion-Based Drug Transport across Cellular Barriers.

    Science.gov (United States)

    Kadakia, Ekta; Shah, Lipa; Amiji, Mansoor M

    2017-07-01

    Nanoemulsions have shown potential in delivering drug across epithelial and endothelial cell barriers, which express efflux transporters. However, their transport mechanisms are not entirely understood. Our goal was to investigate the cellular permeability of nanoemulsion-encapsulated drugs and apply mathematical modeling to elucidate transport mechanisms and sensitive nanoemulsion attributes. Transport studies were performed in Caco-2 cells, using fish oil nanoemulsions and a model substrate, rhodamine-123. Permeability data was modeled using a semi-mechanistic approach, capturing the following cellular processes: endocytotic uptake of the nanoemulsion, release of rhodamine-123 from the nanoemulsion, efflux and passive permeability of rhodamine-123 in aqueous solution. Nanoemulsions not only improved the permeability of rhodamine-123, but were also less sensitive to efflux transporters. The model captured bidirectional permeability results and identified sensitive processes, such as the release of the nanoemulsion-encapsulated drug and cellular uptake of the nanoemulsion. Mathematical description of cellular processes, improved our understanding of transport mechanisms, such as nanoemulsions don't inhibit efflux to improve drug permeability. Instead, their endocytotic uptake, results in higher intracellular drug concentrations, thereby increasing the concentration gradient and transcellular permeability across biological barriers. Modeling results indicated optimizing nanoemulsion attributes like the droplet size and intracellular drug release rate, may further improve drug permeability.

  10. Fuel Class Higher Alcohols

    KAUST Repository

    Sarathy, Mani

    2016-08-17

    This chapter focuses on the production and combustion of alcohol fuels with four or more carbon atoms, which we classify as higher alcohols. It assesses the feasibility of utilizing various C4-C8 alcohols as fuels for internal combustion engines. Utilizing higher-molecular-weight alcohols as fuels requires careful analysis of their fuel properties. ASTM standards provide fuel property requirements for spark-ignition (SI) and compression-ignition (CI) engines such as the stability, lubricity, viscosity, and cold filter plugging point (CFPP) properties of blends of higher alcohols. Important combustion properties that are studied include laminar and turbulent flame speeds, flame blowout/extinction limits, ignition delay under various mixing conditions, and gas-phase and particulate emissions. The chapter focuses on the combustion of higher alcohols in reciprocating SI and CI engines and discusses higher alcohol performance in SI and CI engines. Finally, the chapter identifies the sources, production pathways, and technologies currently being pursued for production of some fuels, including n-butanol, iso-butanol, and n-octanol.

  11. Drug Safety: Managing Multiple Drugs

    Science.gov (United States)

    ... This series is produced by Consumers Union and Consumer Reports Best Buy Drugs , a public information project sup- ported by grants from the Engelberg Foundation and the National Library of Medicine of ... Consumer and Prescriber Education Grant Program which is funded ...

  12. Higher spin gauge theories

    CERN Document Server

    Henneaux, Marc; Vasiliev, Mikhail A

    2017-01-01

    Symmetries play a fundamental role in physics. Non-Abelian gauge symmetries are the symmetries behind theories for massless spin-1 particles, while the reparametrization symmetry is behind Einstein's gravity theory for massless spin-2 particles. In supersymmetric theories these particles can be connected also to massless fermionic particles. Does Nature stop at spin-2 or can there also be massless higher spin theories. In the past strong indications have been given that such theories do not exist. However, in recent times ways to evade those constraints have been found and higher spin gauge theories have been constructed. With the advent of the AdS/CFT duality correspondence even stronger indications have been given that higher spin gauge theories play an important role in fundamental physics. All these issues were discussed at an international workshop in Singapore in November 2015 where the leading scientists in the field participated. This volume presents an up-to-date, detailed overview of the theories i...

  13. INTERNATIONALIZATION IN HIGHER EDUCATION

    Directory of Open Access Journals (Sweden)

    Catalina Crisan-Mitra

    2016-03-01

    Full Text Available Internationalization of higher education is one of the key trends of development. There are several approaches on how to achieve competitiveness and performance in higher education and international academic mobility; students’ exchange programs, partnerships are some of the aspects that can play a significant role in this process. This paper wants to point out the student’s perception regarding two main directions: one about the master students’ expectation regarding how an internationalized master should be organized and should function, and second the degree of satisfaction of the beneficiaries of internationalized master programs from Babe-Bolyai University. This article is based on an empirical qualitative research that was implemented to students of an internationalized master from the Faculty of Economics and Business Administration. This research can be considered a useful example for those preoccupied to increase the quality of higher education and conclusions drawn have relevance both theoretically and especially practically.

  14. Quality of Higher Education

    DEFF Research Database (Denmark)

    Zou, Yihuan; Zhao, Yingsheng; Du, Xiangyun

    . This transformation involves a broad scale of change at individual level, organizational level, and societal level. In this change process in higher education, staff development remains one of the key elements for university innovation and at the same time demands a systematic and holistic approach.......This paper starts with a critical approach to reflect on the current practice of quality assessment and assurance in higher education. This is followed by a proposal that in response to the global challenges for improving the quality of higher education, universities should take active actions...... of change by improving the quality of teaching and learning. From a constructivist perspective of understanding education and learning, this paper also discusses why and how universities should give more weight to learning and change the traditional role of teaching to an innovative approach of facilitation...

  15. Legal Drugs Are Good Drugs And Illegal Drugs Are Bad Drugs

    Directory of Open Access Journals (Sweden)

    Dina Indrati

    2011-07-01

    Full Text Available ABSTRACT : Labelling drugs are important issue nowadays in a modern society. Although it is generally believed that legal drugs are good drugs and illegal drugs are bad drugs, it is evident that some people do not aware about the side effects of drugs used. Therefore, a key contention of this philosophical essay is that explores harms minimisation policy, discuss whether legal drugs are good drugs and illegal drugs are bad drugs and explores relation of drugs misuse in a psychiatric nursing setting and dual diagnosis.Key words: Legal, good drugs, illegal, bad drugs.

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

    International Nuclear Information System (INIS)

    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 Na v 1.5 sodium and Ca v 1.2 calcium currents. Ion currents were as well reduced by 18-MC, yet with diminished potency. Unexpectedly, although blocking hERG channels, ibogaine did not prolong the action potential (AP) in guinea pig cardiomyocytes at low micromolar concentrations. Higher concentrations (≥ 10 μM) even shortened the AP. These findings can be explained by the drug's calcium channel inhibition, which counteracts the AP-prolonging effect generated by hERG blockade. Implementation of ibogaine's inhibitory effects on human ion channels in a computer model of a ventricular cardiomyocyte, on the other hand, suggested that ibogaine does prolong the AP in the human heart. We conclude that therapeutic concentrations of ibogaine have the propensity to prolong the QT interval of the electrocardiogram in humans. In some cases this may lead to cardiac arrhythmias. - Highlights: • We study effects of anti-addiction drug ibogaine on ionic currents in cardiomyocytes. • We assess the cardiac ion channel profile of ibogaine. • Ibogaine inhibits hERG potassium, sodium and calcium channels. • Ibogaine’s effects on ion channels are a potential

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

    Energy Technology Data Exchange (ETDEWEB)

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

  18. Reputation in Higher Education

    DEFF Research Database (Denmark)

    Martensen, Anne; Grønholdt, Lars

    2005-01-01

    leaders of higher education institutions to set strategic directions and support their decisions in an effort to create even better study programmes with a better reputation. Finally, managerial implications and directions for future research are discussed.Keywords: Reputation, image, corporate identity......The purpose of this paper is to develop a reputation model for higher education programmes, provide empirical evidence for the model and illustrate its application by using Copenhagen Business School (CBS) as the recurrent case. The developed model is a cause-and-effect model linking image...

  19. Reputation in Higher Education

    DEFF Research Database (Denmark)

    Plewa, Carolin; Ho, Joanne; Conduit, Jodie

    2016-01-01

    Reputation is critical for institutions wishing to attract and retain students in today's competitive higher education setting. Drawing on the resource based view and configuration theory, this research proposes that Higher Education Institutions (HEIs) need to understand not only the impact...... of independent resources but of resource configurations when seeking to achieve a strong, positive reputation. Utilizing fuzzy set qualitative comparative analysis (fsQCA), the paper provides insight into different configurations of resources that HEIs can utilize to build their reputation within their domestic...

  20. Navigating in higher education

    DEFF Research Database (Denmark)

    Thingholm, Hanne Balsby; Reimer, David; Keiding, Tina Bering

    Denne rapport er skrevet på baggrund af spørgeskemaundersøgelsen – Navigating in Higher Education (NiHE) – der rummer besvarelser fra 1410 bachelorstuderende og 283 undervisere fordelt på ni uddannelser fra Aarhus Universitet: Uddannelsesvidenskab, Historie, Nordisk sprog og litteratur, Informati......Denne rapport er skrevet på baggrund af spørgeskemaundersøgelsen – Navigating in Higher Education (NiHE) – der rummer besvarelser fra 1410 bachelorstuderende og 283 undervisere fordelt på ni uddannelser fra Aarhus Universitet: Uddannelsesvidenskab, Historie, Nordisk sprog og litteratur...

  1. Glucantime drug delivery comparison between crosslinked membranes irradiation versus esterification

    International Nuclear Information System (INIS)

    Oliveira, Maria J.A.; Parra, Duclerc F.; Lugao, Ademar B.; Amato, Valdir S.

    2009-01-01

    Pentavalent Antimony (Glucantime) is the drug of choice for the treatment of Leishmaniasis. The disease is transmitted by the female bite of Phlebotomine sandflies. The sandflies inject the infective stage, metacyclic promastigotes, during blood meals. The protozoan parasite causes a spectrum of clinical diseases afflicting 12 million people worldwide. The use of hydrogels matrices for particular drug-release applications has been investigated with the synthesis of modified polymeric hydrogel of poly (vinyl alcohol) (PVAl), poly (N-viny-2- pyrrolidone) (PVP) and poly (ethylene glycol). They were processed using gamma radiation from Cobalt-60 source at 25 kGy dose. The characterization of the hydrogels was conducted and toxicity was evaluated. The dried hydrogel was analyzed for differential scanning calorimetry (DSC), thermogravimetry (TGA), swelling and gel content determinations. The membranes have no toxicity and gel content has revealed the crosslink degree. The chemical crosslinking depends on the acid concentration. Increase of the acid concentration increases the gel content, the thermal stability of the PVAl component and decreases the swelling capacity. The thermal stability of irradiated membranes is decreased in the presence of plasticizer. In contrast to ionizing radiation membranes described in the literature and formulated with PVAl/PEG, our new membranes composed by PVAl/PVP/PEG are more flexible and presents higher swelling capacity. The drug was immobilized in the hydrogels structures and the glucantime drug delivery was determined. (author)

  2. Glucantime drug delivery comparison between crosslinked membranes irradiation versus esterification

    Energy Technology Data Exchange (ETDEWEB)

    Oliveira, Maria J.A.; Parra, Duclerc F.; Lugao, Ademar B., E-mail: mariajhho@yahoo.com.b, E-mail: dfparra@ipen.b [Instituto de Pesquisas Energeticas e Nucleares (IPEN-CNEN/SP), Sao Paulo, SP (Brazil). Centro de Quimica e Meio Ambiente (CQMA); Amato, Valdir S. [Hospital das Clinicas (HC/USP), Sao Paulo, SP (Brazil). Div. de Clinica de Molestias Infecciosas e Parasitarias

    2009-07-01

    Pentavalent Antimony (Glucantime) is the drug of choice for the treatment of Leishmaniasis. The disease is transmitted by the female bite of Phlebotomine sandflies. The sandflies inject the infective stage, metacyclic promastigotes, during blood meals. The protozoan parasite causes a spectrum of clinical diseases afflicting 12 million people worldwide. The use of hydrogels matrices for particular drug-release applications has been investigated with the synthesis of modified polymeric hydrogel of poly (vinyl alcohol) (PVAl), poly (N-viny-2- pyrrolidone) (PVP) and poly (ethylene glycol). They were processed using gamma radiation from Cobalt-60 source at 25 kGy dose. The characterization of the hydrogels was conducted and toxicity was evaluated. The dried hydrogel was analyzed for differential scanning calorimetry (DSC), thermogravimetry (TGA), swelling and gel content determinations. The membranes have no toxicity and gel content has revealed the crosslink degree. The chemical crosslinking depends on the acid concentration. Increase of the acid concentration increases the gel content, the thermal stability of the PVAl component and decreases the swelling capacity. The thermal stability of irradiated membranes is decreased in the presence of plasticizer. In contrast to ionizing radiation membranes described in the literature and formulated with PVAl/PEG, our new membranes composed by PVAl/PVP/PEG are more flexible and presents higher swelling capacity. The drug was immobilized in the hydrogels structures and the glucantime drug delivery was determined. (author)

  3. Drug decriminalization and the price of illicit drugs.

    Science.gov (United States)

    Félix, Sónia; Portugal, Pedro

    2017-01-01

    This study is an empirical assessment of the impact of the drug decriminalization policy followed by Portugal in July 2001, on the price of illicit drugs. The analysis is performed using a difference-in-differences approach and the Synthetic Control Method in order to construct a synthetic control unit from a convex combination of countries. The results suggest that the prices of opiates and cocaine in the post-treatment period did not decrease in the sequence of the policy change. We conclude that the drug decriminalization policy seems to have caused no harm through lower illicit drugs prices, which would lead to higher drug usage and dependence. Copyright © 2016 Elsevier B.V. All rights reserved.

  4. Drug induced rhabdomyolysis

    Science.gov (United States)

    Hohenegger, Martin

    2012-01-01

    Rhabdomyolysis is a clinical condition of potential life threatening destruction of skeletal muscle caused by diverse mechanisms including drugs and toxins. Given the fact that structurally not related compounds cause an identical phenotype pinpoints to common targets or pathways, responsible for executing rhabdomyolysis. A drop in myoplasmic ATP paralleled with sustained elevations in cytosolic Ca2+ concentration represents a common signature of rhabdomyolysis. Interestingly, cardiac tissue is hardly affected or only secondary, as a consequence of imbalance in electrolytes or acid–base equilibrium. This dogma is now impaired by compounds, which show up with combined toxicity in heart and skeletal muscle. In this review, cases of rhabdomyolysis with novel recently approved drugs will be explored for new target mechanisms in the light of previously described pathomechanisms. PMID:22560920

  5. Exploring Higher Thinking.

    Science.gov (United States)

    Conover, Willis M.

    1992-01-01

    Maintains that the social studies reform movement includes a call for the de-emphasis of rote memory and more attention to the development of higher-order thinking skills. Discusses the "thinking tasks" concept derived from the work of Hilda Taba and asserts that the tasks can be used with almost any social studies topic. (CFR)

  6. Higher-Order Hierarchies

    DEFF Research Database (Denmark)

    Ernst, Erik

    2003-01-01

    This paper introduces the notion of higher-order inheritance hierarchies. They are useful because they provide well-known benefits of object-orientation at the level of entire hierarchies-benefits which are not available with current approaches. Three facets must be adressed: First, it must be po...

  7. Inflation from higher dimensions

    International Nuclear Information System (INIS)

    Shafi, Q.

    1987-01-01

    We argue that an inflationary phase in the very early universe is related to the transition from a higher dimensional to a four-dimensional universe. We present details of a previously considered model which gives sufficient inflation without fine tuning of parameters. (orig.)

  8. Higher Education Funding Formulas.

    Science.gov (United States)

    McKeown-Moak, Mary P.

    1999-01-01

    One of the most critical components of the college or university chief financial officer's job is budget planning, especially using formulas. A discussion of funding formulas looks at advantages, disadvantages, and types of formulas used by states in budgeting for higher education, and examines how chief financial officers can position the campus…

  9. Liberty and Higher Education.

    Science.gov (United States)

    Thompson, Dennis F.

    1989-01-01

    John Stuart Mill's principle of liberty is discussed with the view that it needs to be revised to guide moral judgments in higher education. Three key elements need to be modified: the action that is constrained; the constraint on the action; and the agent whose action is constrained. (MLW)

  10. Fuel Class Higher Alcohols

    KAUST Repository

    Sarathy, Mani

    2016-01-01

    This chapter focuses on the production and combustion of alcohol fuels with four or more carbon atoms, which we classify as higher alcohols. It assesses the feasibility of utilizing various C4-C8 alcohols as fuels for internal combustion engines

  11. Evaluation in Higher Education

    Science.gov (United States)

    Bognar, Branko; Bungic, Maja

    2014-01-01

    One of the means of transforming classroom experience is by conducting action research with students. This paper reports about the action research with university students. It has been carried out within a semester of the course "Methods of Upbringing". Its goal has been to improve evaluation of higher education teaching. Different forms…

  12. Higher-level Innovization

    DEFF Research Database (Denmark)

    Bandaru, Sunith; Tutum, Cem Celal; Deb, Kalyanmoy

    2011-01-01

    we introduce the higher-level innovization task through an application of a manufacturing process simulation for the Friction Stir Welding (FSW) process where commonalities among two different Pareto-optimal fronts are analyzed. Multiple design rules are simultaneously deciphered from each front...

  13. Benchmarking for Higher Education.

    Science.gov (United States)

    Jackson, Norman, Ed.; Lund, Helen, Ed.

    The chapters in this collection explore the concept of benchmarking as it is being used and developed in higher education (HE). Case studies and reviews show how universities in the United Kingdom are using benchmarking to aid in self-regulation and self-improvement. The chapters are: (1) "Introduction to Benchmarking" (Norman Jackson…

  14. Creativity in Higher Education

    Science.gov (United States)

    Gaspar, Drazena; Mabic, Mirela

    2015-01-01

    The paper presents results of research related to perception of creativity in higher education made by the authors at the University of Mostar from Bosnia and Herzegovina. This research was based on a survey conducted among teachers and students at the University. The authors developed two types of questionnaires, one for teachers and the other…

  15. California's Future: Higher Education

    Science.gov (United States)

    Johnson, Hans

    2015-01-01

    California's higher education system is not keeping up with the changing economy. Projections suggest that the state's economy will continue to need more highly educated workers. In 2025, if current trends persist, 41 percent of jobs will require at least a bachelor's degree and 36 percent will require some college education short of a bachelor's…

  16. Cyberbullying in Higher Education

    Science.gov (United States)

    Minor, Maria A.; Smith, Gina S.; Brashen, Henry

    2013-01-01

    Bullying has extended beyond the schoolyard into online forums in the form of cyberbullying. Cyberbullying is a growing concern due to the effect on its victims. Current studies focus on grades K-12; however, cyberbullying has entered the world of higher education. The focus of this study was to identify the existence of cyberbullying in higher…

  17. Engineering bioceramic microstructure for customized drug delivery

    Science.gov (United States)

    Pacheco Gomez, Hernando Jose

    sCis treatment. Severe side effects were observed in animals treated with sCis including rapid weight loss and decreased liver and kidney function, effects not observed in SCPC-Cis treated animals. Analysis of cisplatin distribution demonstrated drug concentrations in the tumor were 21 and 1.5-times higher in IT and ADJ groups, respectively, as compared to sCis treated animals. These data demonstrate the SCPC drug delivery system can provide an effective localized treatment for HCC with significantly reduced toxicity compared to systemic drug administration. Moreover, it is possible to tailor drug release kinetics from SCPC hybrids by controlling the crystalline structure of the material and the ratios of Cris and Rhe in the composite.

  18. Adverse Drug Reactions Related to Drug Administration in Hospitalized Patients.

    Science.gov (United States)

    Gallelli, Luca; Siniscalchi, Antonio; Palleria, Caterina; Mumoli, Laura; Staltari, Orietta; Squillace, Aida; Maida, Francesca; Russo, Emilio; Gratteri, Santo; De Sarro, Giovambattista

    2017-01-01

    Drug treatment may be related to the development of adverse drug reactions (ADRs). In this paper, we evaluated the ADRs in patients admitted to Catanzaro Hospital. After we obtained the approval by local Ethical Committee, we performed a retrospective study on clinical records from March 01, 2013 to April 30, 2015. The association between drug and ADR or between drug and drug-drug-interactions (DDIs) was evaluated using the Naranjo's probability scale and Drug Interaction Probability Scale (DIPS), respectively. During the study period, we analyzed 2870 clinical records containing a total of 11,138 prescriptions, and we documented the development of 770 ADRs. The time of hospitalization was significantly higher (P<0.05) in women with ADRs (12.6 ± 1.2 days) with respect to men (11.8± 0.83 days). Using the Naranjo score, we documented a probable association in 78% of these reactions, while DIPS revealed that about 22% of ADRs were related to DDIs. Patients with ADRs received 3052 prescriptions on 11,138 (27.4%) having a mean of 6.1±0.29 drugs that was significantly higher (P<0.01) with respect to patients not experiencing ADRs (mean of 3.4±0.13 drugs). About 19% of ADRs were not diagnosed and were treated as new diseases. Our results indicate that drug administration induces the development of ADRs also during the hospitalization, particularly in elderly women. Moreover, we also documented that ADRs in some patients are under-diagnosed, therefore, it is important to motivate healthcare to report the ADRs in order to optimize the patients' safety. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  19. Pharmacokinetics of a concentrated buprenorphine formulation in red-tailed hawks (Buteo jamaicensis).

    Science.gov (United States)

    Gleeson, Molly D; Guzman, David Sanchez-Migallon; Knych, Heather K; Kass, Philip H; Drazenovich, Tracy L; Hawkins, Michelle G

    2018-01-01

    OBJECTIVE To determine the pharmacokinetics and sedative effects of 2 doses of a concentrated buprenorphine formulation after SC administration to red-tailed hawks (Buteo jamaicensis). ANIMALS 6 adult red-tailed hawks. PROCEDURES Concentrated buprenorphine (0.3 mg/kg, SC) was administered to all birds. Blood samples were collected at 10 time points over 24 hours after drug administration to determine plasma buprenorphine concentrations. After a 4-week washout period, the same birds received the same formulation at a higher dose (1.8 mg/kg, SC), and blood samples were collected at 13 time points over 96 hours. Hawks were monitored for adverse effects and assigned agitation-sedation scores at each sample collection time. Plasma buprenorphine concentrations were quantified by liquid chromatography-tandem mass spectrometry. RESULTS Mean time to maximum plasma buprenorphine concentration was 7.2 minutes and 26.1 minutes after administration of the 0.3-mg/kg and 1.8-mg/kg doses, respectively. Plasma buprenorphine concentrations were > 1 ng/mL for mean durations of 24 and 48 hours after low- and high-dose administration, respectively. Mean elimination half-life was 6.23 hours for the low dose and 7.84 hours for the high dose. Mean agitation-sedation scores were higher (indicating some degree of sedation) than the baseline values for 24 hours at both doses. No clinically important adverse effects were observed. CONCLUSIONS AND CLINICAL RELEVANCE Concentrated buprenorphine was rapidly absorbed, and plasma drug concentrations considered to have analgesic effects in other raptor species were maintained for extended periods. Most birds had mild to moderate sedation. Additional studies are needed to evaluate the pharmacodynamics of these doses of concentrated buprenorphine in red-tailed hawks.

  20. Competitiveness - higher education

    Directory of Open Access Journals (Sweden)

    Labas Istvan

    2016-03-01

    Full Text Available Involvement of European Union plays an important role in the areas of education and training equally. The member states are responsible for organizing and operating their education and training systems themselves. And, EU policy is aimed at supporting the efforts of member states and trying to find solutions for the common challenges which appear. In order to make our future sustainable maximally; the key to it lies in education. The highly qualified workforce is the key to development, advancement and innovation of the world. Nowadays, the competitiveness of higher education institutions has become more and more appreciated in the national economy. In recent years, the frameworks of operation of higher education systems have gone through a total transformation. The number of applying students is continuously decreasing in some European countries therefore only those institutions can “survive” this shortfall, which are able to minimize the loss of the number of students. In this process, the factors forming the competitiveness of these budgetary institutions play an important role from the point of view of survival. The more competitive a higher education institution is, the greater the chance is that the students would like to continue their studies there and thus this institution will have a greater chance for the survival in the future, compared to ones lagging behind in the competition. Aim of our treatise prepared is to present the current situation and main data of the EU higher education and we examine the performance of higher education: to what extent it fulfils the strategy for smart, sustainable and inclusive growth which is worded in the framework of Europe 2020 programme. The treatise is based on analysis of statistical data.

  1. Why trash don't pass? pharmaceutical licensing and safety performance of drugs.

    Science.gov (United States)

    Banerjee, Tannista; Nayak, Arnab

    2017-01-01

    This paper examines how asymmetric information in pharmaceutical licensing affects the safety standards of licensed drugs. Pharmaceutical companies often license potential drug molecules at different stages of drug development from other pharmaceutical or biotechnology companies and complete the remaining of research stages before submitting the new drug application(NDA) to the food and drug administration. The asymmetric information associated with the quality of licensed molecules might result in the molecules which are less likely to succeed to be licensed out, while those with greater potential of success being held internally for development. We identify the NDAs submitted between 1993 and 2004 where new molecular entities were acquired through licensing. Controlling for other drug area specific and applicant firm specific factors, we investigate whether drugs developed with licensed molecules face higher probability of safety based recall and ultimate withdrawal from the market than drugs developed internally. Results suggest the opposite of Akerlof's (Q J Econ 84:488-500, 1970) lemons problem. Licensed molecules rather have less probability of facing safety based recalls and ultimate withdrawal from the market comparing to internally developed drug molecules. This suggests that biotechnology and small pharmaceutical firms specializing in pharmaceutical research are more efficient in developing good potential molecules because of their concentrated research. Biotechnology firms license out good potential molecules because it increases their market value and reputation. In addition, results suggest that both the number of previous approved drugs in the disease area, and also the applicant firms' total number of previous approvals in all disease areas reduce the probability that an additional approved drug in the same drug area will potentially be harmful.

  2. DEVELOPMENT OF DOMESTIC INFUSION DRUGS BASED ON PARACETAMOL

    Directory of Open Access Journals (Sweden)

    Almakaeva L.G.

    2016-06-01

    Full Text Available The intravenous form of paracetamol compared with oral more reliably supports effective drug concentration in blood plasma that promotes a higher therapeutic effect. Recent studies have confirmed that the use of the intravenous form of paracetamol to deal with postoperative pain multimodal analgesia modes results in reducing the frequency and quantity of opioids administered , and, as a consequence, its associated side effects. The drug Paracetamol , infusion solution 10 mg / ml to 100 ml glass bottles is a drug - generic . His qualitative and quantitative composition is developed from the study of literature data about the drug - similar to " Perfalhan , 10 mg / ml solution for infusion in 100 mL " company Bristol - Myers Squibb, France and experimental work. The aim of our study is development and support of the national composition of the infusion of the drug on the basis of paracetamol, selection of excipients that provide stability of the active substances. Materials and methods. The object of the study was the substance of paracetamol manufactured by Zhejiang Kangle Pharmaceutical Co. , Ltd, China. During the work conducted qualitative and quantitative monitoring sample preparation for indicators of stability: pH content of the active ingredient , transparency, color, impurities , contamination by the methods described in the SFU [and nor- ral documentation to the drug . One potential factor of instability is the effect of paracetamol oxygen, due to the presence in the molecule of paracetamol and -NH possibility of oxidation. Results and Discussion. Paracetamol is derived atsetamina . Substance acetylation are p - aminophenol with acetic anhydride . Saturated aqueous solution has a pH of paracetamol - ment about 6 . Paracetamol is a crystalline white powder , sparingly soluble in water, soluble in 96% alcohol, very slightly soluble in metilenhloride . . Active substance enters in comparison drug in the concentration of 10 mg/ml. Stable

  3. Treating tuberculosis with high doses of anti-TB drugs: mechanisms and outcomes.

    Science.gov (United States)

    Xu, Yuhui; Wu, Jianan; Liao, Sha; Sun, Zhaogang

    2017-10-03

    Tuberculosis (TB) is considered as one of the most serious threats to public health in many parts of the world. The threat is even more severe in the developing countries where there is a lack of advanced medical amenities and contemporary anti-TB drugs. In such situations, dosage optimization of existing medication regimens seems to be the only viable option. Therapeutic drug monitoring study results suggest that high-dose treatment regimens can compensate the low serum concentration of anti-TB drugs and shorten the therapy duration. The article presents a critical review on the possible changes that occur in the host and the pathogen upon the administration of standard and high-dose regimens. Some of the most common factors that are responsible for low anti-TB drug concentrations in the serum are differences in hosts' body weight, metabolic processing of the drug, malabsorption and/or drug-drug interaction. Furthermore, failure to reach the cavitary pulmonary and extrapulmonary tissues also contributes to the therapeutic inefficiency of the drugs. In such conditions, administration of higher doses can help in compensating the pathogenic outcomes of enhancement of the pathogen's physical barriers, efflux pumps and genetic mutations. The present article also presents a summary of the recorded treatment outcomes of clinical trials that were conducted to test the efficacy of administration of high dose of anti-tuberculosis drugs. This review will help physicians across the globe to understand the underlying pathophysiological changes (including side effects) that dictate the clinical outcomes in patients administered with standard and/or high dose anti-TB drugs.

  4. [Interactions of cytostatic agents with other drugs].

    Science.gov (United States)

    Sauter, C

    1991-08-31

    With the degree of polypharmacy currently practiced in the field of oncology, there are undoubtedly many drug interactions. In the present study the influence of "non-cytotoxic" drugs on anticancer drugs is discussed, but not the reverse. Not only is the augmentation (reversal of multidrug resistance) or the reduction of antitumor properties of cytotoxic drugs observed, but also cytostatic activities of "non-cytotoxic" drugs themselves. Examples are calmodulin inhibitors such as phenothiazines and tricyclic antidepressants. Interactions may also increase side effects of cytostatic drugs or even neutralize the antitumoral activity. To ensure that interactions are not overlooked, all medicaments being administered should be listed. It is, however, not feasible yet to determine serum concentrations of all the drugs given to the patient. The antitumor activity of supportive care could be evaluated in randomized studies (e.g. cytostatic drugs +/- antidepressants).

  5. Radiosensitivity of higher plants

    International Nuclear Information System (INIS)

    Feng Zhijie

    1992-11-01

    The general views on radiosensitivity of higher plants have been introduced from published references. The radiosensitivity varies with species, varieties and organs or tissues. The main factors of determining the radiosensitivity in different species are nucleus volume, chromosome volume, DNA content and endogenous compounds. The self-repair ability of DNA damage and chemical group of biological molecules, such as -SH thiohydroxy of proteins, are main factors to determine the radiosensitivity in different varieties. The moisture, oxygen, temperature radiosensitizer and protector are important external factors for radiosensitivity. Both the multiple target model and Chadwick-Leenhouts model are ideal mathematical models for describing the radiosensitivity of higher plants and the latter has more clear significance in biology

  6. Higher Education Language Policy

    DEFF Research Database (Denmark)

    Lauridsen, Karen M.

    2013-01-01

    Summary of recommendations HEIs are encouraged, within the framework of their own societal context, mission, vision and strategies, to develop the aims and objectives of a Higher Education Language Policy (HELP) that allows them to implement these strategies. In this process, they may want......: As the first step in a Higher Education Language Policy, HEIs should determine the relative status and use of the languages employed in the institution, taking into consideration the answers to the following questions:  What is/are the official language(s) of the HEI?  What is/are the language...... and the level of internationalisation the HEI has or wants to have, and as a direct implication of that, what are the language proficiency levels expected from the graduates of these programme?  Given the profile of the HEI and its educational strategies, which language components are to be offered within...

  7. Concentration-dependent metabolic effects of metformin in healthy and Fanconi anemia lymphoblast cells.

    Science.gov (United States)

    Ravera, Silvia; Cossu, Vanessa; Tappino, Barbara; Nicchia, Elena; Dufour, Carlo; Cavani, Simona; Sciutto, Andrea; Bolognesi, Claudia; Columbaro, Marta; Degan, Paolo; Cappelli, Enrico

    2018-02-01

    Metformin (MET) is the drug of choice for patients with type 2 diabetes and has been proposed for use in cancer therapy and for treating other metabolic diseases. More than 14,000 studies have been published addressing the cellular mechanisms affected by MET. However, several in vitro studies have used concentrations of the drug 10-100-fold higher than the plasmatic concentration measured in patients. Here, we evaluated the biochemical, metabolic, and morphologic effects of various concentrations of MET. Moreover, we tested the effect of MET on Fanconi Anemia (FA) cells, a DNA repair genetic disease with defects in energetic and glucose metabolism, as well as on human promyelocytic leukemia (HL60) cell lines. We found that the response of wild-type cells to MET is concentration dependent. Low concentrations (15 and 150 µM) increase both oxidative phosphorylation and the oxidative stress response, acting on the AMPK/Sirt1 pathway, while the high concentration (1.5 mM) inhibits the respiratory chain, alters cell morphology, becoming toxic to the cells. In FA cells, MET was unable to correct the energetic/respiratory defect and did not improve the response to oxidative stress and DNA damage. By contrast, HL60 cells appear sensitive also at 150 μM. Our findings underline the importance of the MET concentration in evaluating the effect of this drug on cell metabolism and demonstrate that data obtained from in vitro experiments, that have used high concentrations of MET, cannot be readily translated into improving our understanding of the cellular effects of metformin when used in the clinical setting. © 2017 Wiley Periodicals, Inc.

  8. Quantitative analysis of abused drugs in physiological fluids by gas chromatography/chemical ionization mass spectrometry

    International Nuclear Information System (INIS)

    Foltz, R.L.

    1978-01-01

    Methods have been developed for quantitative analysis of commonly abused drugs in physiological fluids using gas chromatography/chemical ionization mass spectrometry. The methods are being evaluated in volunteer analytical and toxicological laboratories, and analytical manuals describing the methods are being prepared. The specific drug and metabolites included in this program are: Δ 9 -tetrahydrocannabinol, methadone, phencyclidine, methaqualone, morphine, amphetamine, methamphetamine, mescaline, 2,5-dimethoxy-4-methyl amphetamine, cocaine, benzoylecgonine, diazepam, and N-desmethyldiazepam. The current analytical methods utilize relatively conventional instrumentation and procedures, and are capable of measuring drug concentrations as low as 1 ng/ml. Various newer techniques such as sample clean-up by high performance liquid chromatography, separation by glass capillary chromatography, and ionization by negative ion chemical ionization are being investigated with respect to their potential for achieving higher sensitivity and specificity, as well as their ability to facilitate simultaneous analysis of more than one drug and metabolite. (Auth.)

  9. Safety and efficacy of generic drugs with respect to brand formulation.

    Science.gov (United States)

    Gallelli, Luca; Palleria, Caterina; De Vuono, Antonio; Mumoli, Laura; Vasapollo, Piero; Piro, Brunella; Russo, Emilio

    2013-12-01

    Generic drugs are equivalent to the brand formulation if they have the same active substance, the same pharmaceutical form and the same therapeutic indications and a similar bioequivalence respect to the reference medicinal product. The use of generic drugs is indicated from many countries in order to reduce medication price. However some points, such as bioequivalence and the role of excipients, may be clarified regarding the clinical efficacy and safety during the switch from brand to generic formulations. In conclusion, the use of generic drugs could be related with an increased days of disease (time to relapse) or might lead to a therapeutic failure; on the other hand, a higher drug concentration might expose patients to an increased risk of dose-dependent side-effects.

  10. Males exceed females in PCB concentrations of cisco (Coregonus artedi) from Lake Superior.

    Science.gov (United States)

    Madenjian, Charles P; Yule, Daniel L; Chernyak, Sergei M; Begnoche, Linda J; Berglund, Eric K; Isaac, Edmund J

    2014-09-15

    We determined whole-fish polychlorinated biphenyl (PCB) concentrations of 25 male and 25 female age-7 ciscoes (Coregonus artedi) captured from a spawning aggregation in Thunder Bay, Lake Superior, during November 2010. We also determined PCB concentrations in the ovaries and somatic tissue of five additional female ciscoes (ages 5-22). All 55 of these ciscoes were in ripe or nearly ripe condition. Bioenergetics modeling was used to determine the contribution of the growth dilution effect toward a difference in PCB concentrations between the sexes, as females grew substantially faster than males. Results showed that the PCB concentration of males (mean = 141 ng/g) was 43% greater than that of females (mean = 98 ng/g), and this difference was highly significant (PPCB concentrations in the ovaries and the somatic tissue of the five females were 135 and 100 ng/g, respectively. Based on these PCB determinations for the ovaries and somatic tissue, we concluded that release of eggs by females at previous spawnings was not a contributing factor to the observed difference in PCB concentrations between the sexes. Bioenergetics modeling results indicated that the growth dilution effect could explain males being higher than females in PCB concentration by only 3-7%. We concluded that the higher PCB concentration in males was most likely due to higher rate of energy expenditure, originating from greater activity and a higher resting metabolic rate. Mean PCB concentration in the cisco eggs was well below the U. S. Food and Drug Administration and Ontario Ministry of Environment guidelines of 2000 and 844 ng/g, respectively, and this finding may have implications for the cisco roe fishery currently operating in Lake Superior. Published by Elsevier B.V.

  11. Pharmacological modification of multi-drug resistance (MDR) in vitro detected by a novel fluorometric microculture cytotoxicity assay. Reversal of resistance and selective cytotoxic actions of cyclosporin A and verapamil on MDR leukemia T-cells.

    Science.gov (United States)

    Larsson, R; Nygren, P

    1990-07-15

    A novel fluorometric microculture cytotoxicity assay (FMCA), based on measurements of fluorescein diacetate (FDA) hydrolysis and DNA staining by Hoechst 33342, was used for drug sensitivity testing and detection of resistance reversal in acute lymphoblastic leukemia (ALL) cell lines. The 72-hr assay was found to be sensitive, reproducible and linearly related to the number of viable cells within a broad range of cell concentrations. At clinically achievable drug concentrations, the calcium channel blocker Verapamil (ver) and the immunosuppressant Cyclosporin A (csA) were found to partly reverse acquired Vincristine (vcr) resistance in multi-drug resistant (MDR) T-ALL L100 cells with little or no effect on the drug-sensitive parental L0 cell line. By combining the fluorometric indices, we found that low concentrations of csA were growth-inhibitory, whereas higher concentrations (greater than 10 micrograms/ml) were progressively cytotoxic for drug-sensitive L0 cells. In MDR L100 cells, on the other hand, csA produced significant cell kill even at low drug concentrations. Ver had no effects on sensitive L0 cells but showed considerable cytotoxic action towards MDR L100 cells. There was no apparent relationship between drug reversal of vcr resistance and the cytotoxic actions of the drug per se since the calcium channel blocker diltiazem (dil) significantly potentiated the actions of vcr on MDR L100 cells without being more toxic to these cells (compared to vcr-sensitive L0 cells).

  12. Volume higher; spot price ranges widen

    International Nuclear Information System (INIS)

    Anon.

    1994-01-01

    This article is the October 1994 uranium market summary. During this reporting period, volume on the spot concentrates market doubled. Twelve deals took place: three in the spot concentrates market, one in the medium and long-term market, four in the conversion market, and four in the enrichment market. The restricted price range widened due to higher prices at the top end of the range, while the unrestricted price range widened because of lower prices at the bottom end. Spot conversion prices were higher, and enrichment prices were unchanged

  13. Optimization of Drug Delivery by Drug-Eluting Stents.

    Directory of Open Access Journals (Sweden)

    Franz Bozsak

    Full Text Available Drug-eluting stents (DES, which release anti-proliferative drugs into the arterial wall in a controlled manner, have drastically reduced the rate of in-stent restenosis and revolutionized the treatment of atherosclerosis. However, late stent thrombosis remains a safety concern in DES, mainly due to delayed healing of the endothelial wound inflicted during DES implantation. We present a framework to optimize DES design such that restenosis is inhibited without affecting the endothelial healing process. To this end, we have developed a computational model of fluid flow and drug transport in stented arteries and have used this model to establish a metric for quantifying DES performance. The model takes into account the multi-layered structure of the arterial wall and incorporates a reversible binding model to describe drug interaction with the cells of the arterial wall. The model is coupled to a novel optimization algorithm that allows identification of optimal DES designs. We show that optimizing the period of drug release from DES and the initial drug concentration within the coating has a drastic effect on DES performance. Paclitaxel-eluting stents perform optimally by releasing their drug either very rapidly (within a few hours or very slowly (over periods of several months up to one year at concentrations considerably lower than current DES. In contrast, sirolimus-eluting stents perform optimally only when drug release is slow. The results offer explanations for recent trends in the development of DES and demonstrate the potential for large improvements in DES design relative to the current state of commercial devices.

  14. Higher Education in Scandinavia

    DEFF Research Database (Denmark)

    Nielsen, Jørgen Lerche; Andreasen, Lars Birch

    2015-01-01

    Higher education systems around the world have been undergoing fundamental changes through the last 50 years from more narrow self-sustaining universities for the elite and into mass universities, where new groups of students have been recruited and the number of students enrolled has increased...... an impact on the educational systems in Scandinavia, and what possible futures can be envisioned?...... dramatically. In adjusting to the role of being a mass educational institution, universities have been challenged on how to cope with external pressures, such as forces of globalization and international markets, increased national and international competition for students and research grants, increased...

  15. Higher engineering mathematics

    CERN Document Server

    John Bird

    2014-01-01

    A practical introduction to the core mathematics principles required at higher engineering levelJohn Bird's approach to mathematics, based on numerous worked examples and interactive problems, is ideal for vocational students that require an advanced textbook.Theory is kept to a minimum, with the emphasis firmly placed on problem-solving skills, making this a thoroughly practical introduction to the advanced mathematics engineering that students need to master. The extensive and thorough topic coverage makes this an ideal text for upper level vocational courses. Now in

  16. Drugs Approved for Neuroblastoma

    Science.gov (United States)

    This page lists cancer drugs approved by the Food and Drug Administration (FDA) for neuroblastoma. The list includes generic names and brand names. The drug names link to NCI's Cancer Drug Information summaries.

  17. Drugs Approved for Leukemia

    Science.gov (United States)

    This page lists cancer drugs approved by the FDA for use in leukemia. The drug names link to NCI's Cancer Drug Information summaries. The list includes generic names, brand names, and common drug combinations, which are shown in capital letters.

  18. Drugs Approved for Retinoblastoma

    Science.gov (United States)

    This page lists cancer drugs approved by the Food and Drug Administration (FDA) for retinoblastoma. The list includes generic names and brand names. The drug names link to NCI’s Cancer Drug Information summaries.

  19. National Drug Code Directory

    Data.gov (United States)

    U.S. Department of Health & Human Services — The Drug Listing Act of 1972 requires registered drug establishments to provide the Food and Drug Administration (FDA) with a current list of all drugs manufactured,...

  20. Other Drugs of Abuse

    Science.gov (United States)

    ... People Abuse » Other Drugs of Abuse Other Drugs of Abuse Listen There are many other drugs of abuse, ... and Rehab Resources About the National Institute on Drug Abuse (NIDA) | About This Website Tools and Resources | Contact ...

  1. Urine drug screen

    Science.gov (United States)

    Drug screen - urine ... detect the presence of illegal and some prescription drugs in your urine. Their presence may indicate that you recently used these drugs. Some drugs may remain in your system for ...

  2. Polypharmacology of Approved Anticancer Drugs.

    Science.gov (United States)

    Amelio, Ivano; Lisitsa, Andrey; Knight, Richard A; Melino, Gerry; Antonov, Alexey V

    2017-01-01

    The major drug discovery efforts in oncology have been concentrated on the development of selective molecules that are supposed to act specifically on one anticancer mechanism by modulating a single or several closely related drug targets. However, a bird's eye view on data from multiple available bioassays implies that most approved anticancer agents do, in fact, target many more proteins with different functions. Here we will review and systematize currently available information on the targets of several anticancer drugs along with revision of their potential mechanisms of action. Polypharmacology of the current antineoplastic agents suggests that drug clinical efficacy in oncology can be achieved only via modulation of multiple cellular mechanisms. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  3. Development and Evaluation of Chronotherapeutic Drug Delivery ...

    African Journals Online (AJOL)

    Conclusion: The developed system is capable of releasing the drug after a 4-h lag period. However ... concentration would be at its maximum level, ... spheronizer (Caleva MBS, UK)operating at .... capsules show that the color intensity of the.

  4. Towards higher intensities

    CERN Multimedia

    CERN Bulletin

    2010-01-01

    Over the past 2 weeks, commissioning of the machine protection system has advanced significantly, opening up the possibility of higher intensity collisions at 3.5 TeV. The intensity has been increased from 2 bunches of 1010 protons to 6 bunches of 2x1010 protons. Luminosities of 6x1028 cm-2s-1 have been achieved at the start of fills, a factor of 60 higher than those provided for the first collisions on 30 March.   The recent increase in LHC luminosity as recorded by the experiments. (Graph courtesy of the experiments and M. Ferro-Luzzi) To increase the luminosity further, the commissioning crews are now trying to push up the intensity of the individual proton bunches. After the successful injection of nominal intensity bunches containing 1.1x1011 protons, collisions were subsequently achieved at 450 GeV with these intensities. However, half-way through the first ramping of these nominal intensity bunches to 3.5 TeV on 15 May, a beam instability was observed, leading to partial beam loss...

  5. Concentrations of buparvaquone in milk and tissue of dairy cows.

    Science.gov (United States)

    McDougall, S; Hillerton, J E; Pegram, D

    2016-11-01

    To determine the concentration of the anti-theilerial drug buparvaquone in the milk and tissue of dairy cattle following treatment with two different formulations, and to assess the effect of clinical theileriosis on the concentration of buparvaquone in milk. Healthy lactating dairy cows (n=25) were injected once (Day 0) I/M with 2.5 mg/kg of one of two formulations of buparvaquone (Butalex; n=12 or Bupaject; n=13). Milk samples were collected from all cows daily until Day 35. Five cows were slaughtered on each of Days 56, 119, 147, 203 and 328, and samples of liver, muscle and injection site tissue collected. Milk samples were also collected from cows (n=14) clinically affected with theileriosis for up to 21 days after treatment with buparvaquone. Milk and tissue samples were analysed by liquid chromatography-mass spectrometry; limits of detection (LOD) were 0.00018 mg/kg for muscle and 0.00023 mg/L for milk. Concentrations of buparvaquone in milk and tissues were log10-transformed for analysis using multivariate models. In healthy cows, concentrations of buparvaquone in milk declined with time post-treatment (pcows at Day 35. Concentration in milk was higher one day after treatment in cows treated with Butalex than in cows treated with Bupaject, but not different thereafter (p=0.007). Concentrations of buparvaquone in muscle were below the LOD for four of five animals at Day 119 and for all animals by Day 147, but were above the LOD at the injection site of one cow, and in the liver of three cows at Day 328. Tissue concentrations did not differ with formulation nor was there a formulation by time interaction (p>0.3). Concentrations of buparvaquone in the milk of clinically affected animals were not different from those of healthy animals at 1 and 21 days post-treatment (p=0.72). Between 21 and 25 days post-treatment concentrations were below the LOD in 9/14 milk samples from clinically affected cows. Detectable concentrations of buparvaquone were found in

  6. Drug susceptibility testing in microaerophilic parasites: Cysteine strongly affects the effectivities of metronidazole and auranofin, a novel and promising antimicrobial

    Directory of Open Access Journals (Sweden)

    David Leitsch

    2017-12-01

    Full Text Available The microaerophilic parasites Entamoeba histolytica, Trichomonas vaginalis, and Giardia lamblia annually cause hundreds of millions of human infections which are treated with antiparasitic drugs. Metronidazole is the most often prescribed drug but also other drugs are in use, and novel drugs with improved characteristics are constantly being developed. One of these novel drugs is auranofin, originally an antirheumatic which has been relabelled for the treatment of parasitic infections. Drug effectivity is arguably the most important criterion for its applicability and is commonly assessed in susceptibility assays using in vitro cultures of a given pathogen. However, drug susceptibility assays can be strongly affected by certain compounds in the growth media. In the case of microaerophilic parasites, cysteine which is added in large amounts as an antioxidant is an obvious candidate because it is highly reactive and known to modulate the toxicity of metronidazole in several microaerophilic parasites.In this study, it was attempted to reduce cysteine concentrations as far as possible without affecting parasite viability by performing drug susceptibility assays under strictly anaerobic conditions in an anaerobic cabinet. Indeed, T. vaginalis and E. histolytica could be grown without any cysteine added and the cysteine concentration necessary to maintain G. lamblia could be reduced to 20%. Susceptibilities to metronidazole were found to be clearly reduced in the presence of cysteine. With auranofin the protective effect of cysteine was extreme, providing protection to concentrations up to 100-fold higher as observed in the absence of cysteine. With three other drugs tested, albendazole, furazolidone and nitazoxanide, all in use against G. lamblia, the effect of cysteine was less pronounced. Oxygen was found to have a less marked impact on metronidazole and auranofin than cysteine but bovine bile which is standardly used in growth media for G

  7. Understanding drugs and behaviour

    National Research Council Canada - National Science Library

    Parrott, Andrew

    2004-01-01

    ... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ix xi Part I Drugs and Their Actions . . . . . . . . . . . . . . . . . . . . . . 1 Psychoactive drugs: introduction and overview . . . . . . . . 2 The brain...

  8. Therapeutic drug monitoring in pregnancy.

    Science.gov (United States)

    Matsui, Doreen M

    2012-10-01

    Therapeutic drug monitoring (TDM) is commonly recommended to optimize drug dosing regimens of various medications. It has been proposed to guide therapy in pregnant women, in whom physiological changes may lead to altered pharmacokinetics resulting in difficulty in predicting the appropriate drug dosage. Ideally, TDM may play a role in enhancing the effectiveness of treatment while minimizing toxicity of both the mother and fetus. Monitoring of drug levels may also be helpful in assessing adherence to prescribed therapy in selected cases. Limitations exist as therapeutic ranges have only been defined for a limited number of drugs and are based on data obtained in nonpregnant patients. TDM has been suggested for anticonvulsants, antidepressants, and antiretroviral drugs, based on pharmacokinetic studies that have shown reduced drug concentrations. However, there is only relatively limited (and sometimes inconsistent) information regarding the clinical impact of these pharmacokinetic changes during pregnancy and the effect of subsequent dose adjustments. Further studies are required to determine whether implementation of TDM during pregnancy improves outcome and is associated with any benefit beyond that achieved by clinical judgment alone. The cost effectiveness of TDM programs during pregnancy also remains to be examined.

  9. Magnetic stimulus responsive vancomycin drug delivery system based on chitosan microbeads embedded with magnetic nanoparticles.

    Science.gov (United States)

    Mohapatra, Ankita; Harris, Michael A; LeVine, David; Ghimire, Madhav; Jennings, Jessica A; Morshed, Bashir I; Haggard, Warren O; Bumgardner, Joel D; Mishra, Sanjay R; Fujiwara, Tomoko

    2017-10-20

    Local antibiotic delivery can overcome some of the shortcomings of systemic therapy, such as low local concentrations and delivery to avascular sites. A localized drug delivery system (DDS), ideally, could also use external stimuli to modulate the normal drug release profile from the DDS to provide efficacious drug administration and flexibility to healthcare providers. To achieve this objective, chitosan microbeads embedded with magnetic nanoparticles were loaded with the antibiotic vancomycin and stimulated by a high frequency alternating magnetic field. Three such stimulation sessions separated by 1.5 h were applied to each test sample. The chromatographic analysis of the supernatant from these stimulated samples showed more than approximately 200% higher release of vancomycin from the DDS after the stimulation periods compared to nonstimulated samples. A 16-day long term elution study was also conducted where the DDS was allowed to elute drug through normal diffusion over a period of 11 days and stimulated on day 12 and day 15, when vancomycin level had dropped below therapeutic levels. Magnetic stimulation boosted elution of test groups above minimum inhibitory concentration (MIC), as compared to control groups (with no stimulation) which remained below MIC. The drug release from test groups in the intervals where no stimulation was given showed similar elution behavior to control groups. These results indicate promising possibilities of controlled drug release using magnetic excitation from a biopolymer-based DDS. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 2017. © 2017 Wiley Periodicals, Inc.

  10. Rational Drug Use of Nurses

    Directory of Open Access Journals (Sweden)

    Mehtap Sahingoz

    2013-02-01

    Full Text Available ABSTRACT Objective: At this study to be aimed to assess status of the knowledge of nurses who working in public and private health institutions in Sivas province use of medication fort he treatment during their illnesses and patients and the attitudes of rational drug application. Matherials and methods: the researc planned to attend 750 nurses but it has been completed with participation of 641 nurses (Reaching rate 85,5%. This is a descriptive and cross-sectional study. in the study data were collected with a questionaire, percentages stated and chi square test was used for analysis. Results: %95,3 of nurses were females and mean age of them 29.21±4.85 years. The rate of contacting a doktor in case of illness is higher in 39.1% of nurses in the 21-30 age group and 48.6% of nurses working in primary care institutions. The level of self-treating is higher in 45.5 % of nurses working less than a year in profession .In the case of illness, 53% of nurses stated that they had left the medicine when signs of disease over. %98.8 of nurses expressed that they know effects of drugs used and 99.1% of them stated they know the side effects of drugs used. The entire group of postgraduate education status stated that they have not received the drug recommended by others. The level of suggesting a drug to someone else fort he same disease is higher in 65.8% of the group 31 years and older and group working over 40 hours per week. It were determined that used in consultation with the physician 65.2% of nurses antibiotics, 87.5% of them weiht loss drug and 82.7% of them contraceptive . 99.5% of the nurses have expressed that they inform to patients about use of their medications. Among the issues that expressed informations took place the application form of drugs (51.0 %and information of need to consult one if deemed one unexpected effect (59.6% . Also has been identified that of nurses acquired inform about drugs from drug book (vademecum (87.5 % and they

  11. Patient Counseling about Herbal-Drug Interactions | Hussain ...

    African Journals Online (AJOL)

    The multitude of pharmacologically active compounds obviously increases the likelihood of interactions taking place. Hence, the likelihood of herb-drug interactions is theoretically higher than drug-drug interactions because synthetic drugs usually contain single chemical entity. Case reports and clinical studies have ...

  12. Teaching at higher levels

    Science.gov (United States)

    1998-11-01

    Undergraduate physics programmes for the 21st century were under discussion at a recent event held in Arlington, USA, open to two or three members of the physics faculties of universities from across the whole country. The conference was organized by the American Association of Physics Teachers with co-sponsorship from the American Institute of Physics, the American Physical Society and Project Kaleidoscope. Among the various aims were to learn about physics departments that have successfully revitalized their undergraduate physics programmes with innovative introductory physics courses and multi-track majors programmes. Engineers and life scientists were to be asked directly how physics programmes can better serve their students, and business leaders would be speaking on how physics departments can help to prepare their students for the diverse careers that they will eventually follow. It was planned to highlight ways that departments could fulfil their responsibilities towards trainee teachers, to identify the resources needed for revitalizing a department's programme, and to develop guidelines and recommendations for a funding programme to support collaborative efforts among physics departments for carrying out the enhancements required. More details about the conference can be found on the AAPT website (see http://www.aapt.org/programs/rupc.html). Meanwhile the UK's Higher Education Funding Council has proposed a two-pronged approach to the promotion of high quality teaching and learning, as well as widening participation in higher education from 1999-2000. A total of £60m should be available to support these initiatives by the year 2001-2002. As part of this scheme the Council will invite bids from institutions to support individual academics in enhancing learning and teaching, as well as in recognition of individual excellence. As with research grants, such awards would enable staff to pursue activities such as the development of teaching materials

  13. Prescription Drug Abuse

    Science.gov (United States)

    ... drug abuse. And it's illegal, just like taking street drugs. Why Do People Abuse Prescription Drugs? Some people abuse prescription drugs ... common risk of prescription drug abuse is addiction . People who abuse ... as if they were taking street drugs. That's one reason most doctors won't ...

  14. Drug abuse

    International Nuclear Information System (INIS)

    Simon, T.R.; Seastrunk, J.W.; Malone, G.; Knesevich, M.A.; Hickey, D.C.

    1991-01-01

    This paper reports that this study used SPECT to examine patients who have abused drugs to determine whether SPECT could identify abnormalities and whether these findings have clinical importance. Fifteen patients with a history of substance abuse (eight with cocaine, six with amphetamine, and one with organic solvent) underwent SPECT performed with a triple-headed camera and Tc-99m HMPAO both early for blood flow and later for functional information. These images were then processed into a 3D videotaped display used in group therapy. All 15 patients had multiple areas of decreased tracer uptake peppered throughout the cortex but mainly affecting the parietal lobes, expect for the organic solvent abuser who had a large parietal defect. The videotapes were subjectively described by a therapist as an exceptional tool that countered patient denial of physical damage from substance abuse. Statistical studies of recidivism between groups is under way

  15. Zolpidem prescribing practices before and after Food and Drug Administration required product labeling changes

    OpenAIRE

    Norman, Jessica L; Fixen, Danielle R; Saseen, Joseph J; Saba, Laura M; Linnebur, Sunny A

    2017-01-01

    Background: Women have higher morning serum zolpidem concentrations than men after taking an evening dose, potentially leading to increased risk of harm. On 19 April 2013, the United States Food and Drug Administration required labeling changes for zolpidem, recommending an initial dose of no greater than 5 mg (immediate release) or 6.25 mg (controlled release) per night in women. Objectives: The primary objective of this study was to compare prescribing practices before and after the 2013 zo...

  16. Higher Order Mode Fibers

    DEFF Research Database (Denmark)

    Israelsen, Stine Møller

    This PhD thesis considers higher order modes (HOMs) in optical fibers. That includes their excitation and characteristics. Within the last decades, HOMs have been applied both for space multiplexing in optical communications, group velocity dispersion management and sensing among others......-radial polarization as opposed to the linear polarization of the LP0X modes. The effect is investigated numerically in a double cladding fiber with an outer aircladding using a full vectorial modesolver. Experimentally, the bowtie modes are excited using a long period grating and their free space characteristics...... and polarization state are investigated. For this fiber, the onset of the bowtie effect is shown numerically to be LP011. The characteristics usually associated with Bessel-likes modes such as long diffraction free length and selfhealing are shown to be conserved despite the lack of azimuthal symmetry...

  17. Spiky higher genus strings

    International Nuclear Information System (INIS)

    Ambjoern, J.; Bellini, A.; Johnston, D.

    1990-10-01

    It is clear from both the non-perturbative and perturbative approaches to two-dimensional quantum gravity that a new strong coupling regime is setting in at d=1, independent of the genus of the worldsheet being considered. It has been suggested that a Kosterlitz-Thouless (KT) phase transition in the Liouville theory is the cause of this behaviour. However, it has recently been pointed out that the XY model, which displays a KT transition on the plane and the sphere, is always in the strong coupling, disordered phase on a surface of constant negative curvature. A higher genus worldsheet can be represented as a fundamental region on just such a surface, which might seem to suggest that the KT picture predicts a strong coupling region for arbitrary d, contradicting the known results. We resolve the apparent paradox. (orig.)

  18. Lipid nanoparticles as drug/gene delivery systems to the retina.

    Science.gov (United States)

    del Pozo-Rodríguez, Ana; Delgado, Diego; Gascón, Alicia R; Solinís, Maria Ángeles

    2013-03-01

    This review highlights the application of lipid nanoparticles (Solid Lipid Nanoparticles, Nanostructured Lipid Carriers, or Lipid Drug Conjugates) as effective drug/gene delivery systems for retinal diseases. Most drug products for ocular disease treatment are marketed as eye drop formulations but, due to ocular barriers, the drug concentration in the retina hardly ever turns out to be effective. Up to this date, several delivery systems have been designed to deliver drugs to the retina. Drug delivery strategies may be classified into 3 groups: noninvasive techniques, implants, and colloidal carriers. The best known systems for drug delivery to the posterior eye are intravitreal implants; in fact, some of them are being clinically used. However, their long-term accumulation might impact the patient's vision. On the contrary, colloidal drug delivery systems (microparticles, liposomes, or nanoparticles) can be easily administered in a liquid form. Nanoparticular systems diffuse rapidly and are better internalized in ocular tissues than microparticles. In comparison with liposomes, nanoparticles have a higher loading capacity and are more stable in biological fluids and during storage. In addition, their capacity to adhere to the ocular surface and interact with the endothelium makes these drug delivery systems interesting as new therapeutic tools in ophthalmology. Within the group of nanoparticles, those composed of lipids (Solid Lipid Nanoparticles, Nanostructred Lipid Carriers, and Lipid Drug Conjugates) are more biocompatible, easy to produce at large scale, and they may be autoclaved or sterilized. The present review summarizes scientific results that evidence the potential application of lipid nanoparticles as drug delivery systems for the retina and also as nonviral vectors in gene therapy of retina disorders, although much more effort is still needed before these lipidic systems could be available in the market.

  19. Concentration and size distribution of particles in abstracted groundwater

    NARCIS (Netherlands)

    Van Beek, C.G.E.M.; de Zwart, A.H.; Balemans, M.; Kooiman, J.W.; van Rosmalen, C.; Timmer, H.; Vandersluys, J.; Stuijfzand, P.J.

    2010-01-01

    Particle number concentrations have been counted and particle size distributions calculated in groundwater derived by abstraction wells. Both concentration and size distribution are governed by the discharge rate: the higher this rate the higher the concentration and the higher the proportion of

  20. Leadership in Higher Education

    Directory of Open Access Journals (Sweden)

    Drugus D.

    2014-12-01

    Full Text Available “The conduct” of an academic institution has suffered a permanent change under external pressure and criticism for its failure to adapt to current social and economic requirements. The degradation of quality in the Romanian education system is a current affairs subject. Successive and rather incoherent reforms suggest the lack of a long-term vision, as well as that of a political consensus on the role and place of education within the Romanian economy and society. The reference points identified as a result of the needs analysis and the student opinion polls have indicated the necessity to focus the academic teaching and learning activities on the student, on their level of development, using active-participative strategies, using a specific academic group management and applying various evaluation techniques focused on the student’s performance and his acquired competences. All of these elements signal, at the level of institutional strategic decisions, a direction towards the improvement of professional development of the teaching staff, one concentrated on education quality and performance. The modern school of leadership is based on applied methods, the delegation of responsibilities, regulation of centralized-decentralized relations, research and creativity development and the reinforcement of psychological and social aspects. Unlike management, considered to be a formal and institutionalized type of leadership, leadership is perceived as a process carried out at an informal group level, while the leader as a boss is someone who leads this group.

  1. Aggregation and phase separation behavior of an amphiphilic drug promazine hydrochloride under the influence of inorganic salts and ureas

    Energy Technology Data Exchange (ETDEWEB)

    Rub, Malik Abdul, E-mail: malikrub@gmail.com [Center of Excellence for Advanced Materials Research, King Abdulaziz University, Jeddah 21589 (Saudi Arabia); Chemistry Department, King Abdulaziz University, Jeddah 21589 (Saudi Arabia); Asiri, Abdullah M.; Azum, Naved; Khan, Anish; Khan, Aftab Aslam Parwaz; Khan, Sher Bahadar; Rahman, Mohammed M. [Center of Excellence for Advanced Materials Research, King Abdulaziz University, Jeddah 21589 (Saudi Arabia); Chemistry Department, King Abdulaziz University, Jeddah 21589 (Saudi Arabia); Kabir-ud-Din [Department of Chemistry, Aligarh Muslim University, Aligarh 202002 (India)

    2013-12-20

    Highlights: • Aggregation and clouding behavior of PMZ-additive (salts/ureas) mixtures have been investigated. • Both urea and thiourea, at low concentrations, decrease the cmc but, at high concentrations, increase it. • However, ΔH{sub m}° for pure drug/drug–additive systems is negative at low temperature and positive at higher temperature. • The ΔS{sub m}° values are positive, their magnitude being more at T = 303.15 K and above. - Abstract: Self-association and phase separation phenomena of an amphiphilic phenothiazine drug promazine hydrochloride (PMZ) in the absence and presence of inorganic salts (NaF, NaCl and NaBr) and ureas (urea and thiourea) have been investigated in the present study. By the increase in temperature the critical micelle concentration (cmc) of drug PMZ first increases then decreases. Maximum cmc values were obtained at 303.15 K in presence or absence of additives (salts/ureas). Decrease in cmc occurs by the addition of the inorganic salts which is explained on the basis of nature and ion size. Ureas (urea and thiourea) decreased the cmc at low concentration; however, at higher concentrations, increase in cmc was observed with both the additives. Increasing inorganic salt concentrations caused an increase in the cloud point (CP) of PMZ, whereas urea decreased the CP. Significant thermodynamic parameters were also evaluated and discussed.

  2. Aggregation and phase separation behavior of an amphiphilic drug promazine hydrochloride under the influence of inorganic salts and ureas

    International Nuclear Information System (INIS)

    Rub, Malik Abdul; Asiri, Abdullah M.; Azum, Naved; Khan, Anish; Khan, Aftab Aslam Parwaz; Khan, Sher Bahadar; Rahman, Mohammed M.; Kabir-ud-Din

    2013-01-01

    Highlights: • Aggregation and clouding behavior of PMZ-additive (salts/ureas) mixtures have been investigated. • Both urea and thiourea, at low concentrations, decrease the cmc but, at high concentrations, increase it. • However, ΔH m ° for pure drug/drug–additive systems is negative at low temperature and positive at higher temperature. • The ΔS m ° values are positive, their magnitude being more at T = 303.15 K and above. - Abstract: Self-association and phase separation phenomena of an amphiphilic phenothiazine drug promazine hydrochloride (PMZ) in the absence and presence of inorganic salts (NaF, NaCl and NaBr) and ureas (urea and thiourea) have been investigated in the present study. By the increase in temperature the critical micelle concentration (cmc) of drug PMZ first increases then decreases. Maximum cmc values were obtained at 303.15 K in presence or absence of additives (salts/ureas). Decrease in cmc occurs by the addition of the inorganic salts which is explained on the basis of nature and ion size. Ureas (urea and thiourea) decreased the cmc at low concentration; however, at higher concentrations, increase in cmc was observed with both the additives. Increasing inorganic salt concentrations caused an increase in the cloud point (CP) of PMZ, whereas urea decreased the CP. Significant thermodynamic parameters were also evaluated and discussed

  3. High sugar consumption and poor nutrient intake among drug addicts in Oslo, Norway.

    Science.gov (United States)

    Saeland, M; Haugen, M; Eriksen, F-L; Wandel, M; Smehaugen, A; Böhmer, T; Oshaug, A

    2011-02-01

    Poor dietary habits among drug addicts represent health hazards. However, very few studies have focused on dietary intake as an independent health risk factor in relation to this group. The objective of the present study was to examine the dietary habits of drug addicts living on the fringes of an affluent society. The study focused on food access, food preferences, intake of energy and nutrients, and related nutrient blood concentrations. The respondent group consisted of 123 male and seventy-two female drug addicts, who participated in a cross-sectional study that included a 24 h dietary recall, blood samples, anthropometrical measurements and a semi-structured interview concerning food access and preferences. Daily energy intake varied from 0 to 37 MJ. Food received from charitable sources and friends/family had a higher nutrient density than food bought by the respondents. Added sugar accounted for 30 % of the energy intake, which was mirrored in biomarkers. Sugar and sugar-sweetened food items were preferred by 61 % of the respondents. Of the respondents, 32 % had a TAG concentration above the reference values, while 35 % had a cholesterol concentration beneath the reference values. An elevated serum Cu concentration indicated inflammation among the respondents. Further research on problems related to the diets of drug addicts should focus on dietary habits and aim to uncover connections that may reinforce inebriation and addiction.

  4. Males exceed females in PCB concentrations of cisco (Coregonus artedi) from Lake Superior

    Science.gov (United States)

    Madenjian, Charles P.; Yule, Daniel L.; Chernyak, Sergei M.; Begnoche, Linda J.; Berglund, Eric K.; Isaac, Edmund J.

    2014-01-01

    We determined whole-fish polychlorinated biphenyl (PCB) concentrations of 25 male and 25 female age-7 ciscoes (Coregonus artedi) captured from a spawning aggregation in Thunder Bay, Lake Superior, during November 2010. We also determined PCB concentrations in the ovaries and somatic tissue of five additional female ciscoes (ages 5–22). All 55 of these ciscoes were in ripe or nearly ripe condition. Bioenergetics modeling was used to determine the contribution of the growth dilution effect toward a difference in PCB concentrations between the sexes, as females grew substantially faster than males. Results showed that the PCB concentration of males (mean = 141 ng/g) was 43% greater than that of females (mean = 98 ng/g), and this difference was highly significant (P ovaries and the somatic tissue of the five females were 135 and 100 ng/g, respectively. Based on these PCB determinations for the ovaries and somatic tissue, we concluded that release of eggs by females at previous spawnings was not a contributing factor to the observed difference in PCB concentrations between the sexes. Bioenergetics modeling results indicated that the growth dilution effect could explain males being higher than females in PCB concentration by only 3–7%. We concluded that the higher PCB concentration in males was most likely due to higher rate of energy expenditure, originating from greater activity and a higher resting metabolic rate. Mean PCB concentration in the cisco eggs was well below the U. S. Food and Drug Administration and Ontario Ministry of Environment guidelines of 2000 and 844 ng/g, respectively, and this finding may have implications for the cisco roe fishery currently operating in Lake Superior.

  5. Design and characterisation of matrix tablets of highly water soluble drug

    Directory of Open Access Journals (Sweden)

    Vijayalakshmi Prakya

    2012-04-01

    Full Text Available Tramadol HCL is a centrally acting opioid analgesic. Although the drug has a higher plasma half life, the steady state plasma concentration is not achieved with frequent dosing of q.i.d at 6 hour intervals. Therefore, the objective of the present work was to formulate a 100mg strength Tramadol matrix tablets to extend the drug release and thus decrease the dosing frequency and achieve steady state plasma concentration. Initially, preformulation studies were carried out to rule out any incompatibility between the drug and the chosen polymer(s after exposing physical mixtures of the drug and the polymer(s to 40 and deg;C/75% RH for three months. A suitable method was developed for drug estimation at 271nm by a UV double beam spectrophotometer. Next, various batches of tablets were designed using different polymers such as Ethylcellulose, Carnauba wax, HPMC-K100M, Carbopol-974P and Kollidon-SR. Direct compression technique was used except for the formulation containing carnauba wax for which melt granulation was done followed by compression. Formulations F-1 to F-15 contained single polymers in increasing concentrations in drug:polymer ratios of 1:1, 1:2 and 1:3 where it was observed that the drug release extended with increasing polymer concentrations. Carbopol-974P extended drug release better followed by HPMC-K100M and Carnauba wax compared to other polymers. A combination of these polymers was also used at various ratios to get formulations F-16 to F-20 and observed that the polymer combinations controlled drug release better. The type of fillers like lactose and microcrystalline cellulose had no effect on the physiochemical characters as well as on the drug release profiles. The in vitro release data from the best formulation fitted well in Higuchi as well as Peppas model, the and #8216;n and #8217; value, which confirmed that the release mechanism shifted from initial dissolution to later extended diffusion in which both diffusion and erosion

  6. DRUG INTERACTIONS WITH DIAZEPAM

    Directory of Open Access Journals (Sweden)

    Zoran Bojanić

    2011-06-01

    Full Text Available Diazepam is a benzodiazepine derivative with anxyolitic, anticonvulsant, hypnotic, sedative, skeletal muscle relaxant, antitremor, and amnestic activity. It is metabolized in the liver by the cytochrome P (CYP 450 enzyme system. Diazepam is N-demethylated by CYP3A4 and CYP2C19 to the active metabolite N-desmethyldiazepam, and is hydroxylated by CYP3A4 to the active metabolite temazepam. N-desmethyl-diazepam and temazepam are both further metabolized to oxazepam. Concomitant intake of inhibitors or inducers of the CYP isozymes involved in the biotransformation of diazepam may alter plasma concentrations of this drug, although this effect is unlikely to be associated with clinically relevant interactions.The goal of this article was to review the current literature on clinically relevant pharmacokinetic drug interactions with diazepam.A search of MEDLINE and EMBASE was conducted for original research and review articles published in English between January 1971. and May 2011. Among the search terms were drug interactions, diazepam, pharmacokinetics, drug metabolism, and cytochrome P450. Only articles published in peer-reviewed journals were included, and meeting abstracts were excluded. The reference lists of relevant articles were hand-searched for additional publications.Diazepam is substantially sorbed by the plastics in flexible containers, volume control set chambers, and tubings of intravenous administration sets. Manufacturers recommend not mixing with any other drug or solution in syringe or solution, although diazepam is compatible in syringe with cimetidine and ranitidine, and in Y-site with cisatracurium, dobutamine, fentanyl, hydromorphone, methadone, morphine, nafcillin, quinidine gluconate, remifentanil, and sufentanil. Diazepam is compatible with: dextrose 5% in water, Ringers injection, Ringers injection lactated and sodium chloride 0.9%. Emulsified diazepam is compatible with Intralipid and Nutralipid.Diazepam has low potential

  7. 21 CFR 146.146 - Frozen concentrated orange juice.

    Science.gov (United States)

    2010-04-01

    ... 21 Food and Drugs 2 2010-04-01 2010-04-01 false Frozen concentrated orange juice. 146.146 Section... Fruit Juices and Beverages § 146.146 Frozen concentrated orange juice. (a) Frozen concentrated orange juice is the food prepared by removing water from the juice of mature oranges as provided in § 146.135...

  8. 21 CFR 146.154 - Concentrated orange juice with preservative.

    Science.gov (United States)

    2010-04-01

    ... 21 Food and Drugs 2 2010-04-01 2010-04-01 false Concentrated orange juice with preservative. 146... Canned Fruit Juices and Beverages § 146.154 Concentrated orange juice with preservative. (a) Concentrated orange juice with preservative complies with the requirements for composition and labeling of optional...

  9. Concentrating solar thermal power.

    Science.gov (United States)

    Müller-Steinhagen, Hans

    2013-08-13

    In addition to wind and photovoltaic power, concentrating solar thermal power (CSP) will make a major contribution to electricity provision from renewable energies. Drawing on almost 30 years of operational experience in the multi-megawatt range, CSP is now a proven technology with a reliable cost and performance record. In conjunction with thermal energy storage, electricity can be provided according to demand. To date, solar thermal power plants with a total capacity of 1.3 GW are in operation worldwide, with an additional 2.3 GW under construction and 31.7 GW in advanced planning stage. Depending on the concentration factors, temperatures up to 1000°C can be reached to produce saturated or superheated steam for steam turbine cycles or compressed hot gas for gas turbine cycles. The heat rejected from these thermodynamic cycles can be used for sea water desalination, process heat and centralized provision of chilled water. While electricity generation from CSP plants is still more expensive than from wind turbines or photovoltaic panels, its independence from fluctuations and daily variation of wind speed and solar radiation provides it with a higher value. To become competitive with mid-load electricity from conventional power plants within the next 10-15 years, mass production of components, increased plant size and planning/operating experience will be accompanied by technological innovations. On 30 October 2009, a number of major industrial companies joined forces to establish the so-called DESERTEC Industry Initiative, which aims at providing by 2050 15 per cent of European electricity from renewable energy sources in North Africa, while at the same time securing energy, water, income and employment for this region. Solar thermal power plants are in the heart of this concept.

  10. [Street prostitution and drug addiction].

    Science.gov (United States)

    Ishøy, Torben; Ishøy, Pelle Lau; Olsen, Lis Raabaek

    2005-09-26

    Street-based prostitution accounts for 10% of the prostitution activity in Denmark, mainly involving female drug addicts. We studied a group of women with a common history of substance abuse and their comparative psychosocial characteristics, correlated with whether they had previously been a prostitute or not. Their psychic symptoms were evaluated and compared with those of controls. 27 females receiving maintenance treatment for substance abuse completed a questionnaire dealing with their social background, substance abuse profile, and history of sexual abuse and prostitution, as well as their current health status, including SCL-90. The scores were compared to those of a control group of an age- and gender-matched Danish standard population. Neglect in childhood and adulthood corresponded to international findings. 14 of the women had previous sex-trading experience, and early use of heroin and cocaine was a predictor for starting a career in prostitution. The SCL-90 scores for the dimensions of somatization and depression were significantly higher for drug-abusing women in general than in the control group. The scores of drug-abusing former prostitutes were similarly significantly higher on most of the dimensions except the hostility dimension when compared to those of drug-abusing women who had never been involved in prostitution. Rape and domestic violence were characteristic phenomena among drug-abusing prostitutes (p prostitution. Various psychosocial stress factors among street-based prostitutes indicate the need for broader psychiatric approaches in Danish drug addiction maintenance programmes.

  11. Finnish Higher Education Expansion and Regional Policy

    Science.gov (United States)

    Saarivirta, Toni

    2010-01-01

    This paper concentrates on the expansion of Finnish higher education between the 1960s and 1970s, exposes its background in the light of the policy decisions that were made, compares the unique features of this expansion with those of certain other countries, discusses the impact of the controlled "top down" governance of higher…

  12. Learning higher mathematics

    CERN Document Server

    Pontrjagin, Lev Semenovič

    1984-01-01

    Lev Semenovic Pontrjagin (1908) is one of the outstanding figures in 20th century mathematics. In a long career he has made fundamental con­ tributions to many branches of mathematics, both pure and applied. He has received every honor that a grateful government can bestow. Though in no way constrained to do so, he has through the years taught mathematics courses at Moscow State University. In the year 1975 he set himself the task of writing a series of books on secondary school and beginning university mathematics. In his own words, "I wished to set forth the foundations of higher mathematics in a form that would have been accessible to myself as a lad, but making use of all my experience as a scientist and a teacher, ac­ cumulated over many years. " The present volume is a translation of the first two out of four moderately sized volumes on this theme planned by Pro­ fessor Pontrjagin. The book begins at the beginning of modern mathematics, analytic ge­ ometry in the plane and 3-dimensional space. Refin...

  13. Chitosan microspheres in novel drug delivery systems.

    Science.gov (United States)

    Mitra, Analava; Dey, Baishakhi

    2011-07-01

    The main aim in the drug therapy of any disease is to attain the desired therapeutic concentration of the drug in plasma or at the site of action and maintain it for the entire duration of treatment. A drug on being used in conventional dosage forms leads to unavoidable fluctuations in the drug concentration leading to under medication or overmedication and increased frequency of dose administration as well as poor patient compliance. To minimize drug degradation and loss, to prevent harmful side effects and to increase drug bioavailability various drug delivery and drug targeting systems are currently under development. Handling the treatment of severe disease conditions has necessitated the development of innovative ideas to modify drug delivery techniques. Drug targeting means delivery of the drug-loaded system to the site of interest. Drug carrier systems include polymers, micelles, microcapsules, liposomes and lipoproteins to name some. Different polymer carriers exert different effects on drug delivery. Synthetic polymers are usually non-biocompatible, non-biodegradable and expensive. Natural polymers such as chitin and chitosan are devoid of such problems. Chitosan comes from the deacetylation of chitin, a natural biopolymer originating from crustacean shells. Chitosan is a biocompatible, biodegradable, and nontoxic natural polymer with excellent film-forming ability. Being of cationic character, chitosan is able to react with polyanions giving rise to polyelectrolyte complexes. Hence chitosan has become a promising natural polymer for the preparation of microspheres/nanospheres and microcapsules. The techniques employed to microencapsulate with chitosan include ionotropic gelation, spray drying, emulsion phase separation, simple and complex coacervation. This review focuses on the preparation, characterization of chitosan microspheres and their role in novel drug delivery systems.

  14. Personality, Drug Preference, Drug Use, and Drug Availability

    Science.gov (United States)

    Feldman, Marc; Boyer, Bret; Kumar, V. K.; Prout, Maurice

    2011-01-01

    This study examined the relationship between drug preference, drug use, drug availability, and personality among individuals (n = 100) in treatment for substance abuse in an effort to replicate the results of an earlier study (Feldman, Kumar, Angelini, Pekala, & Porter, 2007) designed to test prediction derived from Eysenck's (1957, 1967)…

  15. Determination of mercury and vanadium concentration in Johnius belangerii (C) fish in Musa estuary in Persian Gulf

    International Nuclear Information System (INIS)

    Fard, Neamat Jaafarzadeh Haghighi; Ravanbakhsh, Maryam; Ramezani, Zahra; Ahmadi, Mehdi; Angali, Kambiz Ahmadi; Javid, Ahmad Zare

    2015-01-01

    Highlights: • Hg & V in Johnius belangerii fish in Musa estuary, Persian Gulf was determined. • Significant reverse relationship was between concentrations of Hg & V. • Weight and length had significant direct relationship with Hg concentration. • Length had significant reverse relationship with V concentration. • Concentrations of Hg & V were higher than threshold limits. - Abstract: The main aim of this study was to determine the concentrations of mercury and vanadium in Johnius belangerii (C) fish in the Musa estuary. A total of 67 fishes were caught from the Musa estuary during five intervals of 15 days in the summer of 2013. After biometric measurements were conducted, the concentrations of mercury and vanadium were measured in the muscle tissue of fish using a direct method analyzer (DMA) and a graphite furnace atomic absorption spectrophotometer, respectively. The mean concentration of mercury and vanadium in the muscle tissue of fish was 3.154 ± 1.981 and 2.921 ± 0.873 mg/kg w.w, respectively. The generalized linear model (GLM) analysis showed a significantly positive relationship among mercury concentration, length, and weight (P = 0.000). In addition, there was a significantly negative relationship between vanadium concentration and fish length (P = 0.000). A reverse association was found between concentrations of mercury and vanadium. Mercury concentration exceeded the allowable standards of the Environmental Protection Agency (EPA), the World Health Organization (WHO), and the Food and Drug Administration (FDA) in J. belangerii (C)

  16. The Research Progress of Targeted Drug Delivery Systems

    Science.gov (United States)

    Zhan, Jiayin; Ting, Xizi Liang; Zhu, Junjie

    2017-06-01

    Targeted drug delivery system (DDS) means to selectively transport drugs to targeted tissues, organs, and cells through a variety of drugs carrier. It is usually designed to improve the pharmacological and therapeutic properties of conventional drugs and to overcome problems such as limited solubility, drug aggregation, poor bio distribution and lack of selectivity, controlling drug release carrier and to reduce normal tissue damage. With the characteristics of nontoxic and biodegradable, it can increase the retention of drug in lesion site and the permeability, improve the concentration of the drug in lesion site. at present, there are some kinds of DDS using at test phase, such as slow controlled release drug delivery system, targeted drug delivery systems, transdermal drug delivery system, adhesion dosing system and so on. This paper makes a review for DDS.

  17. Análise comparativa da concentração industrial e de turnover da indústria farmacêutica no Brasil para os segmentos de medicamentos de marca e genéricos Comparative analysis of the Industrial Concentration and Turnover of the pharmaceutical industry in Brazil for the segments of mark and generic drugs

    Directory of Open Access Journals (Sweden)

    Gerson Rosenberg

    2010-04-01

    Full Text Available Este artigo analisa a evolução da estrutura do segmento de medicamentos de marca e genéricos no Brasil a partir de 1997. Após a entrada dos medicamentos genéricos, constatou-se que não houve diminuição significativa da concentração na indústria farmacêutica brasileira, porém, o mesmo não ocorreu em nível mundial, verificando-se um aumento da concentração a partir de 2001, impulsionado pelo expressivo processo de fusões e aquisições nos últimos anos da década de 1990. Em relação ao turnover, notou-se que este foi muito baixo para o grupo das maiores empresas em ambos os segmentos de medicamentos. Entretanto, observa-se um elevado turnover com a entrada dos genéricos, mostrando o fortalecimento da indústria nacional. Verifica-se que o processo de fusões e aquisições entre empresas nacionais é pouco significativo, o que pode ser uma alternativa para as pequenas empresas farmacêuticas aumentarem a sua participação no mercado brasileiro.This paper analyzes the evolution of brand-name and generic drugs structure in Brazil since 1997. After the introduction of generic drugs it was not verified a significant decrease in the concentration of Brazilian pharmaceutical industry. The process of mergers and acquisitions in the 90's enhanced the process of concentration in the international market. However, a non-expressive turnover can be demonstrated in both pharmaceutical and generic markets. At the same time, the entrance of the generic industry in Brazil explains the invigoration of the national industry. The mergers and acquisitions process in the pharmaceutical industry is quite intense in Europe and in the USA, although in Brazil it is still not significant.

  18. Higher Efficiency HVAC Motors

    Energy Technology Data Exchange (ETDEWEB)

    Flynn, Charles Joseph [QM Power, Inc., Kansas City, MO (United States)

    2018-02-13

    failure prone capacitors from the power stage. Q-Sync’s simpler electronics also result in higher efficiency because it eliminates the power required by the PCB to perform the obviated power conversions and PWM processes after line synchronous operating speed is reached in the first 5 seconds of operation, after which the PWM circuits drop out and a much less energy intensive “pass through” circuit takes over, allowing the grid-supplied AC power to sustain the motor’s ongoing operation.

  19. Drug-related acute renal failure in hospitalised patients

    Directory of Open Access Journals (Sweden)

    Lujan Iavecchia

    2015-11-01

    Conclusions: Half of ARF episodes during hospitalisation were drug related. Patients with drug-related ARF had higher cardiovascular morbidity than those with ARF related to other causes, but they had a lower frequency of ARF risk factors and mortality.

  20. Drug-Avoidance Self-Efficacy Among Exclusive Cannabis Users vs. Other Drug Users Visiting the Emergency Department.

    Science.gov (United States)

    Clingan, Sarah E; Woodruff, Susan I

    2017-07-29

    Medical care in the emergency department (ED) is a growing and complex area of outpatient care, with about 256 visits made to EDs every minute in 2013. Studies report that, compared to people who do not use drugs, people who use illicit drugs are more likely to use the ED for their medical care. Self-efficacy has been shown to be a predictor of abstinence or reduced use among drug-using individuals. The current study describes drug avoidance self-efficacy among exclusive cannabis-using individuals and other drug-using individuals who use the ED for any reason. Participants were 693 adult patients visiting the trauma units and EDs of two large urban "safety net" hospitals (i.e., providing care to low-income, uninsured, and vulnerable population) in Southern California who reported using illicit drugs in the past 30 days. For people who use only cannabis, higher drug-avoidance self-efficacy was associated with older age, lower drug involvement scores, lower drug severity scores, and higher readiness to change use. For people who use other drugs, higher drug avoidance self-efficacy scores was associated with lower drug severity scores, lower psychiatric severity scores, higher medical severity scores, and higher readiness to change use. This study identified several factors (some common, some unique) related to higher drug-avoidance self-efficacy for both groups. Results may be important when designing intervention protocols for use in the ED.

  1. Chloride concentrations in human hepatic cytosol and mitochondria are a function of age.

    Science.gov (United States)

    Jahn, Stephan C; Rowland-Faux, Laura; Stacpoole, Peter W; James, Margaret O

    2015-04-10

    We recently reported that, in a concentration-dependent manner, chloride protects hepatic glutathione transferase zeta 1 from inactivation by dichloroacetate, an investigational drug used in treating various acquired and congenital metabolic diseases. Despite the importance of chloride ions in normal physiology, and decades of study of chloride transport across membranes, the literature lacks information on chloride concentrations in animal tissues other than blood. In this study we measured chloride concentrations in human liver samples from male and female donors aged 1 day to 84 years (n = 97). Because glutathione transferase zeta 1 is present in cytosol and, to a lesser extent, in mitochondria, we measured chloride in these fractions by high-performance liquid chromatography analysis following conversion of the free chloride to pentafluorobenzylchloride. We found that chloride concentration decreased with age in hepatic cytosol but increased in liver mitochondria. In addition, chloride concentrations in cytosol, (105.2 ± 62.4 mM; range: 24.7-365.7 mM) were strikingly higher than those in mitochondria (4.2 ± 3.8 mM; range 0.9-22.2 mM). These results suggest a possible explanation for clinical observations seen in patients treated with dichloroacetate, whereby children metabolize the drug more rapidly than adults following repeated doses, and also provide information that may influence our understanding of normal liver physiology. Copyright © 2015 Elsevier Inc. All rights reserved.

  2. Polymorphic drug metabolising enzymes : Assessment of activities by phenotyping and genotyping in clinical pharmacology

    NARCIS (Netherlands)

    Tamminga, Willem Jan

    2001-01-01

    Drug effects (pharmacodynamics) are determined by drug concentration at target site and the affinity of the drug for a target. Pharmacogenetics describes inherited differences in drug metabolising enzyme activities and differences in drug transporters and receptors.Answers were sought on the

  3. Studies on the mechanism of the epileptiform activity induced by U18666A. II. concentration, half-life and distribution of radiolabeled U18666A in the brain

    Energy Technology Data Exchange (ETDEWEB)

    Cenedella, R.J.; Sarkar, C.P.; Towns, L.

    1982-06-01

    The concentration, half-life, and distribution in brain of U18666A, a drug that can drastically alter cerebral lipids and induce a chronic epileptiform state, was determined following both acute and chronic drug administration. U18666A specifically labeled with tritium was prepared by custom synthesis. Brain levels of 1 x 10(-6)M and higher were reached soon after giving an acute 10-mg/kg dose (i.p. or s.c.) of U18666A containing 7-/sup 3/H-U18666A of known specific activity. A steady state concentration of 1 to 2 x 10(-6)M was reached with chronic injection of 10 mg/kg every 4th day, a treatment schedule that results in altered brain lipids and induction of epilepsy if begun soon after birth. The disappearance of U18666A from both brain and serum was described by two similar biexponential processes, a brief rapid clearance (t1/2 . 10 h) and a sustained and much slower one (t1/2 . 65 h). Brain levels of the drug were about 10 times higher than serum at all times examined. Few differences were seen in the regional distribution of radiolabeled drug in brain as determined by both direct analysis and by autoradiographic examination; but the drug did concentrate in lipid-rich subcellular fractions. For example, the synaptosome and myelin fractions each contained about 25-35% of both the total /sup 3/H-labeled drug and total lipid in whole brain. The lipid composition of these fractions was drastically altered in treated animals. In conclusion, the chronic epileptiform state induced by U18666A does not appear to involve localization of the drug in a specific brain region or particular cell type. Rather, the condition could involve localization of the drug in lipid-rich membranes and marked changes in the composition of these membranes.

  4. Pharmacokinetic-Pharmacodynamic (PKPD) Analysis with Drug Discrimination.

    Science.gov (United States)

    Negus, S Stevens; Banks, Matthew L

    2016-08-30

    Discriminative stimulus and other drug effects are determined by the concentration of drug at its target receptor and by the pharmacodynamic consequences of drug-receptor interaction. For in vivo procedures such as drug discrimination, drug concentration at receptors in a given anatomical location (e.g., the brain) is determined both by the dose of drug administered and by pharmacokinetic processes of absorption, distribution, metabolism, and excretion that deliver drug to and from that anatomical location. Drug discrimination data are often analyzed by strategies of dose-effect analysis to determine parameters such as potency and efficacy. Pharmacokinetic-Pharmacodynamic (PKPD) analysis is an alternative to conventional dose-effect analysis, and it relates drug effects to a measure of drug concentration in a body compartment (e.g., venous blood) rather than to drug dose. PKPD analysis can yield insights on pharmacokinetic and pharmacodynamic determinants of drug action. PKPD analysis can also facilitate translational research by identifying species differences in pharmacokinetics and providing a basis for integrating these differences into interpretation of drug effects. Examples are discussed here to illustrate the application of PKPD analysis to the evaluation of drug effects in rhesus monkeys trained to discriminate cocaine from saline.

  5. Ultra flat ideal concentrators of high concentration

    Energy Technology Data Exchange (ETDEWEB)

    Chaves, Julio [IST, Physics Dept., Lisboa (Portugal); INETI-DER, Lisboa (Portugal); Collares-Pereira, Manuel [INETI-DER, Lisboa (Portugal)

    2000-07-01

    A new method for the design of nonimaging devices is presented. Its application to the design of ultra flat compact concentrators is analysed. These new concentrators are based on a combination of two stages: the first one is composed of a large number of small structures placed side by side and the second one is a very compact single device concentrating the radiation to the limit. These devices are ideal for 2D. These compact designs are much more compact than the traditional ones like lens-mirror combinations or parabolic primaries with nonimaging secondaries. Besides, they can be designed for any acceptance angle, while the traditional ones are limited to small acceptance angles. (Author)

  6. β-Cyclodextrin-dextran polymers for the solubilization of poorly soluble drugs.

    Science.gov (United States)

    di Cagno, Massimiliano; Terndrup Nielsen, Thorbjørn; Lambertsen Larsen, Kim; Kuntsche, Judith; Bauer-Brandl, Annette

    2014-07-01

    The aim of this study was to assess the potential of novel β-cyclodextrin (βCD)-dextran polymers for drug delivery. The size distribution of βCD-dextrans (for eventual parenteral administration), the influence of the dextran backbones on the stability of the βCD/drug complex, the solubilization efficiency of poorly soluble drugs and drug release properties were investigated. Size analysis of different βCD-dextrans was measured by size exclusion chromatography (SEC) and asymmetrical flow field-flow fractionation (AF4). Stability of drug/βCD-dextrans was assessed by isothermal titration calorimetry (ITC) and molar enthalpies of complexation and equilibrium constants compared to some commercially available βCD derivatives. For evaluation of the solubilization efficiency, phase-solubility diagrams were made employing hydrocortisone (HC) as a model of poorly soluble drugs, whereas reverse dialysis was used to detect potential drug supersaturation (increased molecularly dissolved drug concentration) as well as controlled release effects. Results indicate that all investigated βCD-polymers are of appropriate sizes for parenteral administration. Thermodynamic results demonstrate that the presence of the dextran backbone structure does not affect the stability of the βCD/drug complex, compared to native βCD and commercially available derivatives. Solubility studies evidence higher solubilizing abilities of these new polymers in comparison to commercially available βCDs, but no supersaturation states were induced. Moreover, drug release studies evidenced that diffusion of HC was influenced by the solubilization induced by the βCD-derivatives. Copyright © 2014 Elsevier B.V. All rights reserved.

  7. Drugs Approved for Rhabdomyosarcoma

    Science.gov (United States)

    This page lists cancer drugs approved by the Food and Drug Administration (FDA) for rhabdomyosarcoma. The list includes generic names and brand names. The drug names link to NCI's Cancer Drug Information summaries. There may be drugs used in rhabdomyosarcoma that are not listed here.

  8. Information for Consumers (Drugs)

    Science.gov (United States)

    ... approved drugs Drugs@FDA Information on FDA-approved brand name and generic drugs including labeling and regulatory history Drugs with Approved Risk Evaluation and Mitigation Strategies (REMS) REMS is a risk management plan required by FDA for certain prescription drugs, ...

  9. Drugs and lactation

    International Nuclear Information System (INIS)

    Kelssering, G.; Aguiar, L.F.; Ribeiro, R.M.; Souza, A.Z. de

    1988-01-01

    Different kinds of drugs who can be transferred through the mother's milk to the lactant and its effects are showed in this work. A list of them as below: cardiotonics, diuretics, anti-hypertensives, beta-blockings, anti-arrythmics, drugs with gastrintestinal tract action, hormones, antibiotics and chemotherapeutics, citostatic drugs, central nervous system action drugs and anticoagulants drugs. (L.M.J.) [pt

  10. Highly concentrating Fresnel lenses

    International Nuclear Information System (INIS)

    Kritchman, E.M.; Friesem, A.A.; Yekutieli, G.

    1979-01-01

    A new type of concave Fresnel lens capable of concentrating solar radiation very near the ultimate concentration limit is considered. The differential equations that describe the lens are solved to provide computed solutions which are then checked by ray tracing techniques. The performance (efficiency and concentration) of the lens is investigated and compared to that of a flat Fresnel lens, showing that the new lens is preferable for concentrating solar radiation. (author)

  11. Organizational adoption of preemployment drug testing.

    Science.gov (United States)

    Spell, C S; Blum, T C

    2001-04-01

    This study explored the adoption of preemployment drug testing by 360 organizations. Survival models were developed that included internal organizational and labor market factors hypothesized to affect the likelihood of adoption of drug testing. Also considered was another set of variables that included social and political variables based on institutional theory. An event history analysis using Cox regressions indicated that both internal organizational and environmental variables predicted adoption of drug testing. Results indicate that the higher the proportion of drug testers in the worksite's industry, the more likely it would be to adopt drug testing. Also, the extent to which an organization uses an internal labor market, voluntary turnover rate, and the extent to which management perceives drugs to be a problem were related to likelihood of adoption of drug testing.

  12. Plasma oxytocin concentrations are lower in depressed vs. healthy control women and are independent of cortisol.

    Science.gov (United States)

    Yuen, Kaeli W; Garner, Joseph P; Carson, Dean S; Keller, Jennifer; Lembke, Anna; Hyde, Shellie A; Kenna, Heather A; Tennakoon, Lakshika; Schatzberg, Alan F; Parker, Karen J

    2014-04-01

    The neuropeptide oxytocin (OT) promotes social behavior and attenuates stress responsivity in mammals. Recent clinical evidence suggests OT concentrations may be dysregulated in major depression. This study extends previous research by testing whether: 1) OT concentrations vary systematically in depressive disorders with and without hypercortisolemia, 2) gender differences in OT concentrations are observed in depressed vs. healthy control participants, and 3) OT concentrations are predictive of clinical phenotypes. Plasma OT concentrations of psychotic major depressive (PMD; n = 14: 10 female, 4 male), non-psychotic major depressive (NPMD; n = 17: 12 female, 5 male), and non-depressed, healthy control (n = 19: 11 female, 8 male) participants were assayed at 2000, 2400, 0400, and 0800 h. Plasma cortisol concentrations were quantified at 2300 h, and clinical phenotypes were determined. As expected, PMD participants, compared to NPMD and healthy control participants, showed higher plasma cortisol concentrations. Although both depressed groups showed similar OT concentrations, a significant interaction effect between group and gender was observed. Specifically, depressed females exhibited lower mean OT concentrations than depressed males. Further, depressed vs. healthy control female participants exhibited lower mean OT concentrations, whereas depressed vs. healthy control male participants showed a trend in the opposite direction. OT concentrations were also predictive of desirability, drug dependence, and compulsivity scores as measured by the Million Clinical Multiaxial Inventory-III. All findings were independent of cortisol. These data suggest that OT signaling may provide a mechanism by which to better understand female-biased risk to develop depressive disorders and that plasma OT concentrations may be a useful biomarker of certain clinical phenotypes. Copyright © 2013. Published by Elsevier Ltd.

  13. In Vitro Dissolution of Fluconazole and Dipyridamole in Gastrointestinal Simulator (GIS), Predicting in Vivo Dissolution and Drug-Drug Interaction Caused by Acid-Reducing Agents.

    Science.gov (United States)

    Matsui, Kazuki; Tsume, Yasuhiro; Amidon, Gregory E; Amidon, Gordon L

    2015-07-06

    Weakly basic drugs typically exhibit pH-dependent solubility in the physiological pH range, displaying supersaturation or precipitation along the gastrointestinal tract. Additionally, their oral bioavailabilities may be affected by coadministration of acid-reducing agents that elevate gastric pH. The purpose of this study was to assess the feasibility of a multicompartmental in vitro dissolution apparatus, Gastrointestinal Simulator (GIS), in predicting in vivo dissolution of certain oral medications. In vitro dissolution studies of fluconazole, a BCS class I, and dipyridamole, a BCS class II weak bases (class IIb), were performed in the GIS as well as United States Pharmacopeia (USP) apparatus II and compared with the results of clinical drug-drug interaction (DDI) studies. In both USP apparatus II and GIS, fluconazole completely dissolved within 60 min regardless of pH, reflecting no DDI between fluconazole and acid-reducing agents in a clinical study. On the other hand, seven-fold and 15-fold higher concentrations of dipyridamole than saturation solubility were observed in the intestinal compartments in GIS with gastric pH 2.0. Precipitation of dipyridamole was also observed in the GIS, and the percentage of dipyridamole in solution was 45.2 ± 7.0%. In GIS with gastric pH 6.0, mimicking the coadministration of acid-reducing agents, the concentration of dipyridamole was equal to its saturation solubility, and the percentage of drug in solution was 9.3 ± 2.7%. These results are consistent with the clinical DDI study of dipyridamole with famotidine, which significantly reduced the Cmax and area under the curve. An In situ mouse infusion study combined with GIS revealed that high concentration of dipyridamole in the GIS enhanced oral drug absorption, which confirmed the supersaturation of dipyridamole. In conclusion, GIS was shown to be a useful apparatus to predict in vivo dissolution for BCS class IIb drugs.

  14. Solar cell concentrating system

    International Nuclear Information System (INIS)

    Garg, H.P.; Sharma, V.K.; Agarwal, R.K.

    1986-11-01

    This study reviews fabrication techniques and testing facilities for different solar cells under concentration which have been developed and tested. It is also aimed to examine solar energy concentrators which are prospective candidates for photovoltaic concentrator systems. This may provide an impetus to the scientists working in the area of solar cell technology

  15. Rheology of concentrated biomass

    Science.gov (United States)

    J.R. Samaniuk; J. Wang; T.W. Root; C.T. Scott; D.J. Klingenberg

    2011-01-01

    Economic processing of lignocellulosic biomass requires handling the biomass at high solids concentration. This creates challenges because concentrated biomass behaves as a Bingham-like material with large yield stresses. Here we employ torque rheometry to measure the rheological properties of concentrated lignocellulosic biomass (corn stover). Yield stresses obtained...

  16. The concentration of iodine in horse serum and its relationship with thyroxin concentration by geological difference.

    Science.gov (United States)

    Mochizuki, Mariko; Hayakawa, Noriyuki; Minowa, Fumiko; Saito, Akihiro; Ishioka, Katsumi; Ueda, Fukiko; Okubo, Kimihiro; Tazaki, Hiroyuki

    2016-04-01

    In this study, iodine and thyroxin (T4) concentrations in the serum of 69 horses were investigated. Higher iodine concentrations were obtained from the horses housed in Chiba Prefecture. In contrast, T4 concentrations of horses at Shizuoka Prefecture were higher than those of horses at Chiba Prefecture. There was a significant correlation (r = 0.643, P geological differences. It was thought that equine serum is a useful sample for monitoring.

  17. Microfluidic Devices for Drug Delivery Systems and Drug Screening

    Science.gov (United States)

    Kompella, Uday B.; Damiati, Safa A.

    2018-01-01

    Microfluidic devices present unique advantages for the development of efficient drug carrier particles, cell-free protein synthesis systems, and rapid techniques for direct drug screening. Compared to bulk methods, by efficiently controlling the geometries of the fabricated chip and the flow rates of multiphase fluids, microfluidic technology enables the generation of highly stable, uniform, monodispersed particles with higher encapsulation efficiency. Since the existing preclinical models are inefficient drug screens for predicting clinical outcomes, microfluidic platforms might offer a more rapid and cost-effective alternative. Compared to 2D cell culture systems and in vivo animal models, microfluidic 3D platforms mimic the in vivo cell systems in a simple, inexpensive manner, which allows high throughput and multiplexed drug screening at the cell, organ, and whole-body levels. In this review, the generation of appropriate drug or gene carriers including different particle types using different configurations of microfluidic devices is highlighted. Additionally, this paper discusses the emergence of fabricated microfluidic cell-free protein synthesis systems for potential use at point of care as well as cell-, organ-, and human-on-a-chip models as smart, sensitive, and reproducible platforms, allowing the investigation of the effects of drugs under conditions imitating the biological system. PMID:29462948

  18. Absorption-desorption of drugs in porous polymers obtained by plasma

    International Nuclear Information System (INIS)

    Gonzalez T, M.

    2016-01-01

    from the polymers in a higher concentration in the Kr solution than in water due to the ionic forces of the salt content in the Kr solution. Two linear trends were found, first the drug coated the polymer and later the drug within the pores went into the solution. After the drug is released in water, the polymers returned acquired morphology similar to that obtained with the lyophilization. After the release in Kr, the salts forming the Kr solution agglomerate on the polymer surface. (Author)

  19. Microcrystalline identification of selected designer drugs.

    Science.gov (United States)

    Elie, Leonie; Baron, Mark; Croxton, Ruth; Elie, Mathieu

    2012-01-10

    A microcrystalline test for the detection of 4-methylmethcathinone (mephedrone), benzylpiperazine (BZP) and 5,6-methylenedioxy-2-aminoindane (MDAI) using aqueous solutions of mercury chloride is described. Each of the compounds investigated formed specific drug-reagent crystals within minutes. The uniqueness of the test was confirmed by comparison of the microcrystalline response to that of other psychoactive stimulants and a common cutting agent. The limit of detection and cut-off levels for reference standards were established to 3 g/L and 5 g/L for mephedrone, 0.5 g/L for MDAI and 0.2 g/L and 0.3 g/L for BZP, respectively. Various mixtures of standards of either mephedrone, BZP or MDAI combined with caffeine were investigated for their microcrystalline response. Results showed that simultaneous detection of drug and cutting agent was possible with the concentrations tested but were dependant on the ratio of drug to cutting agent. BZP could be detected alongside caffeine from as low as 20% (v/v), MDAI from 40% (v/v) and mephedrone from 50% (v/v) and higher. Finally, seven samples of online purchased 'legal highs' were analysed using the developed test and the findings were compared to FTIR and GC-MS results. It was shown that 6 out of 7 samples did not contain the advertised active ingredient. Five samples consisted of BZP, caffeine and 1-[3-(trifluoromethyl)phenyl]piperazine (3-TFMPP). The microcrystalline tests carried out on these samples showed positive results for both BZP and caffeine without interference from other substances present. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

  20. Can medical students calculate drug doses? | Harries | Southern ...

    African Journals Online (AJOL)

    ... with calculations when the drug concentration was expressed either as a ratio or a percentage. Conclusion: Our findings support calls for the standardised labelling of drugs in solution and for dosage calculation training in the medical curriculum. Keywords: drug dosage calculations, clinical competence, medication errors