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Sample records for pharmaceutical genotoxic impurities

  1. Recent advances in trace analysis of pharmaceutical genotoxic impurities.

    PubMed

    Liu, David Q; Sun, Mingjiang; Kord, Alireza S

    2010-04-01

    Genotoxic impurities (GTIs) in pharmaceuticals at trace levels are of increasing concerns to both pharmaceutical industries and regulatory agencies due to their potentials for human carcinogenesis. Determination of these impurities at ppm levels requires highly sensitive analytical methodologies, which poses tremendous challenges on analytical communities in pharmaceutical R&D. Practical guidance with respect to the analytical determination of diverse classes of GTIs is currently lacking in the literature. This article provides an industrial perspective with regard to the analysis of various structural classes of GTIs that are commonly encountered during chemical development. The recent literatures will be reviewed, and several practical approaches for enhancing analyte detectability developed in recent years will be highlighted. As such, this article is organized into the following main sections: (1) trace analysis toolbox including sample introduction, separation, and detection techniques, as well as several 'general' approaches for enhancing detectability; (2) method development: chemical structure and property-based approaches; (3) method validation considerations; and (4) testing and control strategies in process chemistry. The general approaches for enhancing detection sensitivity to be discussed include chemical derivatization, 'matrix deactivation', and 'coordination ion spray-mass spectrometry'. Leveraging the use of these general approaches in method development greatly facilitates the analysis of poorly detectable or unstable/reactive GTIs. It is the authors' intent to provide a contemporary perspective on method development and validation that can guide analytical scientists in the pharmaceutical industries. PMID:20022442

  2. The Consultancy Activity on In Silico Models for Genotoxic Prediction of Pharmaceutical Impurities.

    PubMed

    Pavan, Manuela; Kovarich, Simona; Bassan, Arianna; Broccardo, Lorenza; Yang, Chihae; Fioravanzo, Elena

    2016-01-01

    The toxicological assessment of DNA-reactive/mutagenic or clastogenic impurities plays an important role in the regulatory process for pharmaceuticals; in this context, in silico structure-based approaches are applied as primary tools for the evaluation of the mutagenic potential of the drug impurities. The general recommendations regarding such use of in silico methods are provided in the recent ICH M7 guideline stating that computational (in silico) toxicology assessment should be performed using two (Q)SAR prediction methodologies complementing each other: a statistical-based method and an expert rule-based method.Based on our consultant experience, we describe here a framework for in silico assessment of mutagenic potential of drug impurities. Two main applications of in silico methods are presented: (1) support and optimization of drug synthesis processes by providing early indication of potential genotoxic impurities and (2) regulatory evaluation of genotoxic potential of impurities in compliance with the ICH M7 guideline. Some critical case studies are also discussed.

  3. Elemental Impurities in Pharmaceutical Excipients.

    PubMed

    Li, Gang; Schoneker, Dave; Ulman, Katherine L; Sturm, Jason J; Thackery, Lisa M; Kauffman, John F

    2015-12-01

    Control of elemental impurities in pharmaceutical materials is currently undergoing a transition from control based on concentrations in components of drug products to control based on permitted daily exposures in drug products. Within the pharmaceutical community, there is uncertainty regarding the impact of these changes on manufactures of drug products. This uncertainty is fueled in part by a lack of publically available information on elemental impurity levels in common pharmaceutical excipients. This paper summarizes a recent survey of elemental impurity levels in common pharmaceutical excipients as well as some drug substances. A widely applicable analytical procedure was developed and was shown to be suitable for analysis of elements that are subject to United States Pharmacopoeia Chapter <232> and International Conference on Harmonization's Q3D Guideline on Elemental Impurities. The procedure utilizes microwave-assisted digestion of pharmaceutical materials and inductively coupled plasma mass spectrometry for quantitative analysis of these elements. The procedure was applied to 190 samples from 31 different excipients and 15 samples from eight drug substances provided through the International Pharmaceutical Excipient Council of the Americas. The results of the survey indicate that, for the materials included in the study, relatively low levels of elemental impurities are present. PMID:26398581

  4. Elemental Impurities in Pharmaceutical Excipients.

    PubMed

    Li, Gang; Schoneker, Dave; Ulman, Katherine L; Sturm, Jason J; Thackery, Lisa M; Kauffman, John F

    2015-12-01

    Control of elemental impurities in pharmaceutical materials is currently undergoing a transition from control based on concentrations in components of drug products to control based on permitted daily exposures in drug products. Within the pharmaceutical community, there is uncertainty regarding the impact of these changes on manufactures of drug products. This uncertainty is fueled in part by a lack of publically available information on elemental impurity levels in common pharmaceutical excipients. This paper summarizes a recent survey of elemental impurity levels in common pharmaceutical excipients as well as some drug substances. A widely applicable analytical procedure was developed and was shown to be suitable for analysis of elements that are subject to United States Pharmacopoeia Chapter <232> and International Conference on Harmonization's Q3D Guideline on Elemental Impurities. The procedure utilizes microwave-assisted digestion of pharmaceutical materials and inductively coupled plasma mass spectrometry for quantitative analysis of these elements. The procedure was applied to 190 samples from 31 different excipients and 15 samples from eight drug substances provided through the International Pharmaceutical Excipient Council of the Americas. The results of the survey indicate that, for the materials included in the study, relatively low levels of elemental impurities are present.

  5. Development of an LC-MS method for ultra trace-level determination of 2,2,6,6-tetramethylpiperidine-1-oxl (TEMPO), a potential genotoxic impurity within active pharmaceutical ingredients.

    PubMed

    Pennington, Justin; Cohen, Ryan D; Tian, Ye; Boulineau, Fabien

    2015-10-10

    TEMPO (2,2,6,6-tetramethylpiperidine-1-oxyl) is a stable free radical which has been widely used for various research and industrial applications, including the manufacture of many active pharmaceutical ingredients. TEMPO has been identified as a potential genotoxic impurity resulting in the need for analytical methodology to accurately determine its level at several orders of magnitude less than typical impurity quantitation limits. TEMPO can undergo disproportionation to form both oxidized and reduced TEMPO, making individual determination unreliable. To overcome this challenge, all TEMPO related species were converted to the reduced form through reduction with sodium ascorbate. Given the ultra-trace (0.5 ppm) level requirements and the lack of UV response in the reduced form, a single quadrupole mass spectrometer (MS) was utilized. In order to implement a highly sensitive MS method in a GMP environment, several approaches were employed to optimize accuracy and robustness including: internal standard correction for drift elimination, six-level standard addition to reduce matrix effects, and weighted linear regression to cover a broad analytical range. The method was fully validated according to ICH guidelines. The method is specific, linear, accurate, precise, and robust within a range of 0.5-100 ppm.

  6. Analytical advances in pharmaceutical impurity profiling.

    PubMed

    Holm, René; Elder, David P

    2016-05-25

    Impurities will be present in all drug substances and drug products, i.e. nothing is 100% pure if one looks in enough depth. The current regulatory guidance on impurities accepts this, and for drug products with a dose of less than 2g/day identification of impurities is set at 0.1% levels and above (ICH Q3B(R2), 2006). For some impurities, this is a simple undertaking as generally available analytical techniques can address the prevailing analytical challenges; whereas, for others this may be much more challenging requiring more sophisticated analytical approaches. The present review provides an insight into current development of analytical techniques to investigate and quantify impurities in drug substances and drug products providing discussion of progress particular within the field of chromatography to ensure separation of and quantification of those related impurities. Further, a section is devoted to the identification of classical impurities, but in addition, inorganic (metal residues) and solid state impurities are also discussed. Risk control strategies for pharmaceutical impurities aligned with several of the ICH guidelines, are also discussed.

  7. Recent trends in the impurity profile of pharmaceuticals

    PubMed Central

    Pilaniya, Kavita; Chandrawanshi, Harish K.; Pilaniya, Urmila; Manchandani, Pooja; Jain, Pratishtha; Singh, Nitin

    2010-01-01

    Various regulatory authorities such as the International Conference on Harmonization (ICH), the United States Food and Drug administration (FDA), and the Canadian Drug and Health Agency (CDHA) are emphasizing on the purity requirements and the identification of impurities in Active Pharmaceutical Ingredients (APIs). The various sources of impurity in pharmaceutical products are — reagents, heavy metals, ligands, catalysts, other materials like filter aids, charcoal, and the like, degraded end products obtained during \\ after manufacturing of bulk drugs from hydrolysis, photolytic cleavage, oxidative degradation, decarboxylation, enantiomeric impurity, and so on. The different pharmacopoeias such as the British Pharmacopoeia, United State Pharmacopoeia, and Indian Pharmacopoeia are slowly incorporating limits to allowable levels of impurities present in APIs or formulations. Various methods are used to isolate and characterize impurities in pharmaceuticals, such as, capillary electrophoresis, electron paramagnetic resonance, gas–liquid chromatography, gravimetric analysis, high performance liquid chromatography, solid-phase extraction methods, liquid–liquid extraction method, Ultraviolet Spectrometry, infrared spectroscopy, supercritical fluid extraction column chromatography, mass spectrometry, Nuclear magnetic resonance (NMR) spectroscopy, and RAMAN spectroscopy. Among all hyphenated techniques, the most exploited techniques for impurity profiling of drugs are Liquid Chromatography (LC)-Mass Spectroscopy (MS), LC-NMR, LC-NMR-MS, GC-MS, and LC-MS. This reveals the need and scope of impurity profiling of drugs in pharmaceutical research. PMID:22247862

  8. Genotoxicity assessment of a pharmaceutical effluent using four bioassays

    PubMed Central

    2009-01-01

    Pharmaceutical industries are among the major contributors to industrial waste. Their effluents when wrongly handled and disposed of endanger both human and environmental health. In this study, we investigated the potential genotoxicity of a pharmaceutical effluent, by using the Allium cepa, mouse- sperm morphology, bone marrow chromosome aberration (CA) and micronucleus (MN) assays. Some of the physico-chemical properties of the effluent were also determined. The A. cepa and the animal assays were respectively carried out at concentrations of 0.5, 1, 2.5, 5 and 10%; and 1, 5, 10, 25 and 50% of the effluent. There was a statistically different (p < 0.05), concentration-dependent inhibition of onion root growth and mitotic index, and induction of chromosomal aberrations in the onion and mouse CA test. Assessment of sperm shape showed that the fraction of the sperm that was abnormal in shape was significantly (p < 0.05) greater than the negative control value. MN analysis showed a dose-dependent induction of micronucleated polychromatic erythrocytes across the treatment groups. These observations were provoked by the toxic and genotoxic constituents present in test samples. The tested pharmaceutical effluent is a potentially genotoxic agent and germ cell mutagen, and may induce adverse health effects in exposed individuals. PMID:21637694

  9. A review of the genotoxicity of marketed pharmaceuticals.

    PubMed

    Snyder, R D; Green, J W

    2001-05-01

    Information in the 1999 Physician's Desk Reference as well as from the peer-reviewed published literature was used to evaluate the genotoxicity of marketed pharmaceuticals. This survey is a compendium of genotoxicity information and a means to gain perspective on the inherent genotoxicity of structurally diverse pharmaceuticals. Data from 467 marketed drugs were collected. Excluded from analysis were anti-cancer drugs and nucleosides, which are expected to be genotoxic, steroids, biologicals and peptide-based drugs. Of the 467 drugs, 115 had no published gene-tox data. This group was comprised largely of acutely administered drugs such as antibiotics, antifungals, antihistamines decongestants and anesthetics. The remaining 352 had at least one standard gene-tox assay result. Of these, 101 compounds (28.7%) had at least one positive assay result in the pre-ICH/OECD standard four-test battery (bacterial mutagenesis, in vitro cytogenetics, mouse lymphoma assay (MLA), in vivo cytogenetics). Per assay type, the percentage of positive compounds was: bacterial mutagenesis test, 27/323 (8.3%); in vitro cytogenetics 55/222 (24.8%); MLA 24/96 (25%); in vivo cytogenetics 29/252 (11.5%). Of the supplemental genetic toxicology test findings reported, the sister chromatid exchange (SCE) assay had the largest percentage of positives 17/39 (43.5%) and mammalian mutagenesis assays (excluding MLA) had the lowest percentage of positives 2/91 (2.2%). The predictive value of genetic toxicology findings for 2-year bioassay outcomes is difficult to assess since carcinogenicity can occur via non-genotoxic mechanisms. Nevertheless, the following survey findings were made: 201 drugs had both gene-tox data and rodent carcinogenicity data. Of these, 124 were negative and 77 were equivocal or positive for carcinogenicity in at least 1 gender/1 species. Of the 124 non-carcinogens, 100 had no positive gene-tox findings. Of the remaining 24, 19 were positive in in vitro cytogenetics assays. Among

  10. Impurity profile tracking for active pharmaceutical ingredients: case reports.

    PubMed

    Zhou, Lili; Mao, Bing; Reamer, Robert; Novak, Tom; Ge, Zhihong

    2007-06-28

    Tracking the impurity profile of an active pharmaceutical ingredient (API) is a very important task for all stages of drug development. A systematic approach for tracking impurity profile of API is described. Various real pharmaceutical applications are presented through successful examples of impurity profile tracking for three different novel APIs. These include MK-0969, an M3 antagonist; MK-0677, an oral-active growth hormone secretagogue and API-A, a cathepsin K inhibitor. A general strategy including selection of a reversed phase high performance liquid chromatographic (RP-HPLC) impurity profile method based on screening various stationary phases and changing the pH of the mobile phase and elucidation of impurity structures through the utilization of LC-MS, preparative-LC and NMR is demonstrated. A series of studies were conducted on the peak purity check by using the LC-UV diode-array and LC-MS detections. The advantages and disadvantages of each technique in the evaluation of peak purity are discussed. PMID:17142001

  11. A Validated HPLC/MS Limit Test Method for a Potential Genotoxic Impurity in Cilostazol and its Quantification in the API and in the Commercially Available Drug Product.

    PubMed

    Bray, Luigi; Monzani, Luca; Brunoldi, Enrico; Allegrini, Pietro

    2015-01-01

    Cilostazol is a selective inhibitor of type 3 phosphodiesterase. 5-(3-Chloropropyl)-1-cyclohexyl-1H-tetrazole, used as an intermediate in the synthesis of cilostazol, has a primary alkyl chloride group, a well-known alerting function for genotoxic activity. Upon request from a regulatory agency, a limit test in accordance with ICH Q2(R1) added with the accuracy of a recovery test of 5-(4-chlorobutyl)-1-cyclohexyl-1H-tetrazole in cilostazol was developed and validated. The application of the method highlighted the need to optimize the purification process to ensure levels of this potential genotoxic impurity in the final active pharmaceutical ingredient below the established limit. Also, the analytical method was suitable to determine the amount of the impurity in samples of the commercially available drug product, which showed the levels to be above the established threshold of toxicological concern (TTC). PMID:26839820

  12. A Validated HPLC/MS Limit Test Method for a Potential Genotoxic Impurity in Cilostazol and its Quantification in the API and in the Commercially Available Drug Product.

    PubMed

    Bray, Luigi; Monzani, Luca; Brunoldi, Enrico; Allegrini, Pietro

    2015-01-01

    Cilostazol is a selective inhibitor of type 3 phosphodiesterase. 5-(3-Chloropropyl)-1-cyclohexyl-1H-tetrazole, used as an intermediate in the synthesis of cilostazol, has a primary alkyl chloride group, a well-known alerting function for genotoxic activity. Upon request from a regulatory agency, a limit test in accordance with ICH Q2(R1) added with the accuracy of a recovery test of 5-(4-chlorobutyl)-1-cyclohexyl-1H-tetrazole in cilostazol was developed and validated. The application of the method highlighted the need to optimize the purification process to ensure levels of this potential genotoxic impurity in the final active pharmaceutical ingredient below the established limit. Also, the analytical method was suitable to determine the amount of the impurity in samples of the commercially available drug product, which showed the levels to be above the established threshold of toxicological concern (TTC).

  13. A Validated HPLC/MS Limit Test Method for a Potential Genotoxic Impurity in Cilostazol and its Quantification in the API and in the Commercially Available Drug Product

    PubMed Central

    Bray, Luigi; Monzani, Luca; Brunoldi, Enrico; Allegrini, Pietro

    2015-01-01

    Cilostazol is a selective inhibitor of type 3 phosphodiesterase. 5-(3-Chloropropyl)-1-cyclohexyl-1H-tetrazole, used as an intermediate in the synthesis of cilostazol, has a primary alkyl chloride group, a well-known alerting function for genotoxic activity. Upon request from a regulatory agency, a limit test in accordance with ICH Q2(R1) added with the accuracy of a recovery test of 5-(4-chlorobutyl)-1-cyclohexyl-1H-tetrazole in cilostazol was developed and validated. The application of the method highlighted the need to optimize the purification process to ensure levels of this potential genotoxic impurity in the final active pharmaceutical ingredient below the established limit. Also, the analytical method was suitable to determine the amount of the impurity in samples of the commercially available drug product, which showed the levels to be above the established threshold of toxicological concern (TTC). PMID:26839820

  14. Acute Toxicity and Genotoxicity of Carbendazim, Main Impurities and Metabolite to Earthworms (Eisenia foetida).

    PubMed

    Huan, Zhibo; Luo, Jinhui; Xu, Zhi; Xie, Defang

    2016-01-01

    The acute toxicity and genotoxicity of carbendazim, two impurities (3-amino-2-hydroxyphenazine and 2,3-diaminophenazine) and one metabolite (2-aminobenzimidazole) to Eisenia foetida were assessed using artificial soil test and comet assay respectively. Acute toxicity results showed carbendazim was moderately toxic to the earthworms with 14 day-LC50 of 8.6 mg/kg dry soil while 3-amino-2-hydroxyphenazine, 2,3-diaminophenazine, and 2-aminobenzimidazole were of low toxicity with 14 day-LC50 values of 19.0, 14.9, and 27.7 mg/kg dry soil respectively (nominal concentration). The olive tail moment and percentage of DNA in the tail were used as genotoxicity indices, and carbendazim could significantly induce DNA damage to the earthworm coelomocytes with obviously positive dose- and duration-response relationships while the other three substances showed similar (p = 0.05) genotoxicity results to the negative controls in all of the tests. PMID:26370277

  15. Acute Toxicity and Genotoxicity of Carbendazim, Main Impurities and Metabolite to Earthworms (Eisenia foetida).

    PubMed

    Huan, Zhibo; Luo, Jinhui; Xu, Zhi; Xie, Defang

    2016-01-01

    The acute toxicity and genotoxicity of carbendazim, two impurities (3-amino-2-hydroxyphenazine and 2,3-diaminophenazine) and one metabolite (2-aminobenzimidazole) to Eisenia foetida were assessed using artificial soil test and comet assay respectively. Acute toxicity results showed carbendazim was moderately toxic to the earthworms with 14 day-LC50 of 8.6 mg/kg dry soil while 3-amino-2-hydroxyphenazine, 2,3-diaminophenazine, and 2-aminobenzimidazole were of low toxicity with 14 day-LC50 values of 19.0, 14.9, and 27.7 mg/kg dry soil respectively (nominal concentration). The olive tail moment and percentage of DNA in the tail were used as genotoxicity indices, and carbendazim could significantly induce DNA damage to the earthworm coelomocytes with obviously positive dose- and duration-response relationships while the other three substances showed similar (p = 0.05) genotoxicity results to the negative controls in all of the tests.

  16. Determination of the main impurities formed after acid hydrolysis of soybean extracts and the in vitro mutagenicity and genotoxicity studies of 5-ethoxymethyl-2-furfural.

    PubMed

    Nemitz, Marina C; Picada, Jaqueline N; da Silva, Juliana; Garcia, Ana Letícia H; Papke, Débora K M; Grivicich, Ivana; Steppe, Martin; von Poser, Gilsane L; Teixeira, Helder F

    2016-09-10

    Soybean acid hydrolyzed extracts are raw-materials widely used for manufacturing of pharmaceuticals and cosmetics products due to their high content of isoflavone aglycones. In the present study, the main sugar degradation products 5-hydroxymethyl-2-furfural (HMF) and 5-ethoxymethyl-2-furfural (EMF) were quantitatively determined after acid hydrolysis of extracts from different soybean cultivars by a validated liquid chromatography method. The furanic compounds determined in samples cover the range of 0.16-0.21mg/mL and 0.22-0.33mg/mL for HMF and EMF, respectively. Complementarily, due to the scarce literature regarding the EMF toxicology, this study also assessed the EMF mutagenicity by the Salmonella/microsome test and genotoxicity by the comet assay. The results revealed that EMF did not show mutagenicity at the range of 50-5000μg/plate in S. typhimurium strains TA98, TA97a, TA100, TA102 and TA1535, but induced DNA damage in HepG2 cells at non-cytotoxic doses of 0.1-1.3mg/mL, mainly by oxidative stress mechanisms. Based on literature of HMF genotoxicity, and considering the EMF genotoxicity results herein shown, purification procedures to remove these impurities from extracts are recommended during healthcare products development to ensure the security of the products. PMID:27475406

  17. Pharmaceutical impurities and degradation products: uses and applications of NMR techniques.

    PubMed

    Maggio, Rubén M; Calvo, Natalia L; Vignaduzzo, Silvana E; Kaufman, Teodoro S

    2014-12-01

    Current standards and regulations demand the pharmaceutical industry not only to produce highly pure drug substances, but to achieve a thorough understanding of the impurities accompanying their manufactured drug substances and products. These challenges have become important goals of process chemistry and have steadily stimulated the search of impurities after accelerated or forced degradation procedures. As a result, impurity profiling is one of the most attractive, active and relevant fields of modern pharmaceutical analysis. This activity includes the identification, structural elucidation and quantitative determination of impurities and degradation products in bulk drugs and their pharmaceutical formulations. Nuclear magnetic resonance (NMR) spectroscopy has evolved into an irreplaceable approach for pharmaceutical quality assessment, currently playing a critical role in unequivocal structure identification as well as structural confirmation (qualitative detection), enabling the understanding of the underlying mechanisms of the formation of process and/or degradation impurities. NMR is able to provide qualitative information without the need of standards of the unknown compounds and multiple components can be quantified in a complex sample without previous separation. When coupled to separative techniques, the resulting hyphenated methodologies enhance the analytical power of this spectroscopy to previously unknown levels. As a result, and by enabling the implementation of rational decisions regarding the identity and level of impurities, NMR contributes to the goal of making better and safer medicines. Herein are discussed the applications of NMR spectroscopy and its hyphenated derivate techniques to the study of a wide range pharmaceutical impurities. Details on the advantages and disadvantages of the methodology and well as specific challenges with regards to the different analytical problems are also presented. PMID:24853620

  18. Analysis of 75 marketed pharmaceuticals using the GADD45a-GFP 'GreenScreen HC' genotoxicity assay.

    PubMed

    Hastwell, Paul W; Webster, Thomas W; Tate, Matthew; Billinton, Nicholas; Lynch, Anthony M; Harvey, James S; Rees, Robert W; Walmsley, Richard M

    2009-09-01

    The GADD45a-GFP (GreenScreen HC) reporter assay detects genotoxic damage in the human lymphoblastoid TK6 cell line and gives positive results for all classes of genotoxin, including mutagens, aneugens and clastogens. In this study, a collection of 75 marketed pharmaceuticals were tested in the assay. Compounds in the collection represent a broad range of chemical structures, pharmacologies and therapeutic indications, including neoplasia and viral infection where positive genotoxicity results are often associated with the pharmacological activity. Based on the results of this study, two main conclusions can be drawn: (i) the GreenScreen HC is more predictive of in vivo genotoxicity (88%) and genotoxic carcinogenicity (93%) data than the any of the other regulatory in vitro genotoxicity assay and (ii) no compounds were uniquely positive in the GADD45a-GFP assay. This analysis therefore provides additional evidence to support the use of the GADD45a-GFP assay as an effective tool either in early genotoxic liability identification or non-clinical safety assessment of candidate pharmaceuticals during development. PMID:19592503

  19. Pharmaceutical wastewater being composite mixture of environmental pollutants may be associated with mutagenicity and genotoxicity.

    PubMed

    Sharif, Ali; Ashraf, Muhammad; Anjum, Aftab Ahmed; Javeed, Aqeel; Altaf, Imran; Akhtar, Muhammad Furqan; Abbas, Mateen; Akhtar, Bushra; Saleem, Ammara

    2016-02-01

    Pharmaceutical industries are amongst the foremost contributor to industrial waste. Ecological well-being is endangered owing to its facile discharge. In the present study, heavy metals and organic contaminants in waste water were characterized using atomic absorption spectrophotometer and GC-MS, respectively. Mutagenicity and genotoxic potential of pharmaceutical waste water were investigated through bacterial reverse mutation assay and in vitro comet assay, respectively. Ames test and comet assay of first sample were carried out at concentrations of 100, 50, 25, 12.5, 6.25 % v/v effluent with distilled water. Chromium (Cr), lead (Pb), arsenic (As), and cadmium (Cd) were found in high concentrations as compared to WHO- and EPA-recommended maximum limits. Arsenic was found to be the most abundant metal and its maximum concentration was 0.8 mg.L(-1). GC-MS revealed the presence of lignocaine, digitoxin, trimethoprim, caffeine, and vitamin E in waste water. Dose-dependent decrease in mutagenic index was observed in both strains. Substantial increase in mutagenicity was observed for TA-100, when assay was done by incorporating an enzyme activation system, whereas a slight increase was detected for TA-102. In vitro comet assay of waste water exhibited decrease in damage index and percentage fragmentation with the increase in dilution of waste water. Tail length also decreased with an increase in the dilution factor of waste water. These findings suggest that pharmaceutical waste water being a mix of different heavy metals and organic contaminants may have a potent mutagenic and genotoxic effect on exposed living organisms.

  20. Quantification of active pharmaceutical ingredient and impurities in sildenafil citrate obtained from the Internet

    PubMed Central

    Nutan, Mohammad T.; Dodla, Uday Krishna Reddy

    2014-01-01

    Background: The accessibility of prescription drugs produced outside of the United States, most notably sildenafil citrate (innovator product, Viagra®), has been made much easier by the Internet. Of greatest concern to clinicians and policymakers is product quality and patient safety. The US Food and Drug Administration (FDA) has issued warnings to potential buyers that the safety of drugs purchased from the Internet cannot be guaranteed, and may present a health risk to consumers from substandard products. Objective: The objective of this study was to determine whether generic sildenafil citrate tablets from international markets obtained via the Internet are equivalent to the US innovator product regarding major aspects of pharmaceutical quality: potency, accuracy of labeling, and presence and level of impurities. This will help identify aspects of drug quality that may impact public health risks. Methods: A total of 15 sildenafil citrate tablets were obtained for pharmaceutical analysis: 14 generic samples from international Internet pharmacy websites and the US innovator product. According to US Pharmacopeial guidelines, tablet samples were tested using high-performance liquid chromatography for potency of active pharmaceutical ingredient (API) and levels of impurities (impurities A, B, C, and D). Impurity levels were compared with International Conference on Harmonisation (ICH) limits. Results: Among the 15 samples, 4 samples possessed higher impurity B levels than the ICH qualification threshold, 8 samples possessed higher impurity C levels than the ICH qualification threshold, and 4 samples possessed more than 1% impurity quantity of maximum daily dose (MDD). For API, 6 of the samples failed to fall within the 5% assay limit. Conclusions: Quality assurance tests are often used to detect formulation defects of drug products during the manufacturing and/or storage process. Results suggest that manufacturing standards for sildenafil citrate generic drug

  1. Potential metal impurities in active pharmaceutical substances and finished medicinal products - A market surveillance study.

    PubMed

    Wollein, Uwe; Bauer, Bettina; Habernegg, Renate; Schramek, Nicholas

    2015-09-18

    A market surveillance study has been established by using different atomic spectrometric methods for the determination of selected elemental impurities of particular interest, to gain an overview about the quality of presently marketed drug products and their bulk drug substances. The limit tests were carried out with respect to the existing EMA guideline on the specification limits for residuals of metal catalysts or metal reagents. Also attention was given to the future implementation of two new chapters of the United States Pharmacopoeia (USP) stating limit concentrations of elemental impurities. The methods used for determination of metal residues were inductively coupled plasma-mass spectrometry (ICP-MS), inductively coupled plasma-optical emission spectrometry (ICP-OES), and atomic absorption spectrometry technologies (GFAAS, CVAAS, HGAAS). This article presents the development and validation of the methods used for the determination of 21 selected metals in 113 samples from drug products and their active pharmaceutical ingredients.

  2. Potential metal impurities in active pharmaceutical substances and finished medicinal products - A market surveillance study.

    PubMed

    Wollein, Uwe; Bauer, Bettina; Habernegg, Renate; Schramek, Nicholas

    2015-09-18

    A market surveillance study has been established by using different atomic spectrometric methods for the determination of selected elemental impurities of particular interest, to gain an overview about the quality of presently marketed drug products and their bulk drug substances. The limit tests were carried out with respect to the existing EMA guideline on the specification limits for residuals of metal catalysts or metal reagents. Also attention was given to the future implementation of two new chapters of the United States Pharmacopoeia (USP) stating limit concentrations of elemental impurities. The methods used for determination of metal residues were inductively coupled plasma-mass spectrometry (ICP-MS), inductively coupled plasma-optical emission spectrometry (ICP-OES), and atomic absorption spectrometry technologies (GFAAS, CVAAS, HGAAS). This article presents the development and validation of the methods used for the determination of 21 selected metals in 113 samples from drug products and their active pharmaceutical ingredients. PMID:26036232

  3. Chromatographic resolution of closely related species in pharmaceutical chemistry: dehalogenation impurities and mixtures of halogen isomers.

    PubMed

    Regalado, Erik L; Zhuang, Ping; Chen, Yadan; Makarov, Alexey A; Schafer, Wes A; McGachy, Neil; Welch, Christopher J

    2014-01-01

    In recent years, the use of halogen-containing molecules has proliferated in the pharmaceutical industry, where the incorporation of halogens, especially fluorine, has become vitally important for blocking metabolism and enhancing the biological activity of pharmaceuticals. The chromatographic separation of halogen-containing pharmaceuticals from associated isomers or dehalogenation impurities can sometimes be quite difficult. In an attempt to identify the best current tools available for addressing this important problem, a survey of the suitability of four chromatographic method development platforms (ultra high-performance liquid chromatography (UHPLC), core shell HPLC, achiral supercritical fluid chromatography (SFC) and chiral SFC) for separating closely related mixtures of halogen-containing pharmaceuticals and their dehalogenated isosteres is described. Of the 132 column and mobile phase combinations examined for each mixture, a small subset of conditions were found to afford the best overall performance, with a single UHPLC method (2.1 × 50 mm, 1.9 μm Hypersil Gold PFP, acetonitrile/methanol based aqueous eluents containing either phosphoric or perchloric acid with 150 mM sodium perchlorate) affording excellent separation for all samples. Similarly, a survey of several families of closely related halogen-containing small molecules representing the diversity of impurities that can sometimes be found in purchased starting materials for synthesis revealed chiral SFC (Chiralcel OJ-3 and Chiralpak IB, isopropanol or ethanol with 25 mM isobutylamine/carbon dioxide) as well as the UHPLC (2.1 × 50 mm, 1.8 μm ZORBAX RRHD Eclipse Plus C18 and the Gold PFP, acetonitrile/methanol based aqueous eluents containing phosphoric acid) as preferred methods.

  4. In vitro and in vivo genotoxicity assessment of selected pharmaceuticals in relation to Escherichia coli and Cyprinus carpio.

    PubMed

    Załęska-Radziwiłł, Monika; Affek, Katarzyna; Doskocz, Nina; Affek, Andrzej

    2016-10-14

    Genotoxicity studies (using SOS chromotest and comet assay) of Escherichia coli and carp (Cyprinus carpio) were performed for three pharmaceutically active compounds, ciprofloxacin, 17α-ethinylestradiol and 5-fluorouracil, used in the treatment of humans. The values of genotoxicity induction coefficient (I) in the SOS chromotest clearly showed genotoxicity for ciprofloxacin, both in the presence and in the absence of S9 fraction; 17α-ethinylestradiol demonstrated slight genotoxicity at the highest tested concentration; and 5-fluorouracil did not induce genotoxic effects in Escherichia coli mutants. Statistical analysis of the results of the comet assay revealed significant differences in cell populations derived from carp placed in a solution of 5-fluorouracil in comparison with the negative control. Statistical analysis also showed a significant increase of "% DNA in tail" of comets in cell populations incubated in solutions of 17α-ethinylestradiol at concentrations of 10000, 2000 and 400 µg/L and in solutions of 5-fluorouracil with S9 fraction at concentrations of 50,000 and 2,000 μg/L in comparison with the negative controls. PMID:27410723

  5. Determination of elemental impurities in pharmaceutical products and related matrices by ICP-based methods: a review.

    PubMed

    Barin, Juliano S; Mello, Paola A; Mesko, Marcia F; Duarte, Fabio A; Flores, Erico M M

    2016-07-01

    Interest in the determination of elemental impurities in pharmaceuticals has increased in recent years because of changes in regulatory requirements and the need for changing or updating the current limit tests recommended in pharmacopeias. Inductively coupled plasma (ICP) optical emission spectrometry and ICP mass spectrometry are suitable alternatives to perform multielemental analysis for this purpose. The main advantages and limitations of these techniques are described, covering the applications reported in the literature in the last 10 years mainly for active pharmaceutical ingredients, raw materials, and pharmaceutical dosage forms. Strategies used for sample preparation, including dissolution in aqueous or organic solvents, extraction, wet digestion and combustion methods are described, as well as direct solid analysis and ICP-based systems applied for speciation analysis. Interferences observed during the analysis of pharmaceutical products using ICP-based methods are discussed. Methods currently recommended by pharmacopeias for elemental impurities are also covered, showing that the use of ICP-based methods could be considered as a trend in the determination of these impurities in pharmaceuticals. However, the development of a general method that is accurate for all elemental impurities and the establishment of an official method are still challenges. In this regard, the main drawbacks and suitable alternatives are discussed.

  6. Determination of trace level genotoxic impurities in small molecule drug substances using conventional headspace gas chromatography with contemporary ionic liquid diluents and electron capture detection.

    PubMed

    Ho, Tien D; Yehl, Peter M; Chetwyn, Nik P; Wang, Jin; Anderson, Jared L; Zhong, Qiqing

    2014-09-26

    Ionic liquids (ILs) were used as a new class of diluents for the analysis of two classes of genotoxic impurities (GTIs), namely, alkyl/aryl halides and nitro-aromatics, in small molecule drug substances by headspace gas chromatography (HS-GC) coupled with electron capture detection (ECD). This novel approach using ILs as contemporary diluents greatly broadens the applicability of HS-GC for the determination of high boiling (≥ 130°C) analytes including GTIs with limits of detection (LOD) ranging from 5 to 500 parts-per-billion (ppb) of analytes in a drug substance. This represents up to tens of thousands-fold improvement compared to traditional HS-GC diluents such as dimethyl sulfoxide (DMSO) and dimethylacetamide (DMAC). Various ILs were screened to determine their suitability as diluents for the HS-GC/ECD analysis. Increasing the HS oven temperatures resulted in varying responses for alkyl/aryl halides and a significant increase in response for all nitroaromatic GTIs. Linear ranges of up to five orders of magnitude were found for a number of analytes. The technique was validated on two active pharmaceutical ingredients with excellent recovery. This simple and robust methodology offers a key advantage in the ease of method transfer from development laboratories to quality control environments since conventional validated chromatographic data systems and GC instruments can be used. For many analytes, it is a cost effective alternative to more complex trace analytical methodologies like LC/MS and GC/MS, and significantly reduces the training needed for operation.

  7. Clean Chemistry for Elemental Impurities Analysis of Pharmaceuticals in Compliance with USP 232.

    PubMed

    Jin, Chunguang

    2016-10-01

    United States Pharmacopeia updated its 100 years old metal analysis method with inductively coupled plasma mass spectrometry (ICP-MS) and inductively coupled plasma optical emission spectrometry (ICP-OES). These sensitive instruments require that sample preparation be at least as sophisticated as the instrumentation used in the analysis. Sample contamination during sample preparation has to be controlled to an acceptable level given the low detection limit of these instruments and the ubiquitous presence of elements. This article focused on sample contamination during sample preparation. Contaminations from environment, reagents, and lab apparatus were investigated for their impact on trace element analysis. Advice on clean lab practice was offered to the pharmaceutical industry in regard to contamination control in elemental analysis labs at a time when the industry is preparing for compliance with elemental impurities in drug products.

  8. Quantification of potential impurities by a stability indicating UV-HPLC method in niacinamide active pharmaceutical ingredient.

    PubMed

    Thomas, Saji; Bharti, Amber; Tharpa, Kalsang; Agarwal, Ashutosh

    2012-02-23

    A sensitive, stability indicating reverse phase UV-HPLC method has been developed for the quantitative determination of potential impurities of niacinamide active pharmaceutical ingredient. Efficient chromatographic separation was achieved on C18 stationary phase in isocratic mode using simple mobile phase. Forced degradation study confirmed that the newly developed method was specific and selective to the degradation products. Major degradation of the drug substance was found to occur under oxidative stress conditions to form niacinamide N-oxide. The method was validated according to ICH guidelines with respect to specificity, precision, linearity and accuracy. Regression analysis showed correlation coefficient value greater than 0.999 for niacinamide and its six impurities. Detection limit of impurities was in the range of 0.003-0.005% indicating the high sensitivity of the newly developed method. Accuracy of the method was established based on the recovery obtained between 93.3% and 113.3% for all impurities.

  9. Matrix precipitation: a general strategy to eliminate matrix interference for pharmaceutical toxic impurities analysis.

    PubMed

    Yang, Xiaojing; Xiong, Xuewu; Cao, Ji; Luan, Baolei; Liu, Yongjun; Liu, Guozhu; Zhang, Lei

    2015-01-30

    Matrix interference, which can lead to false positive/negative results, contamination of injector or separation column, incompatibility between sample solution and the selected analytical instrument, and response inhibition or even quenching, is commonly suffered for the analysis of trace level toxic impurities in drug substance. In this study, a simple matrix precipitation strategy is proposed to eliminate or minimize the above stated matrix interference problems. Generally, a sample of active pharmaceutical ingredients (APIs) is dissolved in an appropriate solvent to achieve the desired high concentration and then an anti-solvent is added to precipitate the matrix substance. As a result, the target analyte is extracted into the mixed solution with very less residual of APIs. This strategy has the characteristics of simple manipulation, high recovery and excellent anti-interference capability. It was found that the precipitation ratio (R, representing the ability to remove matrix substance) and the proportion of solvent (the one used to dissolve APIs) in final solution (P, affecting R and also affecting the method sensitivity) are two important factors of the precipitation process. The correlation between R and P was investigated by performing precipitation with various APIs in different solvent/anti-solvent systems. After a detailed mathematical reasoning process, P=20% was proved to be an effective and robust condition to perform the precipitation strategy. The precipitation method with P=20% can be used as a general strategy for toxic impurity analysis in APIs. Finally, several typical examples are described in this article, where the challenging matrix interference issues have been resolved successfully.

  10. Topiramate: A Review of Analytical Approaches for the Drug Substance, Its Impurities and Pharmaceutical Formulations.

    PubMed

    Pinto, Eduardo Costa; Dolzan, Maressa Danielli; Cabral, Lucio Mendes; Armstrong, Daniel W; de Sousa, Valéria Pereira

    2016-02-01

    An important step during the development of high-performance liquid chromatography (HPLC) methods for quantitative analysis of drugs is choosing the appropriate detector. High sensitivity, reproducibility, stability, wide linear range, compatibility with gradient elution, non-destructive detection of the analyte and response unaffected by changes in the temperature/flow are some of the ideal characteristics of a universal HPLC detector. Topiramate is an anticonvulsant drug mainly used for the treatment of different types of seizures and prophylactic treatment of migraine. Different analytical approaches to quantify topiramate by HPLC have been described because of the lack of chromophoric moieties on its structure, such as derivatization with fluorescent moieties and UV-absorbing moieties, conductivity detection, evaporative light scattering detection, refractive index detection, chemiluminescent nitrogen detection and MS detection. Some methods for the determination of topiramate by capillary electrophoresis and gas chromatography have also been published. This systematic review provides a description of the main analytical methods presented in the literature to analyze topiramate in the drug substance and in pharmaceutical formulations. Each of these methods is briefly discussed, especially considering the detector used with HPLC. In addition, this article presents a review of the data available regarding topiramate stability, degradation products and impurities.

  11. Determination of atracurium, cisatracurium and mivacurium with their impurities in pharmaceutical preparations by liquid chromatography with charged aerosol detection.

    PubMed

    Błazewicz, Agata; Fijałek, Zbigniew; Warowna-Grześkiewicz, Małgorzata; Jadach, Magdalena

    2010-02-19

    The Corona CAD (charged aerosol detection) is a new type of detector introduced for LC applications that has recently become widely applied in pharmaceutical analysis. The Corona CAD measures a physical property of analyte and responds to almost all non-volatile species, independently of their nature and spectral or physicochemical properties. The LC method with charged aerosol detection was developed for the determination of three isomers of atracurium, cisatracurium and also three isomers of mivacurium with their impurities. The limit of quantitation for laudanosine was 1 microg ml(-1). The elaborate method for the analysis of those active substances and laudanosine proved to be fast, precise, accurate and sensitive. All other impurities were identified using time-of-flight mass spectrometry with electrospray ionization.

  12. Development and validation of a stability-indicating reverse phase ultra performance liquid chromatographic method for the estimation of nebivolol impurities in active pharmaceutical ingredients and pharmaceutical formulation.

    PubMed

    Thummala, Veera Raghava Raju; Lanka, Mohana Krishna

    2015-10-01

    A sensitive, stability-indicating gradient reverse phase ultra performance liquid chromatographic method has been developed for the quantitative estimation of nebivolol impurities in active pharmaceutical ingredient (API) and pharmaceutical formulation. Efficient chromatographic separation was achieved on an Acquity BEH C18 column (100 mm x 2.1 mm, 1.7 μm) with mobile phase of a gradient mixture. The flow rate of the mobile phase was 0.18 mL/min with column temperature of 30 degrees C and detection wavelength of 281 nm. The relative response factor values of (R*)-2-( benzylamino)-1-((S*)-6-fluorochroman-2-yl) ethanol ((R x S*) NBV-), (R)-1-((R)-6-fluorochroman-2-yl)-2-((S)-2-((S)-6-fluoro-chroman-2-yl)-2-hydroxyethyl-amino) ethanol ((RRSS) NBV-3), 1-(chroman-2-yl)-2-(2-(6-fluorochroman-2-yl)-2-hydroxyethyl amino) ethanol (monodesfluoro impurity), (S)-1-((R)-6-fluorochroman-2-yl)-2-((R)-2 (S*)-6-fluoro-chroman-2-yl)-2-hydroxyethylamino) ethanol hydrochloride ((RSRS) NBV-3) and (R*)-1-((S*)-6-fluorochroman-2-yl)-2-((S*)-2-((S*)-6-fluoro-chroman-2-yl)-2-hydroxyethylamino) ethanol ((R* S* S* S*) NBV-2) were 0.65, 0.91, 0.68, 0.92 and 0.91 respectively. Nebivolol formulation sample was subjected to the stress conditions of acid, base, oxidative, hydrolytic, thermal, humidity and photolytic degradation. Nebivolol was found to degrade significantly under peroxide stress condition. The degradation products were well resolved from nebivolol and its impurities. The peak purity test results confirmed that the nebivolol peak was homogenous and pure in all stress samples and the mass balance was found to be more than 98%, thus proving the stability-indicating power of the method. The developed method was validated according to International Conference on Hormonization (ICH) guidelines with respect to specificity, linearity, limits of detection and quantification, accuracy, precision and robustness. PMID:26930962

  13. Impact of Pharmaceutical Impurities in Ecstasy Tablets: Gas Chromatography-Mass Spectrometry Study.

    PubMed

    Jalali, Amir; Hatamie, Amir; Saferpour, Tahere; Khajeamiri, Alireza; Safa, Tahere; Buazar, Foad

    2016-01-01

    In this study, a simple and reliable method by gas chromatograph-mass spectrometry (GC-MS) was developed for the fast and regular identification of 3, 4-MDMA impurities in ecstasy tablets. In so doing, 8 samples of impurities were extracted by diethyl ether under alkaline condition and then analyzed by GC-MS. The results revealed high MDMA levels ranging from 37.6% to 57.7%. The GC-MS method showed that unambiguous identification can be achieved for MDMA from 3, 4-methylenedioxyamphetamine (MDA), Amphetamine (AM), methamphetamine (MA) and ketamine (Keta) compounds, respectively. The experimental results indicated the acceptable time window without interfering peaks. It is found that GC-MS was provided a suitable and rapid identification approach for MDMA (Ecstacy) tablets, particularly in the Forensic labs. Consequently, the intense MDMA levels would support the police to develop a simple quantification of impurity in Ecstasy tablets. PMID:27610162

  14. Impact of Pharmaceutical Impurities in Ecstasy Tablets: Gas Chromatography-Mass Spectrometry Study

    PubMed Central

    Jalali, Amir; Hatamie, Amir; Saferpour, Tahere; Khajeamiri, Alireza; Safa, Tahere; Buazar, Foad

    2016-01-01

    In this study, a simple and reliable method by gas chromatograph–mass spectrometry (GC–MS) was developed for the fast and regular identification of 3, 4-MDMA impurities in ecstasy tablets. In so doing, 8 samples of impurities were extracted by diethyl ether under alkaline condition and then analyzed by GC–MS. The results revealed high MDMA levels ranging from 37.6% to 57.7%. The GC-MS method showed that unambiguous identification can be achieved for MDMA from 3, 4-methylenedioxyamphetamine (MDA), Amphetamine (AM), methamphetamine (MA) and ketamine (Keta) compounds, respectively. The experimental results indicated the acceptable time window without interfering peaks. It is found that GC-MS was provided a suitable and rapid identification approach for MDMA (Ecstacy) tablets, particularly in the Forensic labs. Consequently, the intense MDMA levels would support the police to develop a simple quantification of impurity in Ecstasy tablets. PMID:27610162

  15. Determination of the impurities in drug products containing montelukast and in silico/in vitro genotoxicological assessments of sulfoxide impurity.

    PubMed

    Emerce, Esra; Cok, Ismet; Degim, I Tuncer

    2015-10-14

    Impurities affecting safety, efficacy, and quality of pharmaceuticals are of increasing concern for regulatory agencies and pharmaceutical industries, since genotoxic impurities are understood to play important role in carcinogenesis. The study aimed to analyse impurities of montelukast chronically used in asthma theraphy and perform genotoxicological assessment considering regulatory approaches. Impurities (sulfoxide, cis-isomer, Michael adducts-I&II, methylketone, methylstyrene) were quantified using RP-HPLC analysis on commercial products available in Turkish market. For sulfoxide impurity, having no toxicity data and found to be above the qualification limit, in silico mutagenicity prediction analysis, miniaturized bacterial gene mutation test, mitotic index determination and in vitro chromosomal aberration test w/wo metabolic activation system were conducted. In the analysis of different batches of 20 commercial drug products from 11 companies, only sulfoxide impurity exceeded qualification limit in pediatric tablets from 2 companies and in adult tablets from 7 companies. Leadscope and ToxTree programs predicted sulfoxide impurity as nonmutagenic. It was also found to be nonmutagenic in Ames MPF Penta I assay. Sulfoxide impurity was dose-dependent cytotoxic in human peripheral lymphocytes, however, it was found to be nongenotoxic. It was concluded that sulfoxide impurity should be considered as nonmutagenic and can be classified as ordinary impurity according to guidelines. PMID:26205398

  16. A novel stability-indicating UPLC method development and validation for the determination of seven impurities in various diclofenac pharmaceutical dosage forms.

    PubMed

    Azougagh, M; Elkarbane, M; Bakhous, K; Issmaili, S; Skalli, A; Iben Moussad, S; Benaji, B

    2016-09-01

    An innovative simple, fast, precise and accurate ultra-high performance liquid chromatography (UPLC) method was developed for the determination of diclofenac (Dic) along with its impurities including the new dimer impurity in various pharmaceutical dosage forms. An Acquity HSS T3 (C18, 100×2.1mm, 1.8μm) column in gradient mode was used with mobile phase comprising of phosphoric acid, which has a pH value of 2.3 and methanol. The flow rate and the injection volume were set at 0.35ml·min(-1) and 1μl, respectively, and the UV detection was carried out at 254nm by using photodiode array detector. Dic was subjected to stress conditions from acid, base, hydrolytic, thermal, oxidative and photolytic degradation. The new developed method was successfully validated in accordance to the International Conference on Harmonization (ICH) guidelines with respect to specificity, limit of detection, limit of quantitation, precision, linearity, accuracy and robustness. The degradation products were well resolved from main peak and its seven impurities, proving the specificity power of the method. The method showed good linearity with consistent recoveries for Dic content and its impurities. The relative percentage of standard deviation obtained for the repeatability and intermediate precision experiments was less than 3% and LOQ was less than 0.5μg·ml(-1) for all compounds. The new proposed method was found to be accurate, precise, specific, linear and robust. In addition, the method was successfully applied for the assay determination of Dic and its impurities in the several pharmaceutical dosage forms. PMID:27475309

  17. Development and Validation of a Stability-Indicating RP-HPLC Method for the Estimation of Drotaverine Impurities in API and Pharmaceutical Formulation.

    PubMed

    Thummala, Veera Raghava Raju; Tharlapu, Satya Sankarsana Jagan Mohan; Rekulapalli, Vijay Kumar; Ivaturi, Mrutyunjaya Rao; Nittala, Someswara Rao

    2014-03-01

    A sensitive, stability-indicating gradient RP-HPLC method with PDA detection has been developed for the simultaneous analysis of drotaverine impurities in active pharmaceutical ingredient (API) and pharmaceutical formulations. Efficient chromatographic separation was achieved on an XTerra RP18, 150 × 4.6 mm, 5 μm column using gradient elution at 230 nm detection wavelength. The optimized mobile phase consisted of a 0.02 M potassium dihydrogen orthophosphate buffer of pH 3.0 as solvent A and acetonitrile as solvent B. The flow rate of the mobile phase was 1.0 mL min(-1) with a column temperature of 25°C. The method showed linearity over the range of 0.251-10.033 μg/mL, 0.231-9.995 μg/mL, 0.230-10.089 μg/mL, 0.334-10.011 μg/mL, and 0.324-10.050 μg/mL for impurities 1, 2, 3, 4, and drotaverine, respectively, with a correlation coefficient greater than 0.999. The relative retention times and relative response factors of impurities 1, 2, 3, 4 were 0.36, 0.90, 1.42, 1.55 and 1.04, 0.84, 1.10, 1.30, respectively. The drotaverine formulation sample was subjected to the stress conditions of acid, base, oxidative, thermal, humidity, and photolytic degradation. Drotaverine was found to degrade significantly in peroxide, base, and heat stress conditions. The degradation products were well-resolved from drotaverine and its impurities. The peak purity test results confirmed that the drotaverine peak was homogenous and pure in all stress samples and the mass balance was found to be more than 98%, thus proving the stability-indicating power of the method. The developed method was validated according to ICH guidelines with respect to specificity, linearity, limit of detection and quantification, accuracy, precision, and robustness.

  18. Development and Validation of a Stability-Indicating RP-HPLC Method for the Estimation of Drotaverine Impurities in API and Pharmaceutical Formulation

    PubMed Central

    Thummala, Veera Raghava Raju; Tharlapu, Satya Sankarsana Jagan Mohan; Rekulapalli, Vijay Kumar; Ivaturi, Mrutyunjaya Rao; Nittala, Someswara Rao

    2014-01-01

    A sensitive, stability-indicating gradient RP-HPLC method with PDA detection has been developed for the simultaneous analysis of drotaverine impurities in active pharmaceutical ingredient (API) and pharmaceutical formulations. Efficient chromatographic separation was achieved on an XTerra RP18, 150 × 4.6 mm, 5 μm column using gradient elution at 230 nm detection wavelength. The optimized mobile phase consisted of a 0.02 M potassium dihydrogen orthophosphate buffer of pH 3.0 as solvent A and acetonitrile as solvent B. The flow rate of the mobile phase was 1.0 mL min−1 with a column temperature of 25°C. The method showed linearity over the range of 0.251–10.033 μg/mL, 0.231–9.995 μg/mL, 0.230–10.089 μg/mL, 0.334–10.011 μg/mL, and 0.324–10.050 μg/mL for impurities 1, 2, 3, 4, and drotaverine, respectively, with a correlation coefficient greater than 0.999. The relative retention times and relative response factors of impurities 1, 2, 3, 4 were 0.36, 0.90, 1.42, 1.55 and 1.04, 0.84, 1.10, 1.30, respectively. The drotaverine formulation sample was subjected to the stress conditions of acid, base, oxidative, thermal, humidity, and photolytic degradation. Drotaverine was found to degrade significantly in peroxide, base, and heat stress conditions. The degradation products were well-resolved from drotaverine and its impurities. The peak purity test results confirmed that the drotaverine peak was homogenous and pure in all stress samples and the mass balance was found to be more than 98%, thus proving the stability-indicating power of the method. The developed method was validated according to ICH guidelines with respect to specificity, linearity, limit of detection and quantification, accuracy, precision, and robustness. PMID:24634845

  19. Development of high performance liquid chromatography methods with charged aerosol detection for the determination of lincomycin, spectinomycin and its impurities in pharmaceutical products.

    PubMed

    Stypulkowska, K; Blazewicz, A; Brudzikowska, A; Grzeskiewicz, M Warowna-; Sarna, K; Fijalek, Z

    2015-08-10

    Novel and simple liquid chromatography methods with charged aerosol detection (LC-CAD) for simultaneous quantitation of lincomycin and spectinomycin and its related substances have been developed and tested. This type of analysis is complicated due to the different chromatographic behavior of these two agents and the lack of chromophores in spectinomycin complex. CAD seems to be a promising alternative to overcome these difficulties. It shows a consistent inter-analyte response, independent of chemical structure of an analyte. It also enables the direct quantification of related substances for which no reference standards were available, with good accuracy and precision. Chromatographic separations were achieved using a C18 Hypersil(®) Gold column, with mobile phases consisting of water, acetonitrile and trifluoroacetic acid. All impurities were identified using time-of-flight mass spectrometry with electrospray ionization. The developed methods have been successfully used in the routine quality control analysis of pharmaceutical preparations. PMID:25938473

  20. Study and determination of elemental impurities by ICP-MS in active pharmaceutical ingredients using single reaction chamber digestion in compliance with USP requirements.

    PubMed

    Muller, Aline L H; Oliveira, Jussiane S S; Mello, Paola A; Muller, Edson I; Flores, Erico M M

    2015-05-01

    In this work a method for active pharmaceutical ingredients (APIs) digestion using the single reaction chamber (SRC-UltraWave™) system was proposed following the new recommendations of United States Pharmacopeia (USP). Levodope (LEVO), primaquine diphosphate (PRIM), propranolol hydrochloride (PROP) and sulfamethoxazole (SULF) were used to evaluate the digestion efficiency of the proposed method. A comparison of digestion efficiency was performed by measuring the carbon content and residual acidity in digests obtained using SRC and in digests obtained using conventional microwave-assisted digestion system (Multiwave(TM)). Three digestion solutions (concentrated HNO3, aqua regia or inverse aqua regia) were evaluated for digestion of APIs. The determination of Cd, Ir, Mn, Mo, Ni, Os, Pb, Pd, Pt, Rh, Ru was performed using inductively coupled plasma mass spectrometry (ICP-MS) in standard mode. Dynamic reaction cell (DRC) mode was used for the determination of (51)V, (52)Cr, (53)Cr, (63)Cu and (65)Cu in order to solve polyatomic ion interferences. Arsenic and Hg were determined using chemical vapor generation coupled to ICP-MS (FI-CVG-ICP-MS). Masses of 500mg of APIs were efficiently digested in a SRC-UltraWave™ system using only HNO3 and allowing a carbon content lower than 250mg L(-1) in final digests. Inverse aqua regia was suitable for digestion of sample masses up to 250mg allowing the determination of Ir, Pd, Pt, Rh and Ru. By using HNO3 or inverse aqua regia, suitable recoveries were obtained (between 91 and 109%) for all analytes (exception for Os). Limits of quantification were in agreement with USP requirements and they ranged from 0.001 to 0.015µg g(-1) for all elemental impurities (exception for Os). The proposed method was suitable for elemental impurities determination in APIs and it can be used in routine analysis for quality control in pharmaceutical industries. PMID:25702998

  1. Advice on Degradation Products in Pharmaceuticals: A Toxicological Evaluation.

    PubMed

    Melo, Sâmia Rocha de Oliveira; Homem-de-Mello, Maurício; Silveira, Dâmaris; Simeoni, Luiz Alberto

    Degradation products are unwanted chemicals that can develop during the manufacturing, transportation, and storage of drug products and can affect the efficacy of pharmaceutical products. Moreover, even small amounts of degradation products can affect pharmaceutical safety because of the potential to cause adverse effects in patients. Consequently, it is crucial to focus on mechanistic understanding, formulation, storage conditions, and packaging to prevent the formation of degradation products that can negatively affect the quality and safety of the drug product. In this sense, databases and software that help predict the reactions involving the pharmaceutically active substance in the presence of degradation conditions can be used to obtain information on major degradation routes and the main degradation products formed during pharmaceutical product storage. In some cases, when the presence of a genotoxic degradation product is verified, it is necessary to conduct more thorough assessments. It is important to consider the chemical structure to distinguish between compounds with toxicologically alerting structures with associated toxic/genotoxic risks and compounds without active structures that can be treated as ordinary impurities. Evaluating the levels of degradation products based on a risk/benefit analysis is mandatory. Controlling critical variables during early development of drug products and conducting a follow-up study of these impurities can prevent degradation impurities present at concentrations greater than threshold values to ensure product quality. The definition of the impurity profile has become essential per various regulatory requirements. Therefore, this review includes the international regulatory perspective on impurity documents and the toxicological evaluation of degradation products. Additionally, some techniquesused in the investigation of degradation products and stability-indicating assay methods are highlighted.

  2. Advice on Degradation Products in Pharmaceuticals: A Toxicological Evaluation.

    PubMed

    Melo, Sâmia Rocha de Oliveira; Homem-de-Mello, Maurício; Silveira, Dâmaris; Simeoni, Luiz Alberto

    Degradation products are unwanted chemicals that can develop during the manufacturing, transportation, and storage of drug products and can affect the efficacy of pharmaceutical products. Moreover, even small amounts of degradation products can affect pharmaceutical safety because of the potential to cause adverse effects in patients. Consequently, it is crucial to focus on mechanistic understanding, formulation, storage conditions, and packaging to prevent the formation of degradation products that can negatively affect the quality and safety of the drug product. In this sense, databases and software that help predict the reactions involving the pharmaceutically active substance in the presence of degradation conditions can be used to obtain information on major degradation routes and the main degradation products formed during pharmaceutical product storage. In some cases, when the presence of a genotoxic degradation product is verified, it is necessary to conduct more thorough assessments. It is important to consider the chemical structure to distinguish between compounds with toxicologically alerting structures with associated toxic/genotoxic risks and compounds without active structures that can be treated as ordinary impurities. Evaluating the levels of degradation products based on a risk/benefit analysis is mandatory. Controlling critical variables during early development of drug products and conducting a follow-up study of these impurities can prevent degradation impurities present at concentrations greater than threshold values to ensure product quality. The definition of the impurity profile has become essential per various regulatory requirements. Therefore, this review includes the international regulatory perspective on impurity documents and the toxicological evaluation of degradation products. Additionally, some techniquesused in the investigation of degradation products and stability-indicating assay methods are highlighted. PMID:25188345

  3. The application of gas chromatography/atmospheric pressure chemical ionisation time-of-flight mass spectrometry to impurity identification in Pharmaceutical Development.

    PubMed

    Bristow, Tony; Harrison, Mark; Sims, Martin

    2010-06-15

    Accurate mass measurement (used to determine elemental formulae) is an essential tool for impurity identification in pharmaceutical development for process understanding. Accurate mass liquid chromatography/mass spectrometry (LC/MS) is used widely for these types of analyses; however, there are still many occasions when gas chromatography (GC)/MS is the appropriate technique. Therefore, the provision of robust technology to provide accurate mass GC/MS (and GC/MS/MS) for this type of activity is essential. In this report we describe the optimisation and application of a newly available atmospheric pressure chemical ionisation (APCI) interface to couple GC to time-of-flight (TOF) MS.To fully test the potential of the new interface the APCI source conditions were optimised, using a number of standard compounds, with a variety of structures, as used in synthesis at AstraZeneca. These compounds were subsequently analysed by GC/APCI-TOF MS. This study was carried out to evaluate the range of compounds that are amenable to analysis using this technique. The range of compounds that can be detected and characterised using the technique was found to be extremely broad and include apolar hydrocarbons such as toluene. Both protonated molecules ([M + H](+)) and radical cations (M(+.)) were observed in the mass spectra produced by APCI, along with additional ion signals such as [M + H + O](+).The technique has been successfully applied to the identification of impurities in reaction mixtures from organic synthesis in process development. A typical mass accuracy of 1-2 mm/zunits (m/z 80-500) was achieved allowing the reaction impurities to be identified based on their elemental formulae. These results clearly demonstrate the potential of the technique as a tool for problem solving and process understanding in pharmaceutical development. The reaction mixtures were also analysed by GC/electron ionisation (EI)-MS and GC/chemical ionisation (CI)-MS to understand the capability of GC

  4. Trace Level Quantification of the (−)2-(2-amino-5-chlorophenyl)-4-cyclopropyl-1,1,1-trifluoro-3-butyn-2-ol Genotoxic Impurity in Efavirenz Drug Substance and Drug Product Using LC–MS/MS

    PubMed Central

    Jaishetty, Nagadeep; Palanisamy, Kamaraj; Maruthapillai, Arthanareeswari; Jaishetty, Rajamanohar

    2015-01-01

    Efavirenz is a non-nucleoside reverse transcriptase inhibitor used in the treatment of human immunodeficiency virus type-1 (HIV). (2S)-(2-Amino-5-chlorophenyl)-4-cyclopropyl-1,1,1-trifluoro-3-butyn-2-ol (AMCOL), used as an intermediate in the synthesis of efavirenz and a degradation impurity, has an aminoaryl derivative which is a well-known alerting function for genotoxic activity. Upon request from a regulatory agency, a selective and sensitive liquid chromatography–tandem mass spectrometry (LC–MS/MS) method was developed for trace level quantitative determination of AMCOL related compound of efavirenz, for a risk assessment and comparison of impurity levels with the commercially available innovator product (brand name: Sustiva). The method provided excellent sensitivity at a typical target analyte level of <2.5 ppm, an established threshold of toxicological concern (TTC), when the drug substance and drug product samples were prepared at 15.0 mg/mL. The AMCOL sample was analyzed on a Luna C18 (2) (100 mm × 4.6 mm, 3 µm) column interfaced with a triple quadrupole tandem mass spectrometer operated in a multiple reaction monitoring (MRM) mode. Positive electrospray ionization (ESI) was employed as the ionization source and the mobile phase used was 5.0 mM ammonium acetate-methanol (35:65, v/v). The calibration curve showed good linearity over the concentration range of 0.2–5.0 ppm with a correlation coefficient of >0.999. The limit of detection (LOD) and limit of quantification (LOQ) were found to be 0.07 and 0.2 ppm, respectively. The developed method was validated as per international council on harmonization (ICH) guidelines in terms of LOD, LOQ, linearity, precision, accuracy, specificity, and robustness.

  5. Investigating the different mechanisms of genotoxic and non-genotoxic carcinogens by a gene set analysis.

    PubMed

    Lee, Won Jun; Kim, Sang Cheol; Lee, Seul Ji; Lee, Jeongmi; Park, Jeong Hill; Yu, Kyung-Sang; Lim, Johan; Kwon, Sung Won

    2014-01-01

    Based on the process of carcinogenesis, carcinogens are classified as either genotoxic or non-genotoxic. In contrast to non-genotoxic carcinogens, many genotoxic carcinogens have been reported to cause tumor in carcinogenic bioassays in animals. Thus evaluating the genotoxicity potential of chemicals is important to discriminate genotoxic from non-genotoxic carcinogens for health care and pharmaceutical industry safety. Additionally, investigating the difference between the mechanisms of genotoxic and non-genotoxic carcinogens could provide the foundation for a mechanism-based classification for unknown compounds. In this study, we investigated the gene expression of HepG2 cells treated with genotoxic or non-genotoxic carcinogens and compared their mechanisms of action. To enhance our understanding of the differences in the mechanisms of genotoxic and non-genotoxic carcinogens, we implemented a gene set analysis using 12 compounds for the training set (12, 24, 48 h) and validated significant gene sets using 22 compounds for the test set (24, 48 h). For a direct biological translation, we conducted a gene set analysis using Globaltest and selected significant gene sets. To validate the results, training and test compounds were predicted by the significant gene sets using a prediction analysis for microarrays (PAM). Finally, we obtained 6 gene sets, including sets enriched for genes involved in the adherens junction, bladder cancer, p53 signaling pathway, pathways in cancer, peroxisome and RNA degradation. Among the 6 gene sets, the bladder cancer and p53 signaling pathway sets were significant at 12, 24 and 48 h. We also found that the DDB2, RRM2B and GADD45A, genes related to the repair and damage prevention of DNA, were consistently up-regulated for genotoxic carcinogens. Our results suggest that a gene set analysis could provide a robust tool in the investigation of the different mechanisms of genotoxic and non-genotoxic carcinogens and construct a more detailed

  6. 77 FR 33748 - International Conference on Harmonisation; Guidance on S2(R1) Genotoxicity Testing and Data...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-06-07

    ...) Genotoxicity Testing and Data Interpretation for Pharmaceuticals Intended for Human Use; Availability AGENCY... announcing the availability of a guidance entitled ``S2(R1) Genotoxicity Testing and Data Interpretation for... Genotoxicity Testing of Pharmaceuticals.'' ICH S2(R1) provides guidance to drug sponsors on which tests...

  7. UPLC and LC-MS studies on degradation behavior of irinotecan hydrochloride and development of a validated stability-indicating ultra-performance liquid chromatographic method for determination of irinotecan hydrochloride and its impurities in pharmaceutical dosage forms.

    PubMed

    Kumar, Navneet; Sangeetha, Dhanaraj; Reddy, Sunil P

    2012-10-01

    The objective of the current investigation was to study the degradation behavior of irinotecan hydrochloride under different International Conference on Harmonization (ICH) recommended stress conditions using ultra-performance liquid chromatography and liquid chromatography-mass spectrometry and to establish a validated stability-indicating reverse-phase ultra-performance liquid chromatographic method for the quantitative determination of irinotecan hydrochloride and its seven impurities and degradation products in pharmaceutical dosage forms. Irinotecan hydrochloride was subjected to the stress conditions of oxidative, acid, base, hydrolytic, thermal and photolytic degradation. Irinotecan hydrochloride was found to degrade significantly in oxidative and base hydrolysis and photolytic degradation conditions. The degradation products were well resolved from the main peak and its impurities, thus proving the stability-indicating power of the method. Chromatographic separation was achieved on a Waters Acquity BEH C8 (100 × 2.1 mm) 1.7-µm column with a mobile phase containing a gradient mixture of solvent A (0.02M KH(2)PO(4) buffer, pH 3.4) and solvent B (a mixture of acetonitrile and methanol in the ratio of 62:38 v/v). The mobile phase was delivered at a flow rate of 0.3 mL/min with ultraviolet detection at 220 nm. The run time was 8 min, within which irinotecan and its seven impurities and degradation products were satisfactorily separated. The developed method was validated as per ICH guidelines with respect to specificity, linearity, limit of detection, limit of quantification, accuracy, precision and robustness. This method was also suitable for the assay determination of irinotecan hydrochloride in pharmaceutical dosage forms.

  8. The Use of In Silico Models Within a Large Pharmaceutical Company.

    PubMed

    Brigo, Alessandro; Muster, Wolfgang

    2016-01-01

    The present contribution describes how in silico models are applied at different stages of the drug discovery process in the pharmaceutical industry. A thorough description of the most relevant computational methods and tools is given along with an in-depth evaluation of their performance in the context of potential genotoxic impurities assessment.The challenges of predicting the outcome of highly complex studies are discussed followed by considerations on how novel ways to manage, store, share and analyze data may advance knowledge and facilitate modeling efforts.

  9. Development and validation of a stability-indicating RP-HPLC method for the simultaneous estimation of process related impurities and degradation products of rasagiline mesylate in pharmaceutical formulation.

    PubMed

    Reddy, P Sunil; Sudhakar Babu, K; Kumar, Navneet

    2013-03-01

    A sensitive, stability-indicating gradient reverse phase high-performance liquid chromatography-ultraviolet method has been developed for the quantitative determination of process-related impurities and forced degradation products of rasagiline mesylate in pharmaceutical formulation. Efficient chromatographic separation was achieved on an ACE C8, 150 × 4.6 mm, 3 µm column with mobile phase containing a gradient mixture of solvents A and B. The flow rate of the mobile phase was 0.8 mL/min with column temperature of 30°C and detection wavelength at 210 nm. Rasagiline was subjected to the stress conditions of oxidative, acid, base, hydrolytic, thermal and photolytic degradation. Rasagiline was found to degrade significantly in acid and thermal stress conditions. The degradation products were well resolved from rasagiline and its impurities. The peak purity test results confirmed that the rasagiline peak was homogenous and pure in all stress samples and the mass balance was found to be more than 97%, thus proving the stability-indicating power of the method. The developed method was validated according to the guidelines of the International Conference on Harmonization with respect to specificity, linearity, limits of detection and quantification, accuracy, precision and robustness.

  10. Method for protection against genotoxic mutagenesis

    DOEpatents

    Grdina, D.J.

    1996-01-30

    A method and pharmaceutical for protecting against genotoxic damage in irradiated cells are disclosed. Reduction of mutations at the hypoxanthine-guanine phosphoribosyl transferase locus is accomplished by administering an effective dose of a compound having protected sulfhydryl groups which metabolize in vivo to produce both free sulfhydryl groups and disulfides. 10 figs.

  11. Method for protection against genotoxic mutagenesis

    DOEpatents

    Grdina, David J.

    1996-01-01

    A method and pharmaceutical for protecting against genotoxic damage in irradiated cells. Reduction of mutations at the hypoxanthine-guanine phosphoribosyl transferase locus is accomplished by administering an effective dose of a compound having protected sulfhydryl groups which metabolize in vivo to produce both free sulfhydryl groups and disulfides.

  12. Genotoxicity evaluation of hospital wastewaters.

    PubMed

    Gupta, Preeti; Mathur, N; Bhatnagar, P; Nagar, P; Srivastava, S

    2009-10-01

    In hospitals a large variety of substances are in use for medical purposes such as diagnostics and research. After application, diagnostic agents, disinfectants and excreted non-metabolized pharmaceuticals by patients reach the wastewater. Indeed, some of the substances found in wastewaters are genotoxic and are suspected to be a possible cause of the cancers observed in the last decades. Genotoxicity tests are an excellent means to study the toxicity and the risk associated with these releases. This paper points out the areas of concern for hospital wastewater disposal and reports the findings of genotoxicity tests for hospital effluents from 3 major hospitals in Delhi, namely All India Institute of Medical Sciences, Apollo and Escorts. Mutagenicity of hospital wastewaters from effluent treatment plants (before and after treatment) was studied. The results of this study show that the genotoxicity of hospital wastewaters is highly reduced after the treatment process. This study calls for establishment of advanced and effective effluent treatment plants in the hospitals, which are merely dumping the wastewaters in the municipal sewerage system. The results of this study call for further detailed study in this area.

  13. Genotoxicity of titanium dioxide nanoparticles.

    PubMed

    Chen, Tao; Yan, Jian; Li, Yan

    2014-03-01

    Titanium dioxide nanoparticles (TiO(2)-NPs, <100 nm) are increasingly being used in pharmaceuticals and cosmetics due to the unique properties derived from their small sizes. However, their large surface-area to mass ratio and high redox potential may negatively impact human health and the environment. TiO(2)-NPs can cause inflammation, pulmonary damage, fibrosis, and lung tumors and they are possibly carcinogenic to humans. Because cancer is a disease involving mutation, there are a large number of studies on the genotoxicity of TiO(2)-NPs. In this article, we review the results that have been reported in the literature, with a focus on data generated from the standard genotoxicity assays. The data include genotoxicity results from the Ames test, in vitro and in vivo Comet assay, in vitro and in vivo micronucleus assay, sister chromatid exchange assay, mammalian cell hypoxanthine-guanine phosphoribosyl transferase gene assay, the wing somatic mutation and recombination assay, and the mouse phosphatidylinositol glycan, class A gene assay. Inconsistent results have been found in these assays, with both positive and negative responses being reported. The in vitro systems for assessing the genotoxicity of TiO(2)-NPs have generated a greater number of positive results than the in vivo systems, and tests for DNA and chromosome damage have produced more positive results than the assays measuring gene mutation. Nearly all tests for measuring the mutagenicity of TiO(2)-NPs were negative. The current data indicate that the genotoxicity of TiO(2)-NPs is mediated mainly through the generation of oxidative stress in cells.

  14. Isolation and Structural Elucidation of an Unknown Impurity in Prasugrel by Semi-Preparative Liquid Chromatography.

    PubMed

    Liu, Chao; Yu, Zhangxin; Wang, Fujun; Zhong, Xing; Jiang, Li; Zhang, Feifei; Tang, Yinxia; Yan, Zhaohua; Zeng, Su; Pu, Tong

    2015-08-01

    A brand-new impurity was detected by RP-HPLC in the prasugrel. The impurity was named as Impurity X. Impurity X was isolated by using semi-preparative HPLC followed by characterization using nuclear magnetic resonance spectroscopy and liquid chromatography-mass spectrometry. The functional mechanism of Impurity X was speculated. Impurity X could be controlled in the manufacture process of the prasugrel active pharmaceutical ingredient effectively. PMID:25644811

  15. Forced degradation and impurity profiling: recent trends in analytical perspectives.

    PubMed

    Jain, Deepti; Basniwal, Pawan Kumar

    2013-12-01

    This review describes an epigrammatic impression of the recent trends in analytical perspectives of degradation and impurities profiling of pharmaceuticals including active pharmaceutical ingredient (API) as well as drug products during 2008-2012. These recent trends in forced degradation and impurity profiling were discussed on the head of year of publication; columns, matrix (API and dosage forms) and type of elution in chromatography (isocratic and gradient); therapeutic categories of the drug which were used for analysis. It focuses distinctly on comprehensive update of various analytical methods including hyphenated techniques for the identification and quantification of thresholds of impurities and degradants in different pharmaceutical matrices. PMID:23969330

  16. Forced degradation and impurity profiling: recent trends in analytical perspectives.

    PubMed

    Jain, Deepti; Basniwal, Pawan Kumar

    2013-12-01

    This review describes an epigrammatic impression of the recent trends in analytical perspectives of degradation and impurities profiling of pharmaceuticals including active pharmaceutical ingredient (API) as well as drug products during 2008-2012. These recent trends in forced degradation and impurity profiling were discussed on the head of year of publication; columns, matrix (API and dosage forms) and type of elution in chromatography (isocratic and gradient); therapeutic categories of the drug which were used for analysis. It focuses distinctly on comprehensive update of various analytical methods including hyphenated techniques for the identification and quantification of thresholds of impurities and degradants in different pharmaceutical matrices.

  17. Impurity gettering

    SciTech Connect

    Picraux, S.T.

    1995-06-01

    Transition metal impurities are well known to cause detrimental effects when present in the active regions of Si devices. Their presence degrades minority carrier lifetime, provides recombination-generation centers, increases junction leakage current and reduces gate oxide integrity. Thus, gettering processes are used to reduce the available metal impurities from the active region of microelectronic circuits. Gettering processes are usually divided into intrinsic (or internal) and extrinsic (or external) categories. Intrinsic refers to processing the Si wafer in a way to make available internal gettering sites, whereas extrinsic implies externally introduced gettering sites. Special concerns have been raised for intrinsic gettering. Not only will the formation of the precipitated oxide and denuded zone be difficult to achieve with the lower thermal budgets, but another inherent limit may set in. In this or any process which relies on the precipitation of metal silicides the impurity concentration can only be reduced as low as the solid solubility limit. However, the solubilities of transition metals relative to silicide formation are typically found to be {approx_gt}10{sup 12}/cm{sup 3} at temperatures of 800 C and above, and thus inadequate to getter to the needed concentration levels. It is thus anticipated that future microelectronic device processing will require one or more of the following advances in gettering technology: (1) new and more effective gettering mechanisms; (2) quantitative models of gettering to allow process optimization at low process thermal budgets and metal impurity concentrations, and/or (3) development of front side gettering methods to allow for more efficient gettering close to device regions. These trend-driven needs provide a driving force for qualitatively new approaches to gettering and provide possible new opportunities for the use of ion implantation in microelectronics processing.

  18. Electrochemical flow injection analysis of hydrazine in an excess of an active pharmaceutical ingredient: achieving pharmaceutical detection limits electrochemically.

    PubMed

    Channon, Robert B; Joseph, Maxim B; Bitziou, Eleni; Bristow, Anthony W T; Ray, Andrew D; Macpherson, Julie V

    2015-10-01

    The quantification of genotoxic impurities (GIs) such as hydrazine (HZ) is of critical importance in the pharmaceutical industry in order to uphold drug safety. HZ is a particularly intractable GI and its detection represents a significant technical challenge. Here, we present, for the first time, the use of electrochemical analysis to achieve the required detection limits by the pharmaceutical industry for the detection of HZ in the presence of a large excess of a common active pharmaceutical ingredient (API), acetaminophen (ACM) which itself is redox active, typical of many APIs. A flow injection analysis approach with electrochemical detection (FIA-EC) is utilized, in conjunction with a coplanar boron doped diamond (BDD) microband electrode, insulated in an insulating diamond platform for durability and integrated into a two piece flow cell. In order to separate the electrochemical signature for HZ such that it is not obscured by that of the ACM (present in excess), the BDD electrode is functionalized with Pt nanoparticles (NPs) to significantly shift the half wave potential for HZ oxidation to less positive potentials. Microstereolithography was used to fabricate flow cells with defined hydrodynamics which minimize dispersion of the analyte and optimize detection sensitivity. Importantly, the Pt NPs were shown to be stable under flow, and a limit of detection of 64.5 nM or 0.274 ppm for HZ with respect to the ACM, present in excess, was achieved. This represents the first electrochemical approach which surpasses the required detection limits set by the pharmaceutical industry for HZ detection in the presence of an API and paves the wave for online analysis and application to other GI and API systems. PMID:26302058

  19. Genotoxicity of 2-bromo-3′-chloropropiophenone

    SciTech Connect

    Meng, Fanxue; Yan, Jian; Li, Yan; Fu, Peter P.; Fossom, Linda H.; Sood, Ramesh K.; Mans, Daniel J.; Chu, Pei-I; Moore, Martha M.; Chen, Tao

    2013-07-15

    Impurities are present in any drug substance or drug product. They can be process-related impurities that are not completely removed during purification or are formed due to the degradation of the drug substance over the product shelf-life. Unlike the drug substance, impurities generally do not have beneficial effects and may present a risk without associated benefit. Therefore, their amount should be minimized. 2-Bromo-3′-chloropropiophenone (BCP) is an impurity of bupropion, a second-generation antidepressant and a smoking cessation aid. The United States Pharmacopeia recommends an acceptable level for BCP that is not more than 0.1% of the bupropion. Because exposure to genotoxic impurities even at low levels is of significant concern, it is important to determine whether or not BCP is genotoxic. Therefore, in this study the Ames test and the in vitro micronucleus assay were conducted to evaluate the genotoxicity of BCP. BCP was mutagenic with S9 metabolic activation, increasing the mutant frequencies in a concentration-dependent manner, up to 22- and 145-fold induction over the controls in Salmonella strains TA100 and TA1535, respectively. BCP was also positive in the in vitro micronucleus assay, resulting in up to 3.3- and 5.1-fold increase of micronucleus frequency for treatments in the absence and presence of S9, respectively; and 9.9- and 7.4-fold increase of aneuploidies without and with S9, respectively. The addition of N-acetyl-L-cysteine, an antioxidant, reduced the genotoxicity of BCP in both assays. Further studies showed that BCP treatment resulted in induction of reactive oxygen species (ROS) in the TK6 cells. The results suggest that BCP is mutagenic, clastogenic, and aneugenic, and that these activities are mediated via generation of reactive metabolites. - Highlights: • 2-Bromo-3′-chloropropiophenone is an impurity of bupropion. • BCP was positive in both the Ames test and the in vitro micronucleus assay. • It induced high frequencies of

  20. Use of in silico systems and expert knowledge for structure-based assessment of potentially mutagenic impurities.

    PubMed

    Sutter, Andreas; Amberg, Alexander; Boyer, Scott; Brigo, Alessandro; Contrera, Joseph F; Custer, Laura L; Dobo, Krista L; Gervais, Veronique; Glowienke, Susanne; van Gompel, Jacky; Greene, Nigel; Muster, Wolfgang; Nicolette, John; Reddy, M Vijayaraj; Thybaud, Veronique; Vock, Esther; White, Angela T; Müller, Lutz

    2013-10-01

    Genotoxicity hazard identification is part of the impurity qualification process for drug substances and products, the first step of which being the prediction of their potential DNA reactivity using in silico (quantitative) structure-activity relationship (Q)SAR models/systems. This white paper provides information relevant to the development of the draft harmonized tripartite guideline ICH M7 on potentially DNA-reactive/mutagenic impurities in pharmaceuticals and their application in practice. It explains relevant (Q)SAR methodologies as well as the added value of expert knowledge. Moreover, the predictive value of the different methodologies analyzed in two surveys conveyed in the US and European pharmaceutical industry is compared: most pharmaceutical companies used a rule-based expert system as their primary methodology, yielding negative predictivity values of ⩾78% in all participating companies. A further increase (>90%) was often achieved by an additional expert review and/or a second QSAR methodology. Also in the latter case, an expert review was mandatory, especially when conflicting results were obtained. Based on the available data, we concluded that a rule-based expert system complemented by either expert knowledge or a second (Q)SAR model is appropriate. A maximal transparency of the assessment process (e.g. methods, results, arguments of weight-of-evidence approach) achieved by e.g. data sharing initiatives and the use of standards for reporting will enable regulators to fully understand the results of the analysis. Overall, the procedures presented here for structure-based assessment are considered appropriate for regulatory submissions in the scope of ICH M7.

  1. Genotoxicity of phthalates.

    PubMed

    Erkekoglu, Pınar; Kocer-Gumusel, Belma

    2014-12-01

    Many of the environmental, occupational and industrial chemicals are able to generate reactive oxygen species (ROS) and cause oxidative stress. ROS may lead to genotoxicity, which is suggested to contribute to the pathophysiology of many human diseases, including inflammatory diseases and cancer. Phthalates are ubiquitous environmental chemicals and are well-known peroxisome proliferators (PPs) and endocrine disruptors. Several in vivo and in vitro studies have been conducted concerning the carcinogenic and mutagenic effects of phthalates. Di(2-ethylhexyl)-phthalate (DEHP) and several other phthalates are shown to be hepatocarcinogenic in rodents. The underlying factor in the hepatocarcinogenesis is suggested to be their ability to generate ROS and cause genotoxicity. Several methods, including chromosomal aberration test, Ames test, micronucleus assay and hypoxanthine guanine phosphoribosyl transferase (HPRT) mutation test and Comet assay, have been used to determine genotoxic properties of phthalates. Comet assay has been an important tool in the measurement of the genotoxic potential of many chemicals, including phthalates. In this review, we will mainly focus on the studies, which were conducted on the DNA damage caused by different phthalate esters and protection studies against the genotoxicity of these chemicals.

  2. Genotoxicity of swine effluents.

    PubMed

    Techio, V H; Stolberg, J; Kunz, A; Zanin, E; Perdomo, C C

    2011-01-01

    This study aimed at the investigation of genotoxic effects of swine effluents from different stages of a treatment system for swine wastes through bioassay of stamen hairs and micronuclei in Tradescantia (clone BNL 4430). No significant differences (p≥0.05) regarding the genic mutations were found in the bioassay of stamen hairs, independently of the effluent analysed. For the genotoxicity test with micronuclei, the plants exposed to raw wastes, to sludge, and to effluent of the biodigester have presented higher rates of chromosomal damages (micronuclei), with significant differences in relation to the control group and other effluent of the waste treatment system (p≤0.05). The association between the chemical parameters and the genotoxicity data have shown that the variables COD and TKN have presented significant correlation (p≤0.05) with the number of mutagenic events in the tetrads.

  3. Acute toxicity and genotoxic activity of avocado seed extract (Persea americana Mill., c.v. Hass).

    PubMed

    Padilla-Camberos, Eduardo; Martínez-Velázquez, Moisés; Flores-Fernández, José Miguel; Villanueva-Rodríguez, Socorro

    2013-01-01

    The use of vegetal extracts requires toxicological and genotoxic evaluations to establish and verify safety before being added to human cosmetic, pharmaceutical medicine, or alimentary products. Persea americana seeds have been used in traditional medicine as treatment for several diseases. In this work, the ethanolic seed extract of Persea americana was evaluated with respect to its genotoxic potential through micronucleus assay in rodents. The frequency of micronuclei in groups of animals treated with avocado seed extract showed no differences compared to the negative control (vehicle); therefore, it is considered that the avocado seed extract showed no genotoxic activity in the micronucleus test. PMID:24298206

  4. Acute toxicity and genotoxic activity of avocado seed extract (Persea americana Mill., c.v. Hass).

    PubMed

    Padilla-Camberos, Eduardo; Martínez-Velázquez, Moisés; Flores-Fernández, José Miguel; Villanueva-Rodríguez, Socorro

    2013-01-01

    The use of vegetal extracts requires toxicological and genotoxic evaluations to establish and verify safety before being added to human cosmetic, pharmaceutical medicine, or alimentary products. Persea americana seeds have been used in traditional medicine as treatment for several diseases. In this work, the ethanolic seed extract of Persea americana was evaluated with respect to its genotoxic potential through micronucleus assay in rodents. The frequency of micronuclei in groups of animals treated with avocado seed extract showed no differences compared to the negative control (vehicle); therefore, it is considered that the avocado seed extract showed no genotoxic activity in the micronucleus test.

  5. Acute Toxicity and Genotoxic Activity of Avocado Seed Extract (Persea americana Mill., c.v. Hass)

    PubMed Central

    Padilla-Camberos, Eduardo; Martínez-Velázquez, Moisés; Flores-Fernández, José Miguel; Villanueva-Rodríguez, Socorro

    2013-01-01

    The use of vegetal extracts requires toxicological and genotoxic evaluations to establish and verify safety before being added to human cosmetic, pharmaceutical medicine, or alimentary products. Persea americana seeds have been used in traditional medicine as treatment for several diseases. In this work, the ethanolic seed extract of Persea americana was evaluated with respect to its genotoxic potential through micronucleus assay in rodents. The frequency of micronuclei in groups of animals treated with avocado seed extract showed no differences compared to the negative control (vehicle); therefore, it is considered that the avocado seed extract showed no genotoxic activity in the micronucleus test. PMID:24298206

  6. Consequences of New Approach to Chemical Stability Tests to Active Pharmaceutical Ingredients

    PubMed Central

    Jamrógiewicz, Marzena

    2016-01-01

    There is a great need of broaden look on stability tests of active pharmaceutical ingredients (APIs) in comparison with current requirements contained in pharmacopeia. By usage of many modern analytical methods the conception of monitoring the changes of APIs during initial stage of their exposure to harmful factors has been developed. New knowledge must be acquired in terms of identification of each degradation products, especially volatile ones. Further research as toxicology prediction during in silico studies of determined and identified degradation products is necessary. In silico methods are known as computational toxicology or computer-assisted technologies which are used for predicting toxicology of pharmaceutical substances such as impurities or degradation products. This is a specialized software and databases intended to calculate probability of genotoxicity or mutagenicity of these substances through a chemical structure-based screening process and algorithm specific to a given software program. Applying of new analytical approach is proposed as the usage of PAT tools, XRD, HS-SPME GC-MS/MS, LC-MS/MS for stability testing. Described improvements should be taken into account in case of each drug existing already in the market as well as being implemented as new one. PMID:26955356

  7. Genotoxicity of arsenical compounds.

    PubMed

    Gebel, T W

    2001-03-01

    With respect to global human health hazard, arsenic (As) is one of the most important environmental single substance toxicants. Currently, millions of people all over the world are exposed to the ubiquitous element in exposure levels leading to long-term toxicity, in particular cancer. Unfortunately, it has not been elucidated up to now how As mechanistically leads to the induction of neoplasia. Besides its tumorigenic potential, As has been shown to be genotoxic in a wide variety of different experimental set-ups and biological endpoints. In vitro, the element was shown to induce chromosomal mutagenicity like micronuclei, chromosome aberrations, and sister chromatid exchanges. It mainly acts clastogenic but also has an aneugenic potential. Instead, its potential to induce point mutations is very low in bacterial as well as in mammalian cell systems. However, in combined exposure with point mutagens in vitro, As was shown to enhance the frequency of chemical mutations in a synergistic manner. Additionally, As was shown to induce chromosome aberrations and micronuclei in vivo in experiments with mice. After long-term exposure to As-contaminated drinking water, the great majority of human biomonitoring studies found elevated frequencies of DNA lesions like micronuclei or chromosome aberrations. Respective occupational studies are few. Like it is the case for As carcinogenicity, it is not known through which mechanism the genotoxicity of As is mediated, although the data available indicate that As may act indirectly on DNA, i.e. via mechanisms like interference of regulation of DNA repair or integrity. Because of the indirect mode of action, it has been discussed as well that As's genotoxicity may underlie a sublinear dose-response relationship. However, various problems like non-standardized test systems and experimental variability make it impossible to prove such statement. Basically, to be able to improve risk assessment, it is of crucial importance to

  8. Bacterial genotoxicity bioreporters

    PubMed Central

    Biran, Alva; Yagur‐Kroll, Sharon; Pedahzur, Rami; Buchinger, Sebastian; Reifferscheid, Georg; Ben‐Yoav, Hadar; Shacham‐Diamand, Yosi; Belkin, Shimshon

    2010-01-01

    Summary Ever since the introduction of the Salmonella typhimurium mammalian microsome mutagenicity assay (the ‘Ames test’) over three decades ago, there has been a constant development of additional genotoxicity assays based upon the use of genetically engineered microorganisms. Such assays rely either on reversion principles similar to those of the Ames test, or on promoter–reporter fusions that generate a quantifiable dose‐dependent signal in the presence of potential DNA damaging compounds and the induction of repair mechanisms; the latter group is the subject of the present review. Some of these assays were only briefly described in the scientific literature, whereas others have been developed all the way to commercial products. Out of these, only one, the umu‐test, has been fully validated and ISO‐ and OECD standardized. Here we review the main directions undertaken in the construction and testing of bacterial‐based genotoxicity bioassays, including the attempts to incorporate at least a partial metabolic activation capacity into the molecular design. We list the genetic modifications introduced into the tester strains, compare the performance of the different assays, and briefly describe the first attempts to incorporate such bacterial reporters into actual genotoxicity testing devices. PMID:21255340

  9. Genotoxicity of phytoestrogens.

    PubMed

    Stopper, H; Schmitt, E; Kobras, K

    2005-07-01

    Plant extracts containing phytohormones are very popular as 'alternative' medicine for many kinds of diseases. They are especially favored by women who enter menopause and are concerned about the side effects of hormone replacement therapy. However, adverse health effects of phytoestrogens have often been ignored. This review examines the literature on genotoxicity and apoptotic effects of phytohormones. Genistein, coumestrol, quercetin, zearalenone, and resveratrol exerted genotoxic effects in in vitro test systems. Other phytoestrogens such as lignans, the isoflavones daidzein and glycetein, anthocyanidins, and the flavonol fisetin exhibited only weak or no effects in vitro. However, some metabolites of daidzein showed a genotoxic activity in vitro. Practically all of the phytoestrogens exhibit pro-apoptotic effects in some cell systems. Further investigations regarding dose-response-relationships and other aspects relevant for extrapolation to human exposure seem necessary. Until then, care may be advised in taking concentrated phytohormones. Nevertheless, the intake of substantial amounts of plant-food in a normal diet constitutes an important, individual contribution to cancer prevention.

  10. Strategies for the investigation and control of process-related impurities in drug substances.

    PubMed

    Argentine, Mark D; Owens, Paul K; Olsen, Bernard A

    2007-01-10

    The understanding, identification, quantification and control of impurities in drug substances are essential as new molecular entities are evaluated in clinical development. As chemical processes used to produce drug substances mature from the early phases of development through registration, a concomitant maturing of process-related impurity understanding and control is required. This paper outlines strategies available to pharmaceutical scientists to aid in that understanding. Methodology aspects for impurity investigations are discussed along with an emphasis on understanding the origin and fate of impurities to guide decisions on process controls and specifications. Orthogonal analytical approaches for impurity investigations to provide a complete understanding of a drug substance impurity profile and to aid chemical process development are described. Special considerations necessary for stereochemical impurity investigations are also discussed. Considerations for control of toxic impurities include sensitive and selective analytical methodology and determination of the process capability for removing the impurity. A case study is given where routine analytical testing for a toxic impurity was not required because a high impurity rejection efficiency of the synthetic process was demonstrated. Quality assessment of starting materials from multiple sources and the impact of starting material impurities on the impurity profile of the drug substance are discussed with illustrative examples. Knowledge gained from these investigations provides a sound basis for setting specifications for impurities in key starting materials. PMID:17189658

  11. Impurity transport in Tokamaks

    NASA Astrophysics Data System (ADS)

    Amano, T.

    1983-12-01

    Theoretical and experimental efforts directed towards gaining an understanding of impurity behavior in Tokamaks are reviewed. In the Alcator Tokamak experiments, a laser blow-off technique was used to introduce trace amounts of impurities into ohmically heated plasmas. After a series of experiments in which they injected Si, Al, Fe, Mo impurities, an equation representing empirical impurity confinement time was derived. The scaling of this equation was compared with the results of impurity injection experiments on other Tokamaks, FT-I, PDX, TFR, ISX-B. Impurity confinement times in all these cases agree remarkably well, except for the TFR confinement times, which were about a factor of two larger than predicted. In the presence of intense neutral beam injection impurity ions behave differently. Specifically, in the ISX-B experiments, a marked accumulation of impurity ions toward the center of the plasma was observed in the case of counter neutral beam injection. This was interpreted semi-quantitatively by the neoclassical effect of the rotation of the plasma driven by the neutral beam.

  12. Pharmaceutical Psychology.

    ERIC Educational Resources Information Center

    Dolinsky, Donna

    1979-01-01

    Defines areas that could comprise pharmaceutical psychology. The discussion includes a review of literature, outline of areas in pharmacy in which psychologists could become involved, description of a project involving the application of psychology to pharmacy, and analysis of the concept of pharmaceutical psychology. A 99-item bibliography is…

  13. Genotoxicity of poorly soluble particles.

    PubMed

    Schins, Roel P F; Knaapen, Ad M

    2007-01-01

    Poorly soluble particles such as TiO2, carbon black, and diesel exhaust particles have been evaluated for their genotoxicity using both in vitro and in vivo assays, since inhalation of these compounds by rats at high concentrations has been found to lead to tumor formation. Two principle modes of genotoxic action can be considered for particles, referred to as primary and secondary genotoxicity. Primary genotoxicity is defined as genetic damage elicited by particles in the absence of pulmonary inflammation, whereas secondary genotoxicity implies a pathway of genetic damage resulting from the oxidative DNA attack by reactive oxygen/nitrogen species (ROS/RNS), generated during particle-elicited inflammation. Conceptually, primary genotoxicity might operate via various mechanisms, such as the actions of ROS (e.g., as generated from reactive particle surfaces), or DNA-adduct formation by reactive metabolites of particle-associated organic compounds (e.g., polycyclic aromatic hydrocarbons). Currently available literature data, however, merely indicate that the tumorigenesis of poorly soluble particles involves a mechanism of secondary genotoxicity. However, further research is urgently required, since (1) causality between pulmonary inflammation and genotoxicity has not yet been established, and (2) effects of inflammation on fundamental DNA damage responses that orchestrate mutagenesis and carcinogenic outcome,that is, cell cycle arrest, DNA repair, proliferation, and apoptosis, are currently poorly understood. PMID:17886067

  14. Genotoxicity testing of biotechnology-derived products. Report of a GUM task force. Gesellschaft für Umweltmutationsforschung.

    PubMed

    Gocke, E; Albertini, S; Brendler-Schwaab, S; Müller, L; Suter, W; Würgler, F E

    1999-03-01

    . All information, including also information on the occurrence of genotoxic impurities, has been utilized to formulate a decision tree approach for the genotoxicity testing of biotechnology-derived products.

  15. Detection of genotoxic and non-genotoxic carcinogens in Xpc{sup −/−}p53{sup +/−} mice

    SciTech Connect

    Melis, Joost P.M.; Speksnijder, Ewoud N.; Kuiper, Raoul V.; Salvatori, Daniela C.F.; Schaap, Mirjam M.; Maas, Saskia; Robinson, Joke; Verhoef, Aart; Benthem, Jan van; Luijten, Mirjam; Steeg, Harry van

    2013-01-15

    An accurate assessment of the carcinogenic potential of chemicals and pharmaceutical drugs is essential to protect humans and the environment. Therefore, substances are extensively tested before they are marketed to the public. Currently, the rodent two-year bioassay is still routinely used to assess the carcinogenic potential of substances. However, over time it has become clear that this assay yields false positive results and also has several economic and ethical drawbacks including the use of large numbers of animals, the long duration, and the high cost. The need for a suitable alternative assay is therefore high. Previously, we have proposed the Xpa*p53 mouse model as a very suitable alternative to the two-year bioassay. We now show that the Xpc*p53 mouse model preserves all the beneficial traits of the Xpa*p53 model for sub-chronic carcinogen identification and can identify both genotoxic and non-genotoxic carcinogens. Moreover, Xpc*p53 mice appear to be more responsive than Xpa*p53 mice towards several genotoxic and non-genotoxic carcinogens. Furthermore, Xpc*p53 mice are far less sensitive than Xpa*p53 mice for the toxic activity of DNA damaging agents and as such clearly respond in a similar way as wild type mice do. These advantageous traits of the Xpc*p53 model make it a better alternative for in vivo carcinogen testing than Xpa*p53. This pilot study suggests that Xpc*p53 mice are suited for routine sub-chronic testing of both genotoxic and non-genotoxic carcinogens and as such represent a suitable alternative to possibly replace the murine life time cancer bioassay. Highlights: ► The Xpc*p53 mouse model is able to identify genotoxic and non-genotoxic carcinogens. ► Time, animals and cost can be significantly reduced compared to the 2-year bioassay. ► Xpc*p53 mice are more advantageous for carcinogen identification than Xpa*p53 mice. ► Xpc*p53 mice exhibit a wild type response upon exposure to genotoxicants.

  16. Genotoxicity of aspartame.

    PubMed

    Rencüzoğullari, Eyyüp; Tüylü, Berrin Ayaz; Topaktaş, Mehmet; Ila, Hasan Basri; Kayraldiz, Ahmet; Arslan, Mehmet; Diler, Songül Budak

    2004-08-01

    In the present study, the genotoxic effects of the low-calorie sweetener aspartame (ASP), which is a dipeptide derivative, was investigated using chromosome aberration (CA) test, sister chromatid exchange (SCE) test, micronucleus test in human lymphocytes and also Ames/Salmonella/ microsome test. ASP induced CAs at all concentrations (500, 1000 and 2000 microg/ml) and treatment periods (24 and 48 h) dose-dependently, while it did not induce SCEs. On the other hand, ASP decreased the replication index (RI) only at the highest concentration for 48 h treatment period. However, ASP decreased the mitotic index (MI) at all concentrations and treatment periods dose-dependently. In addition, ASP induced micronuclei at the highest concentrations only. This induction was also dose-dependent for 48 hours treatment period. ASP was not mutagenic for Salmonella typhimurium TA98 and TA100 strains in the absence and presence of S9 mix.

  17. Impurity gettering in semiconductors

    DOEpatents

    Sopori, B.L.

    1995-06-20

    A process for impurity gettering in a semiconductor substrate or device such as a silicon substrate or device is disclosed. The process comprises hydrogenating the substrate or device at the back side thereof with sufficient intensity and for a time period sufficient to produce a damaged back side. Thereafter, the substrate or device is illuminated with electromagnetic radiation at an intensity and for a time period sufficient to cause the impurities to diffuse to the back side and alloy with a metal there present to form a contact and capture the impurities. The impurity gettering process also can function to simultaneously passivate defects within the substrate or device, with the defects likewise diffusing to the back side for simultaneous passivation. Simultaneously, substantially all hydrogen-induced damage on the back side of the substrate or device is likewise annihilated. Also taught is an alternate process comprising thermal treatment after hydrogenation of the substrate or device at a temperature of from about 500 C to about 700 C for a time period sufficient to cause the impurities to diffuse to the damaged back side thereof for subsequent capture by an alloying metal. 1 fig.

  18. Dynamical impurity problems

    SciTech Connect

    Emery, V.J.; Kivelson, S.A.

    1993-12-31

    In the past few years there has been a resurgence of interest in dynamical impurity problems, as a result of developments in the theory of correlated electron systems. The general dynamical impurity problem is a set of conduction electrons interacting with an impurity which has internal degrees of freedom. The simplest and earliest example, the Kondo problem, has attracted interest since the mid-sixties not only because of its physical importance but also as an example of a model displaying logarithmic divergences order by order in perturbation theory. It provided one of the earliest applications of the renormalization group method, which is designed to deal with just such a situation. As we shall see, the antiferromagnetic Kondo model is controlled by a strong-coupling fixed point, and the essence of the renormalization group solution is to carry out the global renormalization numerically starting from the original (weak-coupling) Hamiltonian. In these lectures, we shall describe an alternative route in which we identify an exactly solvable model which renormalizes to the same fixed point as the original dynamical impurity problem. This approach is akin to determining the critical behavior at a second order phase transition point by solving any model in a given universality class.

  19. Beryllium: genotoxicity and carcinogenicity.

    PubMed

    Gordon, Terry; Bowser, Darlene

    2003-12-10

    Beryllium (Be) has physical-chemical properties, including low density and high tensile strength, which make it useful in the manufacture of products ranging from space shuttles to golf clubs. Despite its utility, a number of standard setting agencies have determined that beryllium is a carcinogen. Only a limited number of studies, however, have addressed the underlying mechanisms of the carcinogenicity and mutagenicity of beryllium. Importantly, mutation and chromosomal aberration assays have yielded somewhat contradictory results for beryllium compounds and whereas bacterial tests were largely negative, mammalian test systems showed evidence of beryllium-induced mutations, chromosomal aberrations, and cell transformation. Although inter-laboratory differences may play a role in the variability observed in genotoxicity assays, it is more likely that the different chemical forms of beryllium have a significant effect on mutagenicity and carcinogenicity. Because workers are predominantly exposed to airborne particles which are generated during the machining of beryllium metal, ceramics, or alloys, testing of the mechanisms of the mutagenic and carcinogenic activity of beryllium should be performed with relevant chemical forms of beryllium.

  20. Quality analytics of Internet pharmaceuticals.

    PubMed

    Baert, B; De Spiegeleer, B

    2010-09-01

    Trading pharmaceutical products through the Internet poses several challenges related to legal responsibilities, good distribution practices, information content and patient use, financial implications, but also regarding product quality. One of the major concerns is the well-known phenomenon of counterfeited and/or substandard drugs commercialized through rogue Internet sites. Therefore, controlling and assuring the quality of those products has become an important and challenging task for the authorities. This review gives an overview of the different quality attributes that can be evaluated to have a complete understanding of the quality of the finished pharmaceutical product traded through the Internet, as well as the current analytical techniques that serve this objective. Aspects considered are labelling and packaging, physicochemical quality attributes, identification and assay of active substances and/or excipients, impurity profiling, biopharmaceutical testing and data interpretation.

  1. Genotoxicity assessment of some cosmetic and food additives.

    PubMed

    Di Sotto, Antonella; Maffei, Francesca; Hrelia, Patrizia; Di Giacomo, Silvia; Pagano, Ester; Borrelli, Francesca; Mazzanti, Gabriela

    2014-02-01

    α-Hexylcinnamaldehyde (HCA) and p-tert-butyl-alpha-methylhydrocinnamic aldehyde (BMHCA) are synthetic aldehydes, characterized by a typical floral scent, which makes them suitable to be used as fragrances in personal care (perfumes, creams, shampoos, etc.) and household products, and as flavouring additives in food and pharmaceutical industry. The aldehydic structure suggests the need for a safety assessment for these compounds. Here, HCA and BMHCA were evaluated for their potential genotoxic risk, both at gene level (frameshift or base-substitution mutations) by the bacterial reverse mutation assay (Ames test), and at chromosomal level (clastogenicity and aneuploidy) by the micronucleus test. In order to evaluate a primary and repairable DNA damage, the comet assay has been also included. In spite of their potential hazardous chemical structure, a lack of mutagenicity was observed for both compounds in all bacterial strains tested, also in presence of the exogenous metabolic activator, showing that no genotoxic derivatives were produced by CYP450-mediated biotransformations. Neither genotoxicity at chromosomal level (i.e. clastogenicity or aneuploidy) nor single-strand breaks were observed. These findings will be useful in further assessing the safety of HCA and BMHCA as either flavour or fragrance chemicals.

  2. Genotoxicity assessment of some cosmetic and food additives.

    PubMed

    Di Sotto, Antonella; Maffei, Francesca; Hrelia, Patrizia; Di Giacomo, Silvia; Pagano, Ester; Borrelli, Francesca; Mazzanti, Gabriela

    2014-02-01

    α-Hexylcinnamaldehyde (HCA) and p-tert-butyl-alpha-methylhydrocinnamic aldehyde (BMHCA) are synthetic aldehydes, characterized by a typical floral scent, which makes them suitable to be used as fragrances in personal care (perfumes, creams, shampoos, etc.) and household products, and as flavouring additives in food and pharmaceutical industry. The aldehydic structure suggests the need for a safety assessment for these compounds. Here, HCA and BMHCA were evaluated for their potential genotoxic risk, both at gene level (frameshift or base-substitution mutations) by the bacterial reverse mutation assay (Ames test), and at chromosomal level (clastogenicity and aneuploidy) by the micronucleus test. In order to evaluate a primary and repairable DNA damage, the comet assay has been also included. In spite of their potential hazardous chemical structure, a lack of mutagenicity was observed for both compounds in all bacterial strains tested, also in presence of the exogenous metabolic activator, showing that no genotoxic derivatives were produced by CYP450-mediated biotransformations. Neither genotoxicity at chromosomal level (i.e. clastogenicity or aneuploidy) nor single-strand breaks were observed. These findings will be useful in further assessing the safety of HCA and BMHCA as either flavour or fragrance chemicals. PMID:24239523

  3. Pharmaceutical virtue.

    PubMed

    Martin, Emily

    2006-06-01

    In the early history of psychopharmacology, the prospect of developing technologically sophisticated drugs to alleviate human ills was surrounded with a fervor that could be described as religious. This paper explores the subsequent history of the development of psychopharmacological agents, focusing on the ambivalent position of both the industry and its employees. Based on interviews with retired pharmaceutical employees who were active in the industry in the 1950s and 1960s when the major breakthroughs were made in the development of MAOIs and SSRIs, the paper explores the initial development of educational materials for use in sales campaigns. In addition, based on interviews with current employees in pharmaceutical sales and marketing, the paper describes the complex perspective of contemporary pharmaceutical employees who must live surrounded by the growing public vilification of the industry as rapacious and profit hungry and yet find ways to make their jobs meaningful and dignified. The paper will contribute to the understudied problem of how individuals function in positions that require them to be part of processes that on one description constitute a social evil, but on another, constitute a social good.

  4. Genotoxicity and genotoxic enhancing effect of tetrandrine in Salmonella typhimurium.

    PubMed

    Whong, W Z; Lu, C H; Stewart, J D; Jiang, H X; Ong, T

    1989-03-01

    Tetrandrine has been used for the treatment of silicosis in China. The potential genotoxic and carcinogenic hazards of this drug were studied using the Salmonella/histidine reversion assay and the SOS/Umu test. The results show that tetrandrine was weakly mutagenic to Salmonella typhimurium TA98 with metabolic activation and did not induce SOS response. However, tetrandrine increased the mutagenic activity of benzo[alpha]pyrene, trinitrofluorenone (TNF), 2-aminoanthracene (2AA), diesel emission particles, airborne particles, and cigarette smoke condensate by more than 100%; the activity of aflatoxin B1 and fried beef was increased by over 75%. It also increased the 2AA and TNF-induced SOS response by more than 300%. These results indicated that tetrandrine was a weak promutagen inducing frameshift mutations and was a potent genotoxic enhancer. The mechanism for the genotoxic enhancement is not known. However, the fact that the increase in mutagenicity was noted only in TA98 and not in TA1538 suggested that the enhancement of genotoxicity by tetrandrine may result from an increase in error-prone DNA repair. PMID:2646534

  5. Arsenic Is A Genotoxic Carcinogen

    EPA Science Inventory

    Arsenic is a recognized human carcinogen; however, there is controversy over whether or not it should be considered a genotoxic carcinogen. Many possible modes of action have been proposed on how arsenic induces cancer, including inhibiting DNA repair, altering methylation patter...

  6. Is tetrachloroethylene genotoxic or not?

    PubMed

    Lovell, David

    2010-09-01

    A recent study published in Mutagenesis, in which the ability of tetrachloroethylene to induce DNA damage, detected by the alkaline comet assay, in mouse tissues (liver and kidney) was examined, has resulted in different interpretations of the data for liver as either positive or negative for genotoxicity. Here, I discuss the statistical approaches used and comment on the different conclusions reached.

  7. Impurity effects of transverse Ising model with multi-impurity

    NASA Astrophysics Data System (ADS)

    Huang, Xuchu; Yang, Zhihua

    2015-02-01

    We study the transverse Ising spin model with multi-impurity under the exact solution. The influence mechanisms of the concentration, configuration, impurity-inducing-interaction are investigated through the deformation energy, long-range order and the specific heat. It reveals a way that the impurities have crucial effects on the magnetic order of the system, which can be used to scale the order-disorder transition. In particular, the change of the exchange coupling interaction or magnetic field can lead to the deviation of the phase point. Moreover, the impurity excitation cannot be neglected in thermodynamic properties even though the concentration is only a few percent.

  8. Impurity sources in TEXTOR

    NASA Astrophysics Data System (ADS)

    Pospieszczyk, A.; Bay, H. L.; Bogen, P.; Hartwig, H.; Hintz, E.; Konen, L.; Ross, G. G.; Rusbuldt, D.; Samm, U.; Schweer, B.

    1987-02-01

    The deuterium, oxygen and carbon fluxes from the main limiter and the deuterium fluxes from the wall are measured in TEXTOR for an "all carbon" surrounding as a function of central density ne, of applied ICRH-power and of different wall conditions (carbonization). For this purpose, emission spectroscopy both with filter systems and spectrometers has been used. It is found that a major release mechanism for light impurities is via the formation of molecules. Oxygen seems to enter the discharge from the liner via O-D containing molecules, whereas the limiter acts as the main carbon source by the release of hydro-carbons as indicated by the observed CD-band spectra. Both oxygen and carbon fluxes are reduced by about a factor of two after a fresh carbonization. Above a certain critical density the plasma detaches from the limiter and forms a stable discharge with a radiation cooled boundary layer and with a major fraction of particles now reaching the wall instead of the limiter. The critical density rises with decreasing impurity fluxes or with increasing heating powers.

  9. Characterization and validation of an in silico toxicology model to predict the mutagenic potential of drug impurities*

    SciTech Connect

    Valerio, Luis G.; Cross, Kevin P.

    2012-05-01

    Control and minimization of human exposure to potential genotoxic impurities found in drug substances and products is an important part of preclinical safety assessments of new drug products. The FDA's 2008 draft guidance on genotoxic and carcinogenic impurities in drug substances and products allows use of computational quantitative structure–activity relationships (QSAR) to identify structural alerts for known and expected impurities present at levels below qualified thresholds. This study provides the information necessary to establish the practical use of a new in silico toxicology model for predicting Salmonella t. mutagenicity (Ames assay outcome) of drug impurities and other chemicals. We describe the model's chemical content and toxicity fingerprint in terms of compound space, molecular and structural toxicophores, and have rigorously tested its predictive power using both cross-validation and external validation experiments, as well as case studies. Consistent with desired regulatory use, the model performs with high sensitivity (81%) and high negative predictivity (81%) based on external validation with 2368 compounds foreign to the model and having known mutagenicity. A database of drug impurities was created from proprietary FDA submissions and the public literature which found significant overlap between the structural features of drug impurities and training set chemicals in the QSAR model. Overall, the model's predictive performance was found to be acceptable for screening drug impurities for Salmonella mutagenicity. -- Highlights: ► We characterize a new in silico model to predict mutagenicity of drug impurities. ► The model predicts Salmonella mutagenicity and will be useful for safety assessment. ► We examine toxicity fingerprints and toxicophores of this Ames assay model. ► We compare these attributes to those found in drug impurities known to FDA/CDER. ► We validate the model and find it has a desired predictive performance.

  10. Pharmaceutical Analysis as a Branch of Pharmaceutics

    ERIC Educational Resources Information Center

    Connors, Kenneth A.

    1977-01-01

    Pharmaceutical analysis is incorporated into the pharmaceutics component of the undergraduate curriculum at the University of Wisconsin. Many collaborative demonstrations, lectures, and laboratory experiments can illustrate the close relationship between analysis and modern pharmacy practice. (Author/LBH)

  11. Genotoxic risk of passive smoking.

    PubMed

    Bos, R P; Henderson, P T

    1984-01-01

    More than 60 chemical components are identified in cigarette smoke which have shown to be carcinogenic. The presence of these chemicals is established in mainstream smoke. However, many of them also appear in sidestream smoke resulting in pollution of indoor air, as is shown by the presence of mutagenic substances. Some rather potent carcinogens like N-nitroso-dimethylamine and benzo(a)pyrene have been established in the air of smoke filled rooms. Only a few studies describe internal exposure of passive smokers. Deposition of sidestream smoke in the human respiratory tract has been established for passive smokers. On the other hand, it was shown that inhalation of air contaminated with sidestream smoke results in an increase in the urinary excretion of products mutagenic in the Salmonella/microsome assay. Three epidemiological studies showed an increased risk of lung cancer for non-smoking wives having smoking husbands. Since it is generally acknowledged that most of the genotoxic carcinogens can be detected by in vitro mutagenicity tests, mutagenicity in urine of passive smokers can be considered as an indication of exposure to carcinogens. This observation suggests that there is a causality in the association between increased cancer risk and passive smoking as was found in three epidemiological studies. It is generally accepted that genotoxic chemicals exert their effects in direct proportion to the level of exposure, which means that for these agents no safe thresholds can be established. Several studies clearly show the presence of genotoxic substances in indoor air as a consequence of smoking. Therefore, the outcome of the epidemiological studies is not surprising. As long as half of the human population persists in smoking, the problems of involuntary inhalation of genotoxic substances will continue for the other half. Strategies to control the environmental cancer problem can only be successful if the health hazards of passive smoking are taken seriously.

  12. Cell-Based Genotoxicity Testing

    NASA Astrophysics Data System (ADS)

    Reifferscheid, Georg; Buchinger, Sebastian

    Genotoxicity test systems that are based on bacteria display an important role in the detection and assessment of DNA damaging chemicals. They belong to the basic line of test systems due to their easy realization, rapidness, broad applicability, high sensitivity and good reproducibility. Since the development of the Salmonella microsomal mutagenicity assay by Ames and coworkers in the early 1970s, significant development in bacterial genotoxicity assays was achieved and is still a subject matter of research. The basic principle of the mutagenicity assay is a reversion of a growth inhibited bacterial strain, e.g., due to auxotrophy, back to a fast growing phenotype (regain of prototrophy). Deeper knowledge of the ­mutation events allows a mechanistic understanding of the induced DNA-damage by the utilization of base specific tester strains. Collections of such specific tester strains were extended by genetic engineering. Beside the reversion assays, test systems utilizing the bacterial SOS-response were invented. These methods are based on the fusion of various SOS-responsive promoters with a broad variety of reporter genes facilitating numerous methods of signal detection. A very important aspect of genotoxicity testing is the bioactivation of ­xenobiotics to DNA-damaging compounds. Most widely used is the extracellular metabolic activation by making use of rodent liver homogenates. Again, genetic engineering allows the construction of highly sophisticated bacterial tester strains with significantly enhanced sensitivity due to overexpression of enzymes that are involved in the metabolism of xenobiotics. This provides mechanistic insights into the toxification and detoxification pathways of xenobiotics and helps explaining the chemical nature of hazardous substances in unknown mixtures. In summary, beginning with "natural" tester strains the rational design of bacteria led to highly specific and sensitive tools for a rapid, reliable and cost effective ­genotoxicity

  13. Impurities in Kevlar 49 fibers

    SciTech Connect

    Pruneda, C.O.; Morgan, R.J.; Lim, R.; Gregory, L.J.; Fischer, J.W.

    1984-12-11

    The impurities in Kevlar 49 fibers (poly(p-phenylene terephthalamide)PPTA) are reported and discussed in terms of the fiber fabrication processes. These impurities were monitored by inductively coupled plasma emission and optical emission spectroscopy. The principal impurities Na/sub 2/SO/sub 4/ and total S were analyzed chemically. From these chemical analyses together with C, N, H elemental analyses we show that there are 1.5 wt % impurities present in Kevlar 49 fibers of which approx. 50% are in the form of Na/sub 2/SO/sub 4/ and the remainder probably in the form of benzene sulfonic -SO/sub 3/H PPTA side groups. There are 3 of these acid groups per each PPTA macromolecule. Organic impurities, such as terephthalic acid are discussed in the light of degradation studies of PPTA-H/sub 2/SO/sub 4/ spinning dopes. Electron microprobe x-ray spectroscopy and laser-induced damage studies were utilized to investigate the distribution of impurities through the fiber cross-section. The distribution of impurities throughout the fiber are determined by the fiber fabrication processes and are discussed at the microscopic and molecular level. The defects caused by these impurities and their effect on the deformation and failure modes are also considered. 22 references, 3 tables.

  14. Mobile impurities in ferromagnetic liquids

    NASA Astrophysics Data System (ADS)

    Kantian, Adrian; Schollwoeck, Ulrich; Giamarchi, Thierry

    2011-03-01

    Recent work has shown that mobile impurities in one dimensional interacting systems may exhibit behaviour that differs strongly from that predicted by standard Tomonaga-Luttinger liquid theory, with the appearance of power-law divergences in the spectral function signifying sublinear diffusion of the impurity. Using time-dependent matrix product states, we investigate a range of cases of mobile impurities in systems beyond the analytically accessible examples to assess the existence of a new universality class of low-energy physics in one-dimensional systems. Correspondence: Adrian.Kantian@unige.ch This work was supported in part by the Swiss SNF under MaNEP and division II.

  15. Oxidative stress and genotoxicity induced by ketorolac on the common carp Cyprinus carpio.

    PubMed

    Galar-Martínez, M; García-Medina, S; Gómez-Olivan, L M; Pérez-Coyotl, I; Mendoza-Monroy, D J; Arrazola-Morgain, R E

    2016-09-01

    The nonsteroidal anti-inflammatory drug ketorolac is extensively used in the treatment of acute postoperative pain. This pharmaceutical has been found at concentrations of 0.2-60 µg/L in diverse water bodies around the world; however, its effects on aquatic organisms remain unknown. The present study, evaluated the oxidative stress and genotoxicity induced by sublethal concentrations of ketorolac (1 and 60 µg/L) on liver, brain, and blood of the common carp Cyprinus carpio. This toxicant induced oxidative damage (increased lipid peroxidation, hydroperoxide content, and protein carbonyl content) as well as changes in antioxidant status (superoxide dismutase, catalase, and glutathione peroxidase activity) in liver and brain of carp. In blood, ketorolac increased the frequency of micronuclei and is therefore genotoxic for the test species. The effects observed were time and concentration dependent. © 2015 Wiley Periodicals, Inc. Environ Toxicol 31: 1035-1043, 2016.

  16. Oxidative stress and genotoxicity induced by ketorolac on the common carp Cyprinus carpio.

    PubMed

    Galar-Martínez, M; García-Medina, S; Gómez-Olivan, L M; Pérez-Coyotl, I; Mendoza-Monroy, D J; Arrazola-Morgain, R E

    2016-09-01

    The nonsteroidal anti-inflammatory drug ketorolac is extensively used in the treatment of acute postoperative pain. This pharmaceutical has been found at concentrations of 0.2-60 µg/L in diverse water bodies around the world; however, its effects on aquatic organisms remain unknown. The present study, evaluated the oxidative stress and genotoxicity induced by sublethal concentrations of ketorolac (1 and 60 µg/L) on liver, brain, and blood of the common carp Cyprinus carpio. This toxicant induced oxidative damage (increased lipid peroxidation, hydroperoxide content, and protein carbonyl content) as well as changes in antioxidant status (superoxide dismutase, catalase, and glutathione peroxidase activity) in liver and brain of carp. In blood, ketorolac increased the frequency of micronuclei and is therefore genotoxic for the test species. The effects observed were time and concentration dependent. © 2015 Wiley Periodicals, Inc. Environ Toxicol 31: 1035-1043, 2016. PMID:25899151

  17. TLC chromatographic-densitometric assay of ibuprofen and its impurities.

    PubMed

    Starek, Małgorzata; Krzek, Jan

    2010-11-01

    A simple and sensitive thin-layer chromatographic (TLC)-densitometric method for the quantitative estimation of S(+)-2-[4-isobutylphenyl]propionic acid (ibuprofen) and its impurities in pharmaceutical preparations has been developed. The chromatographic separation was carried out on silica gel 60 F(254) TLC plates using toluene-ethyl acetate-glacial acetic acid (17:13: 1, v/v/v) as the mobile phase. Detection was carried out densitometrically with a UV detector. The developed method has detection and quantitation limits ranging from 0.13 μg per spot to 0.72 μg per spot. For individual constituents the recovery ranged from 96.8% to 99.0%. In addition, the stability of ibuprofen solutions was investigated, including the effect of pH, temperature, and incubation time. The method is rapid, simple, and suitable for routine quality-control analysis of pharmaceuticals containing ibuprofen.

  18. Impurity bubbles in a BEC

    NASA Astrophysics Data System (ADS)

    Timmermans, Eddy; Blinova, Alina; Boshier, Malcolm

    2013-05-01

    Polarons (particles that interact with the self-consistent deformation of the host medium that contains them) self-localize when strongly coupled. Dilute Bose-Einstein condensates (BECs) doped with neutral distinguishable atoms (impurities) and armed with a Feshbach-tuned impurity-boson interaction provide a unique laboratory to study self-localized polarons. In nature, self-localized polarons come in two flavors that exhibit qualitatively different behavior: In lattice systems, the deformation is slight and the particle is accompanied by a cloud of collective excitations as in the case of the Landau-Pekar polarons of electrons in a dielectric lattice. In natural fluids and gases, the strongly coupled particle radically alters the medium, e.g. by expelling the host medium as in the case of the electron bubbles in superfluid helium. We show that BEC-impurities can self-localize in a bubble, as well as in a Landau-Pekar polaron state. The BEC-impurity system is fully characterized by only two dimensionless coupling constants. In the corresponding phase diagram the bubble and Landau-Pekar polaron limits correspond to large islands separated by a cross-over region. The same BEC-impurity species can be adiabatically Feshbach steered from the Landau-Pekar to the bubble regime. This work was funded by the Los Alamos LDRD program.

  19. Transverse Ising model with multi-impurity

    NASA Astrophysics Data System (ADS)

    Huang, Xuchu; Yang, Zhihua

    2015-05-01

    We study the transverse Ising spin model with spin-1 impurities under the exact solution. We develop a universal method to deal with the multi-impurity problem by introducing a displacement quantity in the wave function and get a recursive formula to simplify the calculation of the partition function. This allows us to rigorously determine the impurity effects for a specific distribution of impurity in the thermodynamic limit. The low temperature behaviors are governed by the interplay between host and impurity excitations, and the quantum critical fluctuations around the critical point of the transverse Ising model are tuned by the transverse field and the concentration of impurity. However the impurity effects are limited, which depends on the host-impurity exchange interaction and the coupling strength of impurities.

  20. Endohedral impurities in carbon nanotubes.

    PubMed

    Clougherty, Dennis P

    2003-01-24

    A generalization of the Anderson model that includes pseudo-Jahn-Teller impurity coupling is proposed to describe distortions of an endohedral impurity in a carbon nanotube. Within mean-field theory, spontaneous axial symmetry breaking is found when the vibronic coupling strength g exceeds a critical value. The effective potential is found to have O(2) symmetry, in agreement with numerical calculations. For metallic zigzag nanotubes endohedrally doped with transition metals in the dilute limit, the low-energy properties of the system may display two-channel Kondo behavior; however, strong vibronic coupling is seen to exponentially suppress the Kondo energy scale. PMID:12570507

  1. Endohedral Impurities in Carbon Nanotubes

    NASA Astrophysics Data System (ADS)

    Clougherty, Dennis

    2003-03-01

    A generalization of the Anderson model that includes pseudo-Jahn-Teller impurity coupling is proposed to describe distortions of an endohedral impurity in a carbon nanotube. Treating the distortion within mean-field theory, spontaneous axial symmetry breaking is found when the vibronic coupling strength g exceeds a critical value g_c. The effective potential in the symmetry-broken state is found to have O(2) symmetry, in agreement with numerical calculations. The consequences of such a distortion on electronic transport will be discussed.

  2. Endohedral Impurities in Carbon Nanotubes

    NASA Astrophysics Data System (ADS)

    Clougherty, Dennis P.

    2003-01-01

    A generalization of the Anderson model that includes pseudo-Jahn-Teller impurity coupling is proposed to describe distortions of an endohedral impurity in a carbon nanotube. Within mean-field theory, spontaneous axial symmetry breaking is found when the vibronic coupling strength g exceeds a critical value. The effective potential is found to have O(2) symmetry, in agreement with numerical calculations. For metallic zigzag nanotubes endohedrally doped with transition metals in the dilute limit, the low-energy properties of the system may display two-channel Kondo behavior; however, strong vibronic coupling is seen to exponentially suppress the Kondo energy scale.

  3. ALUMINUM IMPURITY DIFFUSION IN MAGNESIUM

    SciTech Connect

    Brennan, Sarah; Warren, Andrew; Coffey, Kevin; Kulkarni, Nagraj S; Todd, Peter J; Sohn, Yong Ho; Klimov, Mikhail

    2012-01-01

    The Al impurity diffusion in polycrystalline Mg (99.9%) via depth profiling with secondary ion mass spectrometry was studied in the temperature range of 673-573K, utilizing the thin film method and thin film solution to the diffusion equation. Multiple samples were utilized and multiple profiles were obtained to determine statistically confident coefficient with maximum standard deviation of 16%. Activation energy and pre-exponential factor of Al impurity diffusion in Mg was determined as 155 kJ/mole and 3.9 x 10-3 m2/sec.

  4. Control of impurities in toroidal plasma devices

    DOEpatents

    Ohkawa, Tihiro

    1980-01-01

    A method and apparatus for plasma impurity control in closed flux plasma systems such as Tokamak reactors is disclosed. Local axisymmetrical injection of hydrogen gas is employed to reverse the normally inward flow of impurities into the plasma.

  5. Fundamental aspects of metallic impurities and impurity interactions in silicon during device processing

    SciTech Connect

    Graff, K.

    1995-08-01

    A review on the behavior of metallic impurities in silicon can be considerably simplified by a restriction on pure, dislocation-free, monocrystalline silicon. In this case interactions between different impurities and between impurities and grown-in lattice defects can be reduced. This restriction is observed in Chapter 1 for discussing the general behavior of metallic impurities in silicon.

  6. Biological and Pharmaceutical Nanomaterials

    NASA Astrophysics Data System (ADS)

    Kumar, Challa S. S. R.

    2006-01-01

    This first comprehensive yet concise overview of all important classes of biological and pharmaceutical nanomaterials presents in one volume the different kinds of natural biological compounds that form nanomaterials or that may be used to purposefully create them. This unique single source of information brings together the many articles published in specialized journals, which often remain unseen by members of other, related disciplines. Covering pharmaceutical, nucleic acid, peptide and DNA-Chitosan nanoparticles, the book focuses on those innovative materials and technologies needed for the continued growth of medicine, healthcare, pharmaceuticals and human wellness. For chemists, biochemists, cell biologists, materials scientists, biologists, and those working in the pharmaceutical and chemical industries.

  7. [Healthy pharmaceutical policy].

    PubMed

    González Pier, Eduardo

    2008-01-01

    Today, the pharmaceutical industry is experiencing a profound transition. Globalization and technological advancement represent the principal pressures for change in the market, where it is increasingly more difficult for this type of industry to efficiently recoup the growing cost of innovation. Mexico needs to analyze the policy implications of these change factors and promote, in the pharmaceutical market, policies that maximize health gains on invested resources. Pharmaceutical policy offers a rare example for a complementary approach between a sound health policy and an efficient economic policy; that is, a "healthy pharmaceutical policy."

  8. [Pharmaceuticals as pollution].

    PubMed

    Grung, Merete; Langford, Katherine; Thomas, Kevin V

    2012-05-29

    The pharmaceuticals we humans use to treat illness and disease typically enter the aquatic environment via the sewer network and wastewater treatment works. Understanding the risks posed to the aquatic environment by these chemicals requires an understanding of the concentrations that exist in the environment and whether they are sufficiently high to have adverse effects on aquatic organisms. The main source of pharmaceuticals to wastewater treatment works is pharmaceuticals used by the general population. Only a small contribution is believed to come from hospitals. The predicted environmental concentrations of pharmaceuticals suggest that certain pharmaceuticals may pose a risk to the environment, but measurement of the actual concentrations present in effluents and recipient waters suggest that sophisticated wastewater treatment is effective for significantly reducing effluent concentrations, and that environmental concentrations of pharmaceuticals, in the Oslo Fjord, for example, are generally low. Humans also excrete the metabolites of the pharmaceuticals that they have used and these too may be released into the environment, sometimes in greater concentrations than the parent drug. The occurrence of most pharmaceuticals and their metabolites in the environment poses little acute environmental risk. However, the effects of long-term chronic exposure to these compounds are still poorly understood and the long-terms risks to the environment are still not clear. What is clear is that certain pharmaceuticals pose a greater environmental risk than others, and that where possible this knowledge should be used to inform users of more environmentally friendly alternatives.

  9. Using Electron Paramagnetic Resonance Spectroscopy To Facilitate Problem Solving in Pharmaceutical Research and Development.

    PubMed

    Mangion, Ian; Liu, Yizhou; Reibarkh, Mikhail; Williamson, R Thomas; Welch, Christopher J

    2016-08-19

    As new chemical methodologies driven by single-electron chemistry emerge, process and analytical chemists must develop approaches to rapidly solve problems in this nontraditional arena. Electron paramagnetic resonance spectroscopy has been long known as a preferred technique for the study of paramagnetic species. However, it is only recently finding application in contemporary pharmaceutical development, both to study reactions and to track the presence of undesired impurities. Several case studies are presented here to illustrate its utility in modern pharmaceutical development efforts.

  10. Observation of impurity accumulation and concurrent impurity influx in PBX

    SciTech Connect

    Sesnic, S.S.; Fonck, R.J.; Ida, K.; Bol, K.; Couture, P.; Gammel, G.; Kaita, R.; Kaye, S.; Kugel, H.; LeBlanc, B.

    1986-07-01

    Impurity studies in L- and H-mode discharges in PBX have shown that both types of discharges can evolve into either an impurity accumulative or nonaccumulative case. In a typical accumulative discharge, Zeff peaks in the center to values of about 5. The central metallic densities can be high, n/sub met//n/sub e/ approx. = 0.01, resulting in central radiated power densities in excess of 1 W/cm/sup 3/, consistent with bolometric estimates. The radial profiles of metals obtained independently from the line radiation in the soft x-ray and the VUV regions are very peaked. Concurrent with the peaking, an increase in the impurity influx coming from the edge of the plasma is observed. At the beginning of the accumulation phase the inward particle flux for titanium has values of 6 x 10/sup 10/ and 10 x 10/sup 10/ particles/cm/sup 2/s at minor radii of 6 and 17 cm. At the end of the accumulation phase, this particle flux is strongly increased to values of 3 x 10/sup 12/ and 1 x 10/sup 12/ particles/cm/sup 2/s. This increased flux is mainly due to influx from the edge of the plasma and to a lesser extent due to increased convective transport. Using the measured particle flux, an estimate of the diffusion coefficient D and the convective velocity v is obtained.

  11. GENOTOXICITY OF TOBACCO SMOKE AND TOBACCO SMOKE CONDENSATE: A REVIEW

    EPA Science Inventory

    Genotoxicity of Tobacco Smoke and Tobacco Smoke Condensate: A Review
    Abstract
    This report reviews the literature on the genotoxicity of main-stream tobacco smoke and cigarette smoke condensate (CSC) published since 1985. CSC is genotoxic in nearly all systems in which it h...

  12. Natural Antioxidants Against Arsenic-Induced Genotoxicity.

    PubMed

    Kumar, Munesh; Lalit, Minakshi; Thakur, Rajesh

    2016-03-01

    Arsenic is present in water, soil, and air in organic as well as in inorganic forms. However, inorganic arsenic is more toxic than organic and can cause many diseases including cancers in humans. Its genotoxic effect is considered as one of its carcinogenic actions. Arsenic can cause DNA strand breaks, deletion mutations, micronuclei formation, DNA-protein cross-linking, sister chromatid exchange, and DNA repair inhibition. Evidences indicate that arsenic causes DNA damage by generation of reactive free radicals. Nutritional supplementation of antioxidants has been proven highly beneficial against arsenic genotoxicity in experimental animals. Recent studies suggest that antioxidants protect mainly by reducing excess free radicals via restoring the activities of cellular enzymatic as well as non-enzymatic antioxidants and decreasing the oxidation processes such as lipid peroxidation and protein oxidation. The purpose of this review is to summarize the recent literature on arsenic-induced genotoxicity and its mitigation by naturally derived antioxidants in various biological systems.

  13. Environmental genotoxicity: Probing the underlying mechanisms

    SciTech Connect

    Shugart, L.; Theodorakis, C.

    1993-12-31

    Environmental pollution is a complex issue because of the diversity of anthropogenic agents, both chemical and physical, that have been detected and catalogued. The consequences to biota from exposure to genotoxic agents present an additional problem because of the potential for these agents to produce adverse change at the cellular and organismal levels. Past studies in genetic toxicology at the Oak Ridge National Laboratory have focused on structural damage to the DNA of environmental species that may occur after exposure to genotoxic agents and the use of this information to document exposure and to monitor remediation. In an effort to predict effects at the population, community and ecosystem levels, current studies in genetic ecotoxicology are attempting to characterize the biological mechanisms at the gene level that regulate and limit the response of an individual organism to genotoxic factors in their environment.

  14. Control of impurity concentration in liquid metals by neutron scattering

    SciTech Connect

    Morozov, V. A.; Novikov, A. G.; Savostin, V. V.

    2011-12-15

    A technique is proposed for determining the impurity concentration in liquid metal-impurity systems. This technique does not require special measurements or geometry: information about the impurity concentration can be obtained directly from the data collected during the diffraction experiment. The impurity concentrations in a lead melt with a potassium impurity and in a sodium melt with a lead impurity are determined.

  15. Self-pumping impurity control

    DOEpatents

    Brooks, J.N.; Mattas, R.F.

    1983-12-21

    It is an object of the present invention to provide an apparatus for removing impurities from the plasma in a fusion reactor without an external vacuum pumping system. It is also an object of the present invention to provide an apparatus for removing the helium ash from a fusion reactor. It is another object of the present invention to provide an apparatus which removes helium ash and minimizes tritium recycling and inventory.

  16. Screening for impurities in butoprozine.

    PubMed

    Drenth, B F; Jagersma, T; Wormeester, A J; de Zeeuw, R A

    1983-08-26

    The purity analysis of butoprozine is described. Both gas chromatography-mass spectrometry (GC-MS) and high pressure liquid chromatography (HPLC) with UV-vis detection (conventional and multichannel) were used. In the butoprozine example disadvantages for both techniques became apparent: incorrect conclusions with regard to the purity of the drug would have been drawn if only one of these chromatographic techniques had been used. GC-MS allowed the identification of an impurity not found by HPLC. PMID:6622208

  17. Cobalt and antimony: genotoxicity and carcinogenicity.

    PubMed

    De Boeck, Marlies; Kirsch-Volders, Micheline; Lison, Dominique

    2003-12-10

    The purpose of this review is to summarise the data concerning genotoxicity and carcinogenicity of Co and Sb. Both metals have multiple industrial and/or therapeutical applications, depending on the considered species. Cobalt is used for the production of alloys and hard metal (cemented carbide), diamond polishing, drying agents, pigments and catalysts. Occupational exposure to cobalt may result in adverse health effects in different organs or tissues. Antimony trioxide is primarily used as a flame retardant in rubber, plastics, pigments, adhesives, textiles, and paper. Antimony potassium tartrate has been used worldwide as an anti-shistosomal drug. Pentavalent antimony compounds have been used for the treatment of leishmaniasis. Co(II) ions are genotoxic in vitro and in vivo, and carcinogenic in rodents. Co metal is genotoxic in vitro. Hard metal dust, of which occupational exposure is linked to an increased lung cancer risk, is proven to be genotoxic in vitro and in vivo. Possibly, production of active oxygen species and/or DNA repair inhibition are mechanisms involved. Given the recently provided proof for in vitro and in vivo genotoxic potential of hard metal dust, the mechanistic evidence of elevated production of active oxygen species and the epidemiological data on increased cancer risk, it may be advisable to consider the possibility of a new evaluation by IARC. Both trivalent and pentavalent antimony compounds are generally negative in non-mammalian genotoxicity tests, while mammalian test systems usually give positive results for Sb(III) and negative results for Sb(V) compounds. Assessment of the in vivo potential of Sb2O3 to induce chromosome aberrations (CA) gave conflicting results. Animal carcinogenicity data were concluded sufficient for Sb2O3 by IARC. Human carcinogenicity data is difficult to evaluate given the frequent co-exposure to arsenic. Possible mechanisms of action, including potential to produce active oxygen species and to interfere with

  18. Impurity diffusion in transition-metal oxides

    SciTech Connect

    Peterson, N.L.

    1982-06-01

    Intrinsic tracer impurity diffusion measurements in ceramic oxides have been primarily confined to CoO, NiO, and Fe/sub 3/O/sub 4/. Tracer impurity diffusion in these materials and TiO/sub 2/, together with measurements of the effect of impurities on tracer diffusion (Co in NiO and Cr in CoO), are reviewed and discussed in terms of impurity-defect interactions and mechanisms of diffusion. Divalent impurities in divalent solvents seem to have a weak interaction with vacancies whereas trivalent impurities in divalent solvents strongly influence the vacancy concentrations and significantly reduce solvent jump frequencies near a trivalent impurity. Impurities with small ionic radii diffuse more slowly with a larger activation energy than impurities with larger ionic radii for all systems considered in this review. Cobalt ions (a moderate size impurity) diffuse rapidly along the open channels parallel to the c-axis in TiO/sub 2/ whereas chromium ions (a smaller-sized impurity) do not. 60 references, 11 figures.

  19. Radiation treatment of pharmaceuticals

    NASA Astrophysics Data System (ADS)

    Dám, A. M.; Gazsó, L. G.; Kaewpila, S.; Maschek, I.

    1996-03-01

    Product specific doses were calculated for pharmaceuticals to be radiation treated. Radio-pasteurization dose were determined for some heat sensitive pharmaceutical basic materials (pancreaton, neopancreatin, neopancreatin USP, duodenum extract). Using the new recommendation (ISO standards, Method 1) dose calculations were performed and radiation sterilization doses were determined for aprotinine and heparine Na.

  20. Gaseous trace impurity analyzer and method

    DOEpatents

    Edwards, Jr., David; Schneider, William

    1980-01-01

    Simple apparatus for analyzing trace impurities in a gas, such as helium or hydrogen, comprises means for drawing a measured volume of the gas as sample into a heated zone. A segregable portion of the zone is then chilled to condense trace impurities in the gas in the chilled portion. The gas sample is evacuated from the heated zone including the chilled portion. Finally, the chilled portion is warmed to vaporize the condensed impurities in the order of their boiling points. As the temperature of the chilled portion rises, pressure will develop in the evacuated, heated zone by the vaporization of an impurity. The temperature at which the pressure increase occurs identifies that impurity and the pressure increase attained until the vaporization of the next impurity causes a further pressure increase is a measure of the quantity of the preceding impurity.

  1. Genotoxic and immunotoxic potential effects of selected psychotropic drugs and antibiotics on blue mussel (Mytilus edulis) hemocytes.

    PubMed

    Lacaze, Emilie; Pédelucq, Julie; Fortier, Marlène; Brousseau, Pauline; Auffret, Michel; Budzinski, Hélène; Fournier, Michel

    2015-07-01

    The potential toxicity of pharmaceuticals towards aquatic invertebrates is still poorly understood and sometimes controversial. This study aims to document the in vitro genotoxicity and immunotoxicity of psychotropic drugs and antibiotics on Mytilus edulis. Mussel hemocytes were exposed to fluoxetine, paroxetine, venlafaxine, carbamazepine, sulfamethoxazole, trimethoprim and erythromycin, at concentrations ranging from μg/L to mg/L. Paroxetine at 1.5 μg/L led to DNA damage while the same concentration of venlafaxine caused immunomodulation. Fluoxetine exposure resulted in genotoxicity, immunotoxicity and cytotoxicity. In the case of antibiotics, trimethoprim was genotoxic at 200 μg/L and immunotoxic at 20 mg/L whereas erythromycin elicited same detrimental effects at higher concentrations. DNA metabolism seems to be a highly sensitive target for psychotropic drugs and antibiotics. Furthermore, these compounds affect the immune system of bivalves, with varying intensity. This attests the relevance of these endpoints to assess the toxic mode of action of pharmaceuticals in the aquatic environment.

  2. Ovation Pharmaceuticals, Inc.

    PubMed

    Deutsch, Barry

    2002-11-01

    Ovation Pharmaceuticals, Inc. is a privately held specialty pharmaceutical company that focuses on products in central nervous system (CNS) disorders, oncology and other therapeutic areas where a small number of specialized physicians treat patients. Ovation serves unmet medical needs by acquiring underpromoted branded pharmaceutical products and promising late-stage development products no longer being actively promoted or developed by larger companies. Ovation supports acquired products through active sales and marketing activities and a clinical development program focused on new formulations, new indications and other product improvements. In April 2002, Ovation received a US$150 million commitment in private equity financing, believed to be the largest private equity investment received to date by an early-stage specialty pharmaceutical firm. Ovation used a portion of those funds to purchase its first two products from a major pharmaceutical company in August 2002.

  3. FDA pharmaceutical quality oversight.

    PubMed

    Yu, Lawrence X; Woodcock, Janet

    2015-08-01

    The launch of the Center for Drug Evaluation and Research (CDER) Office of Pharmaceutical Quality (OPQ) is a milestone in FDA's efforts to assure that quality medicines are available to the American public. As a new super-office within CDER, OPQ is strategically organized to streamline regulatory processes, advance regulatory standards, align areas of expertise, and originate surveillance of drug quality. Supporting these objectives will be an innovative and systematic approach to product quality knowledge management and informatics. Concerted strategies will bring parity to the oversight of innovator and generic drugs as well as domestic and international facilities. OPQ will promote and encourage the adoption of emerging pharmaceutical technology to enhance pharmaceutical quality and potentially reinvigorate the pharmaceutical manufacturing sector in the United States. With a motto of "One Quality Voice," OPQ embodies the closer integration of review, inspection, surveillance, policy, and research for the purpose of strengthening pharmaceutical quality on a global scale.

  4. Analysis of published data for top concentration considerations in mammalian cell genotoxicity testing.

    PubMed

    Parry, James M; Parry, Elizabeth; Phrakonkham, Pascal; Corvi, Raffaella

    2010-11-01

    The ability of the in vitro mammalian cell tests currently used to identify genotoxins has been shown to be limited by a high rate of false-positive results, triggering further unnecessary testing in vivo. During an European Centre for the Validation of Alternative Methods workshop on how to improve the specificity of these assays, testing at high concentrations was identified as one possible source of false positives. Thus far, Organisation for Economic Co-operation and Development genotoxicity test guidelines have required testing of chemicals using mammalian cells in vitro should be undertaken to concentrations as high as 10 mM (5000 μg/ml). Recently, a draft revision of the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use genotoxicity test guidelines has recommended that testing concentrations should be reduced to 1 mM (500 μg/ml). To assess the impact that this lowering would have on the outcome of in vitro genotoxicity testing, we established a database of 384 chemicals classified as rodent carcinogens and reported Ames test results and the test concentrations that produced positive results in the mouse lymphoma assay (MLA), in vitro chromosome aberration (CA) assay and in vitro micronucleus test. Genotoxicity testing results were illustrated for 229 and 338 compounds in the MLA and in vitro CA assay, respectively. Of these test compounds, 62.5% produced positive results in the MLA, of which 20.3% required testing between 1 and 10 mM. A total of 58.0% produced positive results in in vitro CA assays, of which 25.0% required testing between 1 and 10 mM. If the testing concentration limit for mammalian cell assays was reduced to 1 mM, 24 (6.25%) potential carcinogens would not be detected in any part of the standard in vitro genotoxicity test battery (Ames test, MLA and in vitro CA assay). Further re-evaluation and/or retest of these compounds by Kirkland and Fowler [Kirkland, D. and Fowler

  5. In vitro and in vivo genotoxicity assessment of HI-6 dimethanesulfonate/oxime.

    PubMed

    Nakab, Lauren; Bardot, Isabelle; Bardot, Sébastien; Simar, Sophie; Marzin, Daniel; Nesslany, Fabrice

    2014-03-01

    Organophosphate compounds, which induce organophosphate poisoning, were originally used as pesticides. But this type of product has also been used as warfare nerve agent like sarin, soman, Russian VX, or tabun. HI-6-dimethanesulfonate is a salt of the oxime HI-6 used in the treatment of nerve-agent poisoning. It is known to be the best re-activator component of inactivated acetyl cholinesterase. HI-6-dimethanesulfonate has shown a higher level of solubility with similar potency to reactivate acetyl cholinesterase and a similar pharmacokinetics profile compared with HI-6 dichloride. HI-6 dimethanesulfonate was tested for its mutagenic and genotoxic potential by use of the standard ICH S2R (1) battery for the evaluation of pharmaceuticals. HI-6-dimethanesulfonate was mutagenic in the Ames test only in the presence of metabolic activation. In the mutation assay at the Tk locus in L5178Y mouse-lymphoma cells, HI-6-dimethanesulfonate showed mutagenic activity both with and without metabolic activation, with a significant increase in small colonies. The effects were in favour of a clastogenic activity. It was concluded that the compound was mutagenic and possibly clastogenic in vitro. In contrast, the in vivo micronucleus test in rat bone-marrow did not demonstrate any genotoxic activity and the Comet assay performed in rat liver did not show any statistically or biologically significant increases in DNA strand-breaks. The results of both in vivo studies performed on two different organs with two endpoints are sufficient to conclude the absence of a genotoxic hazard in vivo and to consider that there is no genotoxic concern in humans for HI-6-dimethanesulfonate.

  6. Impurity-induced divertor plasma oscillations

    NASA Astrophysics Data System (ADS)

    Smirnov, R. D.; Kukushkin, A. S.; Krasheninnikov, S. I.; Pigarov, A. Yu.; Rognlien, T. D.

    2016-01-01

    Two different oscillatory plasma regimes induced by seeding the plasma with high- and low-Z impurities are found for ITER-like divertor plasmas, using computer modeling with the DUSTT/UEDGE and SOLPS4.3 plasma-impurity transport codes. The oscillations are characterized by significant variations of the impurity-radiated power and of the peak heat load on the divertor targets. Qualitative analysis of the divertor plasma oscillations reveals different mechanisms driving the oscillations in the cases of high- and low-Z impurity seeding. The oscillations caused by the high-Z impurities are excited near the X-point by an impurity-related instability of the radiation-condensation type, accompanied by parallel impurity ion transport affected by the thermal and plasma friction forces. The driving mechanism of the oscillations induced by the low-Z impurities is related to the cross-field transport of the impurity atoms, causing alteration between the high and low plasma temperature regimes in the plasma recycling region near the divertor targets. The implications of the impurity-induced plasma oscillations for divertor operation in the next generation tokamaks are also discussed.

  7. Impurity-induced divertor plasma oscillations

    DOE PAGESBeta

    Smirnov, R. D.; Kukushkin, A. S.; Krasheninnikov, S. I.; Pigarov, A. Yu.; Rognlien, T. D.

    2016-01-07

    Two different oscillatory plasma regimes induced by seeding the plasma with high- and low-Z impurities are found for ITER-like divertor plasmas, using computer modeling with the DUSTT/UEDGE and SOLPS4.3 plasma-impurity transport codes. The oscillations are characterized by significant variations of the impurity-radiated power and of the peak heat load on the divertor targets. Qualitative analysis of the divertor plasma oscillations reveals different mechanisms driving the oscillations in the cases of high- and low-Z impurity seeding. The oscillations caused by the high-Z impurities are excited near the X-point by an impurity-related instability of the radiation-condensation type, accompanied by parallel impurity ionmore » transport affected by the thermal and plasma friction forces. The driving mechanism of the oscillations induced by the low-Z impurities is related to the cross-field transport of the impurity atoms, causing alteration between the high and low plasma temperature regimes in the plasma recycling region near the divertor targets. As a result, the implications of the impurity-induced plasma oscillations for divertor operation in the next generation tokamaks are also discussed.« less

  8. "Aspartame: A review of genotoxicity data".

    PubMed

    Kirkland, David; Gatehouse, David

    2015-10-01

    Aspartame is a methyl ester of a dipeptide of aspartic acid and phenylalanine. It is 200× sweeter than sucrose and is approved for use in food products in more than 90 countries around the world. Aspartame has been evaluated for genotoxic effects in microbial, cell culture and animal models, and has been subjected to a number of carcinogenicity studies. The in vitro and in vivo genotoxicity data available on aspartame are considered sufficient for a thorough evaluation. There is no evidence of induction of gene mutations in a series of bacterial mutation tests. There is some evidence of induction of chromosomal damage in vitro, but this may be an indirect consequence of cytotoxicity. The weight of evidence from in vivo bone marrow micronucleus, chromosomal aberration and Comet assays is that aspartame is not genotoxic in somatic cells in vivo. The results of germ cell assays are difficult to evaluate considering limited data available and deviations from standard protocols. The available data therefore support the conclusions of the European Food Safety Authority (EFSA) that aspartame is non-genotoxic. PMID:26321723

  9. METHYLATED TRIVALENT ARSENIC SPECIES ARE GENOTOXIC

    EPA Science Inventory

    ABSTRACT

    The genotoxic effects of arsenic compounds are generally believed to result from other than direct interacton with DNA. The reactivties of methyloxarsine (MAsIII) and iododimethylarsine (DMAsIII), two methylated trivalent arsenicals, toward supercoiled X174 RFI ...

  10. "Aspartame: A review of genotoxicity data".

    PubMed

    Kirkland, David; Gatehouse, David

    2015-10-01

    Aspartame is a methyl ester of a dipeptide of aspartic acid and phenylalanine. It is 200× sweeter than sucrose and is approved for use in food products in more than 90 countries around the world. Aspartame has been evaluated for genotoxic effects in microbial, cell culture and animal models, and has been subjected to a number of carcinogenicity studies. The in vitro and in vivo genotoxicity data available on aspartame are considered sufficient for a thorough evaluation. There is no evidence of induction of gene mutations in a series of bacterial mutation tests. There is some evidence of induction of chromosomal damage in vitro, but this may be an indirect consequence of cytotoxicity. The weight of evidence from in vivo bone marrow micronucleus, chromosomal aberration and Comet assays is that aspartame is not genotoxic in somatic cells in vivo. The results of germ cell assays are difficult to evaluate considering limited data available and deviations from standard protocols. The available data therefore support the conclusions of the European Food Safety Authority (EFSA) that aspartame is non-genotoxic.

  11. Anisotropic inflation from vector impurity

    SciTech Connect

    Kanno, Sugumi; Kimura, Masashi; Soda, Jiro; Yokoyama, Shuichiro E-mail: mkimura@sci.osaka-cu.ac.jp E-mail: shu@a.phys.nagoya-u.ac.jp

    2008-08-15

    We study an inflationary scenario with a vector impurity. We show that the universe undergoes anisotropic inflationary expansion due to a preferred direction determined by the vector. Using the slow roll approximation, we find a formula for determining the anisotropy of the inflationary universe. We discuss possible observable predictions of this scenario. In particular, it is stressed that primordial gravitational waves can be induced from curvature perturbations. Hence, even in low scale inflation, a sizable amount of primordial gravitational waves may be produced during inflation.

  12. Impurity-induced moments in underdoped cuprates

    SciTech Connect

    Khaliullin, G. |; Kilian, R.; Krivenko, S.; Fulde, P.

    1997-11-01

    We examine the effect of a nonmagnetic impurity in a two-dimensional spin liquid in the spin-gap phase, employing a drone-fermion representation of spin-1/2 operators. The properties of the local moment induced in the vicinity of the impurity are investigated and an expression for the nuclear-magnetic-resonance Knight shift is derived, which we compare with experimental results. Introducing a second impurity into the spin liquid an antiferromagnetic interaction between the moments is found when the two impurities are located on different sublattices. The presence of many impurities leads to a screening of this interaction as is shown by means of a coherent-potential approximation. Further, the Kondo screening of an impurity-induced local spin by charge carriers is discussed. {copyright} {ital 1997} {ital The American Physical Society}

  13. Pharmaceutical Industry in Syria

    PubMed Central

    2010-01-01

    The aim of this article is to present the development of the pharmaceutical industry in Syria using national and international public data sources. At the end of the 80ies, the pharmaceutical industry in Syria was very poor, covering 6% of the national needs. In less than 20 years, with the government support in terms of legal frame and strategic political engagement, the Syrian pharmaceutical industry finally covered almost 90% of the national needs, in terms of drugs, and exported drugs in around 52 Arabian countries. Beyond covering the local market, the main added values of this huge development consisted in exporting drugs in amount of 150 million dollars per year and providing jobs for 17000 Syrian people, out of which around 85% are women. Strong and weak points of the pharmaceutical sector are taken into consideration in the article and further interventions to support a sustainable development are proposed by the author. PMID:20945828

  14. Trace organic impurities in gaseous helium

    NASA Technical Reports Server (NTRS)

    Schehl, T. A.

    1973-01-01

    A program to determine trace organic impurities present in helium has been initiated. The impurities were concentrated in a cryogenic trap to permit detection and identification by a gas chromatographic-mass spectrometric technique. Gaseous helium (GHe) exhibited 63 GC flame ionization response peaks. Relative GC peak heights and identifications of 25 major impurities by their mass spectra are given. As an aid to further investigation, identities are proposed for 16 other components, and their mass spectra are given.

  15. Method for detecting trace impurities in gases

    DOEpatents

    Freund, Samuel M.; Maier, II, William B.; Holland, Redus F.; Beattie, Willard H.

    1981-01-01

    A technique for considerably improving the sensitivity and specificity of infrared spectrometry as applied to quantitative determination of trace impurities in various carrier or solvent gases is presented. A gas to be examined for impurities is liquefied and infrared absorption spectra of the liquid are obtained. Spectral simplification and number densities of impurities in the optical path are substantially higher than are obtainable in similar gas-phase analyses. Carbon dioxide impurity (.about.2 ppm) present in commercial Xe and ppm levels of Freon 12 and vinyl chloride added to liquefied air are used to illustrate the method.

  16. Method for detecting trace impurities in gases

    DOEpatents

    Freund, S.M.; Maier, W.B. II; Holland, R.F.; Beattie, W.H.

    A technique for considerably improving the sensitivity and specificity of infrared spectrometry as applied to quantitative determination of trace impurities in various carrier or solvent gases is presented. A gas to be examined for impurities is liquefied and infrared absorption spectra of the liquid are obtained. Spectral simplification and number densities of impurities in the optical path are substantially higher than are obtainable in similar gas-phase analyses. Carbon dioxide impurity (approx. 2 ppM) present in commercial Xe and ppM levels of Freon 12 and vinyl chloride added to liquefied air are used to illustrate the method.

  17. Mineral impurities in coal combustion

    SciTech Connect

    Raask, E.

    1985-01-01

    This article discusses the many and varied problems associated with coal combustion and suggests remedial measures to assist in producing electrical energy from coal more efficiently. Contents include: influence of coal mineral matter on boiler design; mineral impurities in coal; quality of coal utilized in power stations; coal grinding, abrasive fuel minerals and plant wear; particulates silicate minerals in boiler flame; reactions of nonsilicate impurities in coal flame; creation, capture and coalescence of particulate ash in boiler flame; slag viscosity; sintering, fusion and slagging propensities of coal ashes, adhesion of ash deposit on boiler tubes and refractory materials; deposition mechanisms, rate measurements and the mode of formation of boiler deposits; thermal radiation and heat transfer properties of boiler deposits; measures to combat boiler fouling and slagging; some specific ash-related problems with US Coals; use of additives in coal fired boilers; high temperature corrosion in coal-fired plants; ash impaction erosion wear; low temeprature fouling and corrosion; comparison of ash-related problems in pulverized fuel and other coal-fired systems.

  18. Identification of specific mRNA signatures as fingerprints for carcinogenesis in mice induced by genotoxic and nongenotoxic hepatocarcinogens.

    PubMed

    Kossler, Nadine; Matheis, Katja A; Ostenfeldt, Nina; Bach Toft, Dorthe; Dhalluin, Stéphane; Deschl, Ulrich; Kalkuhl, Arno

    2015-02-01

    Long-term rodent carcinogenicity studies for evaluation of chemicals and pharmaceuticals concerning their carcinogenic potential to humans are currently receiving critical revision. Additional data from mechanistic studies can support cancer risk assessment by clarifying the underlying mode of action. In the course of the IMI MARCAR project, a European consortium of EFPIA partners and academics, which aims to identify biomarkers for nongenotoxic carcinogenesis, a toxicogenomic mouse liver database was generated. CD-1 mice were orally treated for 3 and 14 days with 3 known genotoxic hepatocarcinogens: C.I. Direct Black 38, Dimethylnitrosamine and 4,4'-Methylenedianiline; 3 nongenotoxic hepatocarcinogens: 1,4-Dichlorobenzene, Phenobarbital sodium and Piperonyl butoxide; 4 nonhepatocarcinogens: Cefuroxime sodium, Nifedipine, Prazosin hydrochloride and Propranolol hydrochloride; and 3 compounds that show ambiguous results in genotoxicity testing: Cyproterone acetate, Thioacetamide and Wy-14643. By liver mRNA expression analysis using individual animal data, we identified 64 specific biomarker candidates for genotoxic carcinogens and 69 for nongenotoxic carcinogens for male mice at day 15. The majority of genotoxic carcinogen biomarker candidates possess functions in DNA damage response (eg, apoptosis, cell cycle progression, DNA repair). Most of the identified nongenotoxic carcinogen biomarker candidates are involved in regulation of cell cycle progression and apoptosis. The derived biomarker lists were characterized with respect to their dependency on study duration and gender and were successfully used to characterize carcinogens with ambiguous genotoxicity test results, such as Wy-14643. The identified biomarker candidates improve the mechanistic understanding of drug-induced effects on the mouse liver that result in hepatocellular adenomas and/or carcinomas in 2-year mouse carcinogenicity studies.

  19. Cryogenic Laser Calorimetry for Impurity Analysis

    NASA Technical Reports Server (NTRS)

    Swimm, R. T.

    1985-01-01

    The results of a one-year effort to determine the applicability of laser-calorimetric spectroscopy to the study of deep-level impurities in silicon are presented. Critical considerations for impurity analysis by laser-calorimetric spectroscopy are discussed, the design and performance of a cryogenic laser calorimeter is described, and measurements of background absorption in high-purity silicon are presented.

  20. Eliminating Impurity Traps in the Silane Process

    NASA Technical Reports Server (NTRS)

    Coleman, L. M.

    1982-01-01

    Redistribution reaction section of silane process progressively separates heavier parts of chlorosilane feedstock until light silane product is available for pyrolysis. Small amount of liquid containing impurities is withdrawn from processing stages in which trapping occurs and passed to earlier processing stage in which impurities tend to be removed via chemical reactions.

  1. [Bacterial pigment prodigiosin and its genotoxic effects].

    PubMed

    Gur'ianov, I D; Karamova, N S; Iusupova, D V; Gnezdilov, O I; Koshkarova, L A

    2013-01-01

    The prodigiosin preparation was isolated and purified from Serratia marcescens ATCC 9986, using chromatographic methods. The analysis of the preparation by TLC, NMR-spectrometry and mass-spectrometry allowed to confirm the red pigment fraction as the prodigiosin and detect its purity. Originally, the specific features of the toxic and genotoxic effects of prodigiosin and the possibility of induction of mutations by pigment in the cells of Salmonella typhimurium TA 100 (Ames test) and chromosome damage of mammalian erythroblasts have been determined.

  2. Mass spectrometry for small molecule pharmaceutical product development: a review.

    PubMed

    Gillespie, Todd A; Winger, Brian E

    2011-01-01

    Developing a pharmaceutical product has become increasingly difficult and expensive. With an emphasis on developing project knowledge at an earlier stage in development, the use of information-rich technologies (particularly MS) has continued to expand throughout product development. Continued improvements in LC/MS technology have widened the scope of utilizing MS methods for performing both qualitative and quantitative applications within product development. This review describes a multi-tiered MS strategy designed to enhance and accelerate the identification and profiling of both process- and degradation-related impurities in either the active pharmaceutical ingredient (API) or formulated product. Such impurities can be formed either during chemical synthesis, formulation, or during storage. This review provides an overview of a variety of orthogonal-mass spectrometric methodologies, namely GC/MS, LC/MS, and ICP-MS, in support of product development. This review is not meant to be all inclusive; however, it has been written to highlight the increasing use of hyphenated MS techniques within the pharmaceutical development area.

  3. Cytotoxicity and genotoxicity of biogenic silver nanoparticles

    NASA Astrophysics Data System (ADS)

    Lima, R.; Feitosa, L. O.; Ballottin, D.; Marcato, P. D.; Tasic, L.; Durán, N.

    2013-04-01

    Biogenic silver nanoparticles with 40.3 ± 3.5 nm size and negative surface charge (- 40 mV) were prepared with Fusarium oxysporum. The cytotoxicity of 3T3 cell and human lymphocyte were studied by a TaliTM image-based cytometer and the genotoxicity through Allium cepa and comet assay. The results of BioAg-w (washed) and BioAg-nw (unwashed) biogenic silver nanoparticles showed cytotoxicity exceeding 50 μg/mL with no significant differences of response in 5 and 10 μg/mL regarding viability. Results of genotoxicity at concentrations 5.0 and 10.0 ug/mL show some response, but at concentrations 0.5 and 1.0 μg/mL the washed and unwashed silver nanoparticles did not present any effect. This in an important result since in tests with different bacteria species and strains, including resistant, MIC (minimal inhibitory concentration) had good answers at concentrations less than 1.9 μg/mL. This work concludes that biogenic silver nanoparticles may be a promising option for antimicrobial use in the range where no cyto or genotoxic effect were observed. Furthermore, human cells were found to have a greater resistance to the toxic effects of silver nanoparticles in comparison with other cells.

  4. Bioavailability of genotoxic mixtures in soil

    SciTech Connect

    Bordelon, N.; Washburn, K.; He, L.Y.; Donnelly, K.C.

    1996-12-31

    Contaminated media at Superfund sites typically consist of complex mixtures of organic and inorganic chemicals which are difficult to characterize, both analytically and toxicologically. The current EPA approach to risk assessment uses solvent extraction to remove chemicals from the soil as a basis for estimating risk to the human population. However, contaminants that can be recovered with a solvent extract may not represent the mixture of chemicals that are available for human exposure. A procedure using an aqueous extraction was investigated to provide a more realistic estimate of what chemicals are bioavailable. A study was conducted with two soil types: creosote-contaminated sandy soil and coal tar-contaminated clay soil spiked with benzo(a)pyrene [B(a)P], and trinitrotoluene (TNT). Samples were extracted with hexane:acetone and water titrated to pH2 and pH7. HPLC analysis demonstrated up to 35% and 29% recovery of contaminants using the aqueous extracts. The estimated cancer risk for the aqueous extract was one order of magnitude less than that for solvent extracts. Analysis using the Salmonella/microsome assay demonstrated that solvent extracts were genotoxic (133 revertants/mg) with metabolic activation while aqueous extracts of clay soil were not genotoxic. Sandy soil showed genotoxicity both with and without metabolic activation. These results suggest that solvent extraction techniques may overestimate the concentration of contaminants that are available for human exposure and, hence, the risk associated with the presence of the contaminants in soil.

  5. Analytical control of process impurities in Pazopanib hydrochloride by impurity fate mapping.

    PubMed

    Li, Yan; Liu, David Q; Yang, Shawn; Sudini, Ravinder; McGuire, Michael A; Bhanushali, Dharmesh S; Kord, Alireza S

    2010-08-01

    Understanding the origin and fate of organic impurities within the manufacturing process along with a good control strategy is an integral part of the quality control of drug substance. Following the underlying principles of quality by design (QbD), a systematic approach to analytical control of process impurities by impurity fate mapping (IFM) has been developed and applied to the investigation and control of impurities in the manufacturing process of Pazopanib hydrochloride, an anticancer drug approved recently by the U.S. FDA. This approach requires an aggressive chemical and analytical search for potential impurities in the starting materials, intermediates and drug substance, and experimental studies to track their fate through the manufacturing process in order to understand the process capability for rejecting such impurities. Comprehensive IFM can provide elements of control strategies for impurities. This paper highlights the critical roles that analytical sciences play in the IFM process and impurity control. The application of various analytical techniques (HPLC, LC-MS, NMR, etc.) and development of sensitive and selective methods for impurity detection, identification, separation and quantification are highlighted with illustrative examples. As an essential part of the entire control strategy for Pazopanib hydrochloride, analytical control of impurities with 'meaningful' specifications and the 'right' analytical methods is addressed. In particular, IFM provides scientific justification that can allow for control of process impurities up-stream at the starting materials or intermediates whenever possible.

  6. Cytotoxicity and Genotoxicity of Panel of Single- and Multiwalled Carbon Nanotubes: In Vitro Effects on Normal Syrian Hamster Embryo and Immortalized V79 Hamster Lung Cells

    PubMed Central

    Darne, C.; Terzetti, F.; Coulais, C.; Fontana, C.; Binet, S.; Gaté, L.; Guichard, Y.

    2014-01-01

    Carbon nanotubes (CNTs) belong to a specific class of nanomaterials with unique properties. Because of their anticipated use in a wide range of industrial applications, their toxicity is of increasing concern. In order to determine whether specific physicochemical characteristics of CNTs are responsible for their toxicological effects, we investigated the cytotoxic and genotoxic effects of eight CNTs representative of each of the commonly encountered classes: single- SW-, double- DW-, and multiwalled (MW) CNTs, purified and raw. In addition, because most previous studies of CNT toxicity were conducted on immortalized cell lines, we decided to compare results obtained from V79 cells, an established cell line, with results from SHE (Syrian hamster embryo) cells, an easy-to-handle normal cell model. After 24 hours of treatment, MWCNTs were generally found to be more cytotoxic than SW- or DWCNTs. MWCNTs also provoked more genotoxic effects. No correlation could be found between CNT genotoxicity and metal impurities, length, surface area, or induction of cellular oxidative stress, but genotoxicity was seen to increase with CNT width. The toxicity observed for some CNTs leads us to suggest that they might also act by interfering with the cell cycle, but no significant differences were observed between normal and immortalized cells. PMID:25548561

  7. [Fourcroy and pharmaceutical journals].

    PubMed

    Bonnemain, Bruno

    2011-04-01

    Cadet de Gassicourt wrote a brief Eloge of Fourcroy in January 1810 as he died in December of 1809. Fourcroy had a major role concerning the new ideas on the place of pharmacy at the beginning of the 19th century. Fourcroy has had a key influence for the start of several pharmaceutical journals that wanted to emphasize the link between the new chemistry and pharmacy. None of these journals created with him will survive and one has to wait for 1909 to see the creation, without Fourcroy, of a new pharmaceutical journal, the "Journal de Pharmacie" that will become "Journal de Pharmacie et des Sciences accessoires", then "Journal de Pharmacie et de Chimie", before taking the name of"Annales Pharmaceutiques Françaises", the present official journal of the French Academy of Pharmacy. In spite of the essential role of Fourcroy at the start of pharmaceutical journals, Cadet did not even mention it in his Eloge of 1810.

  8. Possibilities and limitations of capillary electropherosis in pharmaceutical analysis.

    PubMed

    Borst, C; Belal, F; Holzgrabe, U

    2013-07-01

    Capillary electropherosis (CE) has been proved to be an important alternative to high-performance liquid chromatography (HPLC) in pharmaceutical analysis. However, when it comes to the analysis of compounds, e.g. impurities or metabolites, of very different polarity and water solubility CE and the related techniques come to its limits. This is demonstrated for the antipsychotic drug quetiapine and its impurities. A nonaqueous capillary electrophoresis (NACE) method was developed using a background electrolyte (BGE) composed of ammonium acetate dissolved in a mixture of acetonitrile and methanol including acetic acid to protonate the substances. The NACE method gave an excellent separation of all components. Since the conductivity of the BGE used in the NACE method is quite low and problems with current occurred, an additional aqueous capillary zone electrophoresis (CZE) method was developed for quetiapine and the two water soluble derivatives, using phosphate buffer as BGE. The method was validated with regard to repeatability and limit of detection.

  9. Paramagnetic Attraction of Impurity-Helium Solids

    NASA Technical Reports Server (NTRS)

    Bernard, E. P.; Boltnev, R. E.; Khmelenko, V. V.; Lee, D. M.

    2003-01-01

    Impurity-helium solids are formed when a mixture of impurity and helium gases enters a volume of superfluid helium. Typical choices of impurity gas are hydrogen deuteride, deuterium, nitrogen, neon and argon, or a mixture of these. These solids consist of individual impurity atoms and molecules as well as clusters of impurity atoms and molecules covered with layers of solidified helium. The clusters have an imperfect crystalline structure and diameters ranging up to 90 angstroms, depending somewhat on the choice of impurity. Immediately following formation the clusters aggregate into loosely connected porous solids that are submerged in and completely permeated by the liquid helium. Im-He solids are extremely effective at stabilizing high concentrations of free radicals, which can be introduced by applying a high power RF dis- charge to the impurity gas mixture just before it strikes the super fluid helium. Average concentrations of 10(exp 19) nitrogen atoms/cc and 5 x 10(exp 18) deuterium atoms/cc can be achieved this way. It shows a typical sample formed from a mixture of atomic and molecular hydrogen and deuterium. It shows typical sample formed from atomic and molecular nitrogen. Much of the stability of Im-He solids is attributed to their very large surface area to volume ratio and their permeation by super fluid helium. Heat resulting from a chance meeting and recombination of free radicals is quickly dissipated by the super fluid helium instead of thermally promoting the diffusion of other nearby free radicals.

  10. Method for protection against genotoxic mutagenesis

    DOEpatents

    Grdina, D.J.

    1999-02-09

    This research discloses a method and pharmaceutical for protecting against mutational damage in mammalian cells, irrespective of the nature of the mutagenic event or source of radiational or chemical insult or the like. 54 figs.

  11. GW-1000. GW Pharmaceuticals.

    PubMed

    Smith, Paul F

    2004-07-01

    GW Pharmaceuticals is developing GW-1000 (Sativex), a narrow ratio delta9-tetrahydrocannabinol:cannabidiol product for the potential treatment of multiple sclerosis, spinal cord injury, neurogenic pain and peripheral neuropathy. In March 2003, the company filed for approval for the treatment of MS with the UK Medicines Control Agency, and in May 2004, filed for new drug submission with Health Canada. PMID:15298072

  12. The extended pharmaceutical enterprise.

    PubMed

    Cavalla, David

    2003-03-15

    The availability of widespread contractual services led to the birth of the virtual company in the 1990s. As the concept has matured, and the biotechnology sector diversified, interchange of intellectual property in the form of collaborative and license arrangements opens up still further the opportunities for outsourced forms of pharmaceutical R&D. PMID:12623241

  13. Effects of chronic exposure to benzalkonium chloride in Oncorhynchus mykiss: cholinergic neurotoxicity, oxidative stress, peroxidative damage and genotoxicity.

    PubMed

    Antunes, S C; Nunes, B; Rodrigues, S; Nunes, R; Fernandes, J; Correia, A T

    2016-07-01

    Benzalkonium chloride (BAC) is one of the most used conservatives in pharmaceutical preparations. However, its use is limited to a small set of external use formulations, due to its high toxicity. Benzalkonium chloride effects are related to the potential exertion of deleterious effects, mediated via oxidative stress and through interaction with membrane enzymes, leading to cellular damage. To address the ecotoxicity of this specific compound rainbow trouts were chronically exposed to BAC at environmental relevant concentrations (ranging from 0.100 to 1.050mg/L), and the biological response of cholinergic neurotoxicity, modulation of the antioxidant defense, phase II metabolism, lipid peroxidation and genotoxicity was studied. The obtained results showed a dual pattern of antioxidant response, with significant alterations in catalase activity (starting at 0.180mg/L), and lipid peroxidation, for intermediate (0.180 and 0.324mg/L) concentrations. No significant alterations occurred for glutathione-S-transferases activity. An unexpected increased of the acetylcholinesterase activity was also recorded for the individuals exposed to higher concentrations of BAC (starting at 0.180mg/L). Furthermore, exposure to BAC resulted in the establishment of genotoxic alterations, observable (for the specific case of the comet assay results) for all tested BAC concentrations. However, and considering that the oxidative response was not devisable, other mechanisms may be involved in the genotoxic effects reported here. PMID:27280532

  14. An introduction to blocked impurity band detectors

    NASA Technical Reports Server (NTRS)

    Geist, Jon

    1988-01-01

    Blocked impurity band detectors fabricated using standard silicon technologies offer the possibility of combining high sensitivity and high accuracy in a single detector operating in a low background environment. The solid state photomultiplier described by Petroff et al., which is a new type of blocked impurity band detector, offers even higher sensitivity as well as operation in the visible spectral region. The principle of operation and possible application of blocked impurity band detectors for stellar seismology and the search for extra-solar planets are described.

  15. Genotoxicity of sodium metabisulfite in mouse tissues evaluated by the comet assay and the micronucleus test.

    PubMed

    Carvalho, Ivana M C M M; Melo Cavalcante, Ana A C; Dantas, Alisson F; Pereira, Danilo L A; Costa Rocha, Francisco C; Andrade, Teresinha J A S; Da Silva, Juliana

    2011-02-28

    Sodium metabisulfite (SMB, Na(2)S(2)O(5)) is widely used in the food and pharmaceutical industries, because of its ability to inhibit proliferation of microorganisms and its antioxidant properties. We have evaluated the genotoxic effects of SMB on different tissues of the mouse, by use of the comet assay (liver and blood cells) and the micronucleus test (blood and bone marrow cells). For all tissues, significant increases in damage index and damage frequency values were observed in the SMB-treated groups (1 and 2g/kg doses) compared to the control animals. The Kruskal-Wallis test showed that the mean micronucleus frequencies in peripheral blood and bone marrow cells of mice treated with the highest dose of SMB (2g/kg) showed significant increases, when compared with controls, and a significant reduction in the ratio of polychromatic to normochromatic erythrocytes was also seen. No difference in results between sexes was observed. Our results show that high oral doses of SMB may pose a genotoxic risk.

  16. Cytotoxicity and Genotoxicity Reporter Systems Based on the Use of Mammalian Cells

    NASA Astrophysics Data System (ADS)

    Baumstark-Khan, Christa; Hellweg, Christine E.; Reitz, Günther

    With the dramatic increase in the number of new agents arising from the chemical, pharmaceutical, and agricultural industries, there is an urgent need to develop assays for rapid evaluation of potential risks to man and environment. The panel of conventional tests used for cytotoxicity and genotoxicity and the strategies to progress from small scale assays to high content screening in toxicology are discussed. The properties of components necessary as sensors and reporters for new reporter assays, and the application of genetic strategies to design assays are reviewed. The concept of cellular reporters is based on the use of promoters of chemical stress-regulated genes ligated to a suitable luminescent or fluorescent reporter gene. Current reporter assays designed from constructs transferred into suitable cell lines are presented.

  17. Multiple magnetic impurities on surfaces: Scattering and quasiparticle interference

    NASA Astrophysics Data System (ADS)

    Mitchell, Andrew K.; Derry, Philip G.; Logan, David E.

    2015-06-01

    We study systems of multiple interacting quantum impurities deposited on a metallic surface in a three-dimensional host. For the real-space two-impurity problem, using numerical renormalization group calculations, a rich range of behavior is shown to arise due to the interplay between Kondo physics and effective Ruderman-Kittel-Kasuya-Yosida interactions—provided the impurity separation is small. Such calculations allow identification of the minimum impurity separation required for a description in terms of independent impurities, and thereby the onset of the "dilute-impurity limit" in many-impurity systems. A "dilute-cluster" limit is also identified in systems with higher impurity density, where interimpurity interactions are important only within independent clusters. We calculate the quasiparticle interference due to two and many impurities, and explore the consequences of the independent impurity and cluster paradigms. Our results provide a framework to investigate the effects of disorder due to interacting impurities at experimentally relevant surface coverages.

  18. Development of RP UPLC-TOF/MS, stability indicating method for omeprazole and its related substances by applying two level factorial design; and identification and synthesis of non-pharmacopoeial impurities.

    PubMed

    Jadhav, Sushant Bhimrao; Kumar, C Kiran; Bandichhor, Rakeshwar; Bhosale, P N

    2016-01-25

    A new UPLC-TOF/MS compatible, reverse phase-stability indicating method was developed for determination of Omeprazole (OMP) and its related substances in pharmaceutical dosage forms by implementing Design of Experiment (DoE) i.e. two level full factorial Design (2(3)+3 center points=11 experiments) to understand the Critical Method Parameters (CMP) and its relation with Critical Method Attribute (CMA); to ensure robustness of the method. The separation of eleven specified impurities including conversion product of OMP related compound F (13) and G (14) i.e. Impurity-I (1), OMP related compound-I (11) and OMP 4-chloro analog (12) was achieved in a single method on Acquity BEH shield RP18 100 × 2.1 mm, 1.7 μm column, with inlet filter (0.2 μm) using gradient elution and detector wavelength at 305 nm and validated in accordance with ICH guidelines and found to be accurate, precise, reproducible, robust and specific. The drug was found to degrade extensively in heat, humidity and acidic conditions and forms unknown degradation products during stability studies. The same method was used for LC-MS analysis to identify m/z and fragmentation of maximum unknown impurities (Non-Pharmacopoeial) i.e. Impurity-I (1), Impurity-III (3), Impurity-V (5) and Impurity-VIII (9) formed during stability studies. Based on the results, degradation pathway for the drug has been proposed and synthesis of identified impurities i.e. impurities (Impurity-I (1), Impurity-III (3), Impurity-V (5) and Impurity-VIII (9)) are discussed in detail to ensure in-depth understanding of OMP and its related impurities and optimum performance during lifetime of the product. PMID:26600119

  19. Development of RP UPLC-TOF/MS, stability indicating method for omeprazole and its related substances by applying two level factorial design; and identification and synthesis of non-pharmacopoeial impurities.

    PubMed

    Jadhav, Sushant Bhimrao; Kumar, C Kiran; Bandichhor, Rakeshwar; Bhosale, P N

    2016-01-25

    A new UPLC-TOF/MS compatible, reverse phase-stability indicating method was developed for determination of Omeprazole (OMP) and its related substances in pharmaceutical dosage forms by implementing Design of Experiment (DoE) i.e. two level full factorial Design (2(3)+3 center points=11 experiments) to understand the Critical Method Parameters (CMP) and its relation with Critical Method Attribute (CMA); to ensure robustness of the method. The separation of eleven specified impurities including conversion product of OMP related compound F (13) and G (14) i.e. Impurity-I (1), OMP related compound-I (11) and OMP 4-chloro analog (12) was achieved in a single method on Acquity BEH shield RP18 100 × 2.1 mm, 1.7 μm column, with inlet filter (0.2 μm) using gradient elution and detector wavelength at 305 nm and validated in accordance with ICH guidelines and found to be accurate, precise, reproducible, robust and specific. The drug was found to degrade extensively in heat, humidity and acidic conditions and forms unknown degradation products during stability studies. The same method was used for LC-MS analysis to identify m/z and fragmentation of maximum unknown impurities (Non-Pharmacopoeial) i.e. Impurity-I (1), Impurity-III (3), Impurity-V (5) and Impurity-VIII (9) formed during stability studies. Based on the results, degradation pathway for the drug has been proposed and synthesis of identified impurities i.e. impurities (Impurity-I (1), Impurity-III (3), Impurity-V (5) and Impurity-VIII (9)) are discussed in detail to ensure in-depth understanding of OMP and its related impurities and optimum performance during lifetime of the product.

  20. Isolation, Characterization of a Potential Degradation Product of Aspirin and an HPLC Method for Quantitative Estimation of Its Impurities.

    PubMed

    Acharya, Subasranjan; Daniel, Alex; Gyadangi, Bharath; Ramsamy, Sriramulu

    2015-10-01

    In this work, a new degradation product of Aspirin was isolated, characterized and analyzed along with other impurities. New unknown degradation product referred as UP was observed exceeding the limit of ICH Q3B identification thresholds in the stability study of Aspirin and Dipyridamole capsule. The UP isolated from the thermal degradation sample was further studied by IR, Mass and (1)H NMR spectrometry, revealing structural similarities with the parent molecule. Finally, UP was identified as a new compound generated from the interaction of Aspirin and Salicylic acid to form a dehydrated product. A specific HPLC method was developed and validated for the analysis of UP and other Aspirin impurities (A, B, C, E and other unknown degradation products). The proposed method was successfully employed for estimation of Aspirin impurities in a pharmaceutical preparation of Aspirin (Immediate Release) and Dipyridamole (Extended Release) Capsules.

  1. Genotoxicity of pyrroloquinoline quinone (PQQ) disodium salt (BioPQQ™).

    PubMed

    Nakano, Masahiko; Suzuki, Hiroshi; Imamura, Tadashi; Lau, Annette; Lynch, Barry

    2013-11-01

    The genotoxic potential of pyrroloquinoline quinone (PQQ) disodium salt (BioPQQ™) was evaluated in a battery of genotoxicity tests. The results of the bacterial mutation assay (Ames test) were negative. Weak positive results were obtained in 2 separate in vitro chromosomal aberration test in Chinese hamster lung (CHL) fibroblasts. Upon testing in an in vitro chromosomal aberration test in human peripheral blood lymphocytes, no genotoxic activity of PQQ was noted. In the in vivo micronucleus assay in mice, PQQ at doses up to 2,000 mg/kg body weight demonstrated that no genotoxic effects are expressed in vivo in bone marrow erythrocytes. The weak responses in the in vitro test CHL cells were considered of little relevance under conditions of likely human exposure. PQQ disodium was concluded to have no genotoxic activity in vivo.

  2. Models for impurity effects in tokamaks

    SciTech Connect

    Hogan, J.T.

    1980-03-01

    Models for impurity effects in tokamaks are described with an emphasis on the relationship between attainment of high ..beta.. and impurity problems. We briefly describe the status of attempts to employ neutral beam heating to achieve high ..beta.. in tokamaks and propose a qualitative model for the mechanism by which heavy metal impurities may be produced in the startup phase of the discharge. We then describe paradoxes in impurity diffusion theory and discuss possible resolutions in terms of the effects of large-scale islands and sawtooth oscillations. Finally, we examine the prospects for the Zakharov-Shafranov catastrophe (long time scale disintegration of FCT equilibria) in the context of present and near-term experimental capability.

  3. Influence of magnetic shear on impurity transport

    SciTech Connect

    Nordman, H.; Fueloep, T.; Candy, J.; Strand, P.; Weiland, J.

    2007-05-15

    The magnetic shear dependence of impurity transport in tokamaks is studied using a quasilinear fluid model for ion temperature gradient (ITG) and trapped electron (TE) mode driven turbulence in the collisionless limit and the results are compared with nonlinear gyrokinetic results using GYRO [J. Candy and R. E. Waltz, J. Comput. Phys 186, 545 (2003)]. It is shown that the impurity transport is sensitive to the magnetic shear, in particular for weak, negative, and large positive shear where a strong reduction of the effective impurity diffusivity is obtained. The fluid and gyrokinetic results are in qualitative agreement, with the gyrokinetic diffusivities typically a factor 2 larger than the fluid diffusivities. The steady state impurity profiles in source-free plasmas are found to be considerably less peaked than the electron density profiles for moderate shear. Comparisons between anomalous and neoclassical transport predictions are performed for ITER-like profiles [R. Aymar, P. Barabaschi, and Y. Shimomura, Plasma Phys. Controlled Fusion 44, 519 (2002)].

  4. Numerical Studies of Impurities in Fusion Plasmas

    DOE R&D Accomplishments Database

    Hulse, R. A.

    1982-09-01

    The coupled partial differential equations used to describe the behavior of impurity ions in magnetically confined controlled fusion plasmas require numerical solution for cases of practical interest. Computer codes developed for impurity modeling at the Princeton Plasma Physics Laboratory are used as examples of the types of codes employed for this purpose. These codes solve for the impurity ionization state densities and associated radiation rates using atomic physics appropriate for these low-density, high-temperature plasmas. The simpler codes solve local equations in zero spatial dimensions while more complex cases require codes which explicitly include transport of the impurity ions simultaneously with the atomic processes of ionization and recombination. Typical applications are discussed and computational results are presented for selected cases of interest.

  5. Impurity induced resistivity upturns in underdoped cuprates

    NASA Astrophysics Data System (ADS)

    Das, Nabyendu; Singh, Navinder

    2016-01-01

    Impurity induced low temperature upturns in both the ab-plane and the c-axis dc-resistivities of cuprates in the pseudogap state have been observed in experiments. We provide an explanation of this phenomenon by incorporating impurity scattering of the charge carriers within a phenomenological model proposed by Yang, Rice and Zhang. The scattering between charge carriers and the impurity atom is considered within the lowest order Born approximation. Resistivity is calculated within Kubo formula using the impurity renormalized spectral functions. Using physical parameters for cuprates, we describe qualitative features of the upturn phenomena and its doping evolution that coincides with the experimental findings. We stress that this effect is largely due to the strong electronic correlations.

  6. Genotoxicity testing of esterified propoxylated glycerol (EPG).

    PubMed

    Bechtel, David H

    2014-12-01

    Four versions of esterified propoxylated glycerols (EPGs) were evaluated for potential genotoxicity using a range of in vitro and in vivo assays. H-EPG-05 HR/SO 9:1, H-EPG-05 soyate, and H-EPG-14 soyate were non-mutagenic in reverse mutation assays (maximum concentration 1000 μg/plate) using Salmonella typhimurium and Escherichia coli. Heated and unheated H-EPG-05 HR/SO 9:1 and EPG-05 HR/ST 45:55 were likewise non-mutagenic in reverse mutation assays in S. typhimurium strains TA98 and TA100 (maximum concentration 5000 μg/plate). H-EPG-05 HR/SO 9:1, H-EPG-05 soyate, and H-EPG-14 soyate, were devoid of mutagenic activity in a mouse lymphoma assay in L5178Y tk +/- cells (maximum concentration 200 μg/plate for H-EPG-05 HR/SO 9:1; 100 μg/plate for H-EPG-05 soyate and H-EPG-14 soyate), and a chromosomal aberration test using human lymphocytes (maximum concentration 50 μg/plate for H-EPG-05 HR/SO 9:1 and H-EPG-05 soyate; 60 μg/plate for H-EPG-14 soyate). All assays were conducted with and without metabolic activation. Additionally, H-EPG-05 HR/SO 9:1, H-EPG-05 soyate, and H-EPG-14 soyate were non-genotoxic in unscheduled DNA synthesis tests in rats (maximum dose 2000 mg/kg). Based on the results of these assays it was concluded that these versions of EPG were not genotoxic under any of the conditions of the assays performed.

  7. Genotoxicity studies on licorice flavonoid oil (LFO).

    PubMed

    Nakagawa, K; Hidaka, T; Kitano, M; Asakura, M; Kamigaito, T; Noguchi, T; Hosoe, K

    2008-07-01

    Licorice flavonoid oil (LFO) is a new functional food ingredient. In this study, the genotoxicity of LFO was investigated using a test battery of three different methods. In a reverse mutation assay using four Salmonella typhimurium strains and Escherichia coli, LFO did not increase the number of revertant colonies in any tester strain with or without metabolic activation by rat liver S9 mix. In a chromosomal aberration test using Chinese hamster lung (CHL/IU) cells, LFO did not induce any chromosomal aberrations either in the short period test without rat liver S9 mix or in the continuous treatment (24 h or 48 h) test. However, in the short-period test with rat liver S9 mix, LFO induced structural chromosomal aberrations at concentrations higher than 0.6 mg/mL. A bone marrow micronucleus test using male F344 rats was initially conducted. The animals were dosed by oral gavage at doses up to 5000 mg/kg/day. No significant or dose-dependent increases in the frequency of micronucleated polychromatic erythrocytes (MNPCE) were observed and the high dose suppressed the ratio of polychromatic erythrocytes (PCE) to total erythrocytes. Subsequently, a liver and peripheral blood micronucleus test using male F344 rats was conducted. No micronuclei induction either in hepatocytes or PCE was observed even at the highest dose of 5000 mg/kg/day. From the findings obtained from the genotoxicity assays performed in this study and the published pharmacokinetic studies of LFO, it appears unlikely that dietary consumption of LFO will present any genotoxic hazard to humans.

  8. Evaluation of the genotoxicity of cellulose nanofibers

    PubMed Central

    de Lima, Renata; Feitosa, Leandro Oliveira; Maruyama, Cintia Rodrigues; Barga, Mariana Abreu; Yamawaki, Patrícia Cristina; Vieira, Isolda Jesus; Teixeira, Eliangela M; Corrêa, Ana Carolina; Mattoso, Luiz Henrique Caparelli; Fraceto, Leonardo Fernandes

    2012-01-01

    Background Agricultural products and by products provide the primary materials for a variety of technological applications in diverse industrial sectors. Agro-industrial wastes, such as cotton and curaua fibers, are used to prepare nanofibers for use in thermoplastic films, where they are combined with polymeric matrices, and in biomedical applications such as tissue engineering, amongst other applications. The development of products containing nanofibers offers a promising alternative for the use of agricultural products, adding value to the chains of production. However, the emergence of new nanotechnological products demands that their risks to human health and the environment be evaluated. This has resulted in the creation of the new area of nanotoxicology, which addresses the toxicological aspects of these materials. Purpose and methods Contributing to these developments, the present work involved a genotoxicological study of different nanofibers, employing chromosomal aberration and comet assays, as well as cytogenetic and molecular analyses, to obtain preliminary information concerning nanofiber safety. The methodology consisted of exposure of Allium cepa roots, and animal cell cultures (lymphocytes and fibroblasts), to different types of nanofibers. Negative controls, without nanofibers present in the medium, were used for comparison. Results The nanofibers induced different responses according to the cell type used. In plant cells, the most genotoxic nanofibers were those derived from green, white, and brown cotton, and curaua, while genotoxicity in animal cells was observed using nanofibers from brown cotton and curaua. An important finding was that ruby cotton nanofibers did not cause any significant DNA breaks in the cell types employed. Conclusion This work demonstrates the feasibility of determining the genotoxic potential of nanofibers derived from plant cellulose to obtain information vital both for the future usage of these materials in

  9. Genotoxicity of Anesthetics Evaluated In Vivo (Animals)

    PubMed Central

    Braz, Mariana G.; Karahalil, Bensu

    2015-01-01

    The anesthesia has been improved all over the years. However, it can have impact on health, in both patients and animals anesthetized, as well as professionals exposed to inhaled anesthetics. There is continuing effort to understand the possible effects of anesthetics at molecular levels. Knowing the effects of anesthetic agents on genetic material could be a valuable basic support to better understand the possible mechanisms of these agents. Thus, the purpose of this review is to provide an overview on the genotoxic potential, evaluated in animal models, of many anesthetics that have already been used and those currently used in anesthesia. PMID:26199936

  10. Precipitating Chromium Impurities in Silicon Wafers

    NASA Technical Reports Server (NTRS)

    Salama, A. M.

    1982-01-01

    Two new treatments for silicon wafers improve solar-cell conversion efficiency by precipitating electrically-active chromium impurities. One method is simple heat treatment. Other involves laser-induced damage followed by similar heat treatment. Chromium is one impurity of concern in metallurgical-grade silicon for solar cells. In new treatment, chromium active centers are made electrically inactive by precipitating chromium from solid solution, enabling use of lower grade, lower cost silicon in cell manufacture.

  11. Role of impurities in fusion plasmas

    SciTech Connect

    Tokar, M. Z.

    2008-10-15

    The role of impurity at the plasma edge of fusion devices is considered by analysing the influence on radiation losses and anomalous transport of particle and energy. The conditions critical for the development of radiative instabilities leading to the formation of detachment and MARFE and those necessary for the creation of a stable radiating edge, protecting the wall elements from intensive heat loads, are analyzed. Mechanisms responsible for anomalous transport suppression with impurity seeding are elucidated.

  12. Method of removing phosphorus impurities from yellowcake

    SciTech Connect

    Brown, R.A.; Winkley, D.C.

    1983-04-05

    PhospHorus impurities are removed from yellowcake by dissolving it in hydrochloric or sulfuric acid to a U/sub 3/O/sub 88/ assay of at least 150 g/l at a pH of 2; precipitating uranium peroxide W hydrogen peroxide while keeping the pH between 2.2 and 2.6 and recovering the uranium peroxide from the phosphorus impurities remaining in solution.

  13. Isolation and characterization of degradation products of citalopram and process-related impurities using RP-HPLC.

    PubMed

    Rao, Ramisetti Nageswara; Raju, Ale Narasa; Narsimha, Ramaram

    2008-06-01

    A reversed-phase high-performance liquid chromatographic method for simultaneous separation and determination of citalopram hydrobromide and its process impurities in bulk drugs and pharmaceutical formulations was developed. The separation was accomplished on an Inertsil ODS 3V (250x4.6 mm; particle size 5 mum) column using 0.3% diethylamine (pH = 4.70) and methanol/acetonitrile (55:45 v/v) as mobile phase in a gradient elution mode. The eluents were monitored by a photodiode array detector set at 225 nm. The chromatographic behavior of all the related substances was examined under variable conditions of different solvents, buffer concentrations, and pH. The method was validated in terms of accuracy, precision, and linearity. The method could be of use not only for rapid and routine evaluation of the quality of citalopram in bulk drug manufacturing units but also for the detection of its impurities in pharmaceutical formulations. Three unknown impurities were consistently observed during the analysis of different batches of citalopram. Forced degradation of citalopram was carried out under thermal, photo, acidic, alkaline, and peroxide conditions. The degradation products and unknown impurities were isolated and characterized by ESI-MS/MS, (1)H NMR, and FT-IR spectroscopy.

  14. Isolation and characterization of degradation products of citalopram and process-related impurities using RP-HPLC.

    PubMed

    Rao, Ramisetti Nageswara; Raju, Ale Narasa; Narsimha, Ramaram

    2008-06-01

    A reversed-phase high-performance liquid chromatographic method for simultaneous separation and determination of citalopram hydrobromide and its process impurities in bulk drugs and pharmaceutical formulations was developed. The separation was accomplished on an Inertsil ODS 3V (250x4.6 mm; particle size 5 mum) column using 0.3% diethylamine (pH = 4.70) and methanol/acetonitrile (55:45 v/v) as mobile phase in a gradient elution mode. The eluents were monitored by a photodiode array detector set at 225 nm. The chromatographic behavior of all the related substances was examined under variable conditions of different solvents, buffer concentrations, and pH. The method was validated in terms of accuracy, precision, and linearity. The method could be of use not only for rapid and routine evaluation of the quality of citalopram in bulk drug manufacturing units but also for the detection of its impurities in pharmaceutical formulations. Three unknown impurities were consistently observed during the analysis of different batches of citalopram. Forced degradation of citalopram was carried out under thermal, photo, acidic, alkaline, and peroxide conditions. The degradation products and unknown impurities were isolated and characterized by ESI-MS/MS, (1)H NMR, and FT-IR spectroscopy. PMID:18481321

  15. EU pharmaceutical expenditure forecast

    PubMed Central

    Urbinati, Duccio; Rémuzat, Cécile; Kornfeld, Åsa; Vataire, Anne-Lise; Cetinsoy, Laurent; Aballéa, Samuel; Mzoughi, Olfa; Toumi, Mondher

    2014-01-01

    Background and Objectives With constant incentives for healthcare payers to contain their pharmaceutical budgets, forecasting has become critically important. Some countries have, for instance, developed pharmaceutical horizon scanning units. The objective of this project was to build a model to assess the net effect of the entrance of new patented medicinal products versus medicinal products going off-patent, with a defined forecast horizon, on selected European Union (EU) Member States’ pharmaceutical budgets. This model took into account population ageing, as well as current and future country-specific pricing, reimbursement, and market access policies (the project was performed for the European Commission; see http://ec.europa.eu/health/healthcare/key_documents/index_en.htm). Method In order to have a representative heterogeneity of EU Member States, the following countries were selected for the analysis: France, Germany, Greece, Hungary, Poland, Portugal, and the United Kingdom. A forecasting period of 5 years (2012–2016) was chosen to assess the net pharmaceutical budget impact. A model for generics and biosimilars was developed for each country. The model estimated a separate and combined effect of the direct and indirect impacts of the patent cliff. A second model, estimating the sales development and the risk of development failure, was developed for new drugs. New drugs were reviewed individually to assess their clinical potential and translate it into commercial potential. The forecast was carried out according to three perspectives (healthcare public payer, society, and manufacturer), and several types of distribution chains (retail, hospital, and combined retail and hospital). Probabilistic and deterministic sensitivity analyses were carried out. Results According to the model, all countries experienced drug budget reductions except Poland (+€41 million). Savings were expected to be the highest in the United Kingdom (−€9,367 million), France

  16. Mechanisms of impurity diffusion in rutile

    SciTech Connect

    Peterson, N.L.; Sasaki, J.

    1984-01-01

    Tracer diffusion of /sup 46/Sc, /sup 51/Cr, /sup 54/Mn, /sup 59/Fe, /sup 60/Co, /sup 63/Ni, and /sup 95/Zr, was measured as functions of crystal orientation, temperature, and oxygen partial pressure in rutile single crystals using the radioactive tracer sectioning technique. Compared to cation self-diffusion, divalent impurities (e.g., Co and Ni) diffuse extremely rapidly in TiO/sub 2/ and exhibit a large anisotropy in the diffusion behavior; divalent-impurity diffusion parallel to the c-axis is much larger than it is perpendicular to the c-axis. The diffusion of trivalent impurity ions (Sc and Cr) and tetravalent impurity ions (Zr) is similar to cation self-diffusion, as a function of temperature and of oxygen partial pressure. The divalent impurity ions Co and Ni apparently diffuse as interstitial ions along open channels parallel to the c-axis. The results suggest that Sc, Cr, and Zr ions diffuse by an interstitialcy mechanism involving the simultaneous and cooperative migration of tetravalent interstitial titanium ions and the tracer-impurity ions. Iron ions diffused both as divalent and as trivalent ions. 8 figures.

  17. Photolytic fate and genotoxicity of benzophenone-derived compounds and their photodegradation mixtures in the aqueous environment.

    PubMed

    Kotnik, Kristina; Kosjek, Tina; Žegura, Bojana; Filipič, Metka; Heath, Ester

    2016-03-01

    This study investigates the environmental fate of eight benzophenone derivatives (the pharmaceutical ketoprofen, its phototransformation products 3-ethylbenzophenone and 3-acetylbenzophenone, and five benzophenone-type UV filters) by evaluating their photolytic behaviour. In addition, the genotoxicity of these compounds and the produced photodegradation mixtures was studied. Laboratory-scale irradiation experiments using a medium pressure UV lamp revealed that photodegradation of benzophenones follows pseudo-first-order kinetics. Ketoprofen was the most photolabile (t1/2 = 0.8 min), while UV filters were more resistant to UV light with t1/2 between 17 and 99 h. The compounds were also exposed to irradiation by natural sunlight and showed similar photostability as predicted under laboratory conditions. Solar photodegradation experiments were performed in distilled water, lake and seawater, and revealed that photosensitizers present in natural waters significantly affect the photolytic behaviour of the investigated compounds. In this case, the presence of lake water resulted in accelerated photodecomposition, while seawater showed different effects on photodegradation, depending on a compound. Further, it was shown that the transformation products of ketoprofen 3-ethylbenzophenone and 3-acetylbenzophenone were formed under environmental conditions when ketoprofen was exposed to natural sunlight. Genotoxicity testing of parent benzophenone compounds using the SOS/umuC assay revealed that UV filters exhibited weak genotoxic activity in the presence of a metabolic activation system, however the concentrations tested were much higher than found in the environment (≥125 μg mL(-1)). After irradiation of benzophenones, the produced photodegradation mixtures showed that, with the exception of benzophenone that exhibited weak genotoxic activity, all the other compounds tested did not elicit any activity when exposed to UV light. PMID:26766022

  18. Photolytic fate and genotoxicity of benzophenone-derived compounds and their photodegradation mixtures in the aqueous environment.

    PubMed

    Kotnik, Kristina; Kosjek, Tina; Žegura, Bojana; Filipič, Metka; Heath, Ester

    2016-03-01

    This study investigates the environmental fate of eight benzophenone derivatives (the pharmaceutical ketoprofen, its phototransformation products 3-ethylbenzophenone and 3-acetylbenzophenone, and five benzophenone-type UV filters) by evaluating their photolytic behaviour. In addition, the genotoxicity of these compounds and the produced photodegradation mixtures was studied. Laboratory-scale irradiation experiments using a medium pressure UV lamp revealed that photodegradation of benzophenones follows pseudo-first-order kinetics. Ketoprofen was the most photolabile (t1/2 = 0.8 min), while UV filters were more resistant to UV light with t1/2 between 17 and 99 h. The compounds were also exposed to irradiation by natural sunlight and showed similar photostability as predicted under laboratory conditions. Solar photodegradation experiments were performed in distilled water, lake and seawater, and revealed that photosensitizers present in natural waters significantly affect the photolytic behaviour of the investigated compounds. In this case, the presence of lake water resulted in accelerated photodecomposition, while seawater showed different effects on photodegradation, depending on a compound. Further, it was shown that the transformation products of ketoprofen 3-ethylbenzophenone and 3-acetylbenzophenone were formed under environmental conditions when ketoprofen was exposed to natural sunlight. Genotoxicity testing of parent benzophenone compounds using the SOS/umuC assay revealed that UV filters exhibited weak genotoxic activity in the presence of a metabolic activation system, however the concentrations tested were much higher than found in the environment (≥125 μg mL(-1)). After irradiation of benzophenones, the produced photodegradation mixtures showed that, with the exception of benzophenone that exhibited weak genotoxic activity, all the other compounds tested did not elicit any activity when exposed to UV light.

  19. Pharmaceutical spray freeze drying.

    PubMed

    Wanning, Stefan; Süverkrüp, Richard; Lamprecht, Alf

    2015-07-01

    Pharmaceutical spray-freeze drying (SFD) includes a heterogeneous set of technologies with primary applications in apparent solubility enhancement, pulmonary drug delivery, intradermal ballistic administration and delivery of vaccines to the nasal mucosa. The methods comprise of three steps: droplet generation, freezing and sublimation drying, which can be matched to the requirements given by the dosage form and route of administration. The objectives, various methods and physicochemical and pharmacological outcomes have been reviewed with a scope including related fields of science and technology.

  20. Trade, TRIPS, and pharmaceuticals.

    PubMed

    Smith, Richard D; Correa, Carlos; Oh, Cecilia

    2009-02-21

    The World Trade Organization's Agreement on Trade-Related Aspects of Intellectual Property Rights (TRIPS) set global minimum standards for the protection of intellectual property, substantially increasing and expanding intellectual-property rights, and generated clear gains for the pharmaceutical industry and the developed world. The question of whether TRIPS generates gains for developing countries, in the form of increased exports, is addressed in this paper through consideration of the importance of pharmaceuticals in health-care trade, outlining the essential requirements, implications, and issues related to TRIPS, and TRIPS-plus, in which increased restrictions are imposed as part of bilateral free-trade agreements. TRIPS has not generated substantial gains for developing countries, but has further increased pharmaceutical trade in developed countries. The unequal trade between developed and developing countries (ie, exporting and importing high-value patented drugs, respectively) raises the issue of access to medicines, which is exacerbated by TRIPS-plus provisions, although many countries have not even enacted provision for TRIPS flexibilities. Therefore this paper focuses on options that are available to the health community for negotiation to their advantage under TRIPS, and within the presence of TRIPS-plus.

  1. Trade, TRIPS, and pharmaceuticals.

    PubMed

    Smith, Richard D; Correa, Carlos; Oh, Cecilia

    2009-02-21

    The World Trade Organization's Agreement on Trade-Related Aspects of Intellectual Property Rights (TRIPS) set global minimum standards for the protection of intellectual property, substantially increasing and expanding intellectual-property rights, and generated clear gains for the pharmaceutical industry and the developed world. The question of whether TRIPS generates gains for developing countries, in the form of increased exports, is addressed in this paper through consideration of the importance of pharmaceuticals in health-care trade, outlining the essential requirements, implications, and issues related to TRIPS, and TRIPS-plus, in which increased restrictions are imposed as part of bilateral free-trade agreements. TRIPS has not generated substantial gains for developing countries, but has further increased pharmaceutical trade in developed countries. The unequal trade between developed and developing countries (ie, exporting and importing high-value patented drugs, respectively) raises the issue of access to medicines, which is exacerbated by TRIPS-plus provisions, although many countries have not even enacted provision for TRIPS flexibilities. Therefore this paper focuses on options that are available to the health community for negotiation to their advantage under TRIPS, and within the presence of TRIPS-plus. PMID:19167054

  2. In silico toxicology for the pharmaceutical sciences.

    PubMed

    Valerio, Luis G

    2009-12-15

    The applied use of in silico technologies (a.k.a. computational toxicology, in silico toxicology, computer-assisted tox, e-tox, i-drug discovery, predictive ADME, etc.) for predicting preclinical toxicological endpoints, clinical adverse effects, and metabolism of pharmaceutical substances has become of high interest to the scientific community and the public. The increased accessibility of these technologies for scientists and recent regulations permitting their use for chemical risk assessment supports this notion. The scientific community is interested in the appropriate use of such technologies as a tool to enhance product development and safety of pharmaceuticals and other xenobiotics, while ensuring the reliability and accuracy of in silico approaches for the toxicological and pharmacological sciences. For pharmaceutical substances, this means active and impurity chemicals in the drug product may be screened using specialized software and databases designed to cover these substances through a chemical structure-based screening process and algorithm specific to a given software program. A major goal for use of these software programs is to enable industry scientists not only to enhance the discovery process but also to ensure the judicious use of in silico tools to support risk assessments of drug-induced toxicities and in safety evaluations. However, a great amount of applied research is still needed, and there are many limitations with these approaches which are described in this review. Currently, there is a wide range of endpoints available from predictive quantitative structure-activity relationship models driven by many different computational software programs and data sources, and this is only expected to grow. For example, there are models based on non-proprietary and/or proprietary information specific to assessing potential rodent carcinogenicity, in silico screens for ICH genetic toxicity assays, reproductive and developmental toxicity, theoretical

  3. In silico toxicology for the pharmaceutical sciences

    SciTech Connect

    Valerio, Luis G.

    2009-12-15

    The applied use of in silico technologies (a.k.a. computational toxicology, in silico toxicology, computer-assisted tox, e-tox, i-drug discovery, predictive ADME, etc.) for predicting preclinical toxicological endpoints, clinical adverse effects, and metabolism of pharmaceutical substances has become of high interest to the scientific community and the public. The increased accessibility of these technologies for scientists and recent regulations permitting their use for chemical risk assessment supports this notion. The scientific community is interested in the appropriate use of such technologies as a tool to enhance product development and safety of pharmaceuticals and other xenobiotics, while ensuring the reliability and accuracy of in silico approaches for the toxicological and pharmacological sciences. For pharmaceutical substances, this means active and impurity chemicals in the drug product may be screened using specialized software and databases designed to cover these substances through a chemical structure-based screening process and algorithm specific to a given software program. A major goal for use of these software programs is to enable industry scientists not only to enhance the discovery process but also to ensure the judicious use of in silico tools to support risk assessments of drug-induced toxicities and in safety evaluations. However, a great amount of applied research is still needed, and there are many limitations with these approaches which are described in this review. Currently, there is a wide range of endpoints available from predictive quantitative structure-activity relationship models driven by many different computational software programs and data sources, and this is only expected to grow. For example, there are models based on non-proprietary and/or proprietary information specific to assessing potential rodent carcinogenicity, in silico screens for ICH genetic toxicity assays, reproductive and developmental toxicity, theoretical

  4. Genotoxicity studies performed in the ecuadorian population.

    PubMed

    Paz-Y-Miño, César; Cumbal, Nadia; Sánchez, María Eugenia

    2012-01-01

    Genotoxicity studies in Ecuador have been carried out during the past two decades. The focuses of the research were mainly the area of environmental issues, where the populations have been accidentally exposed to contaminants and the area of occupational exposure of individuals at the workplace. This paper includes studies carried out in the population of the Amazon region, a zone known for its rich biodiversity as well as for the ecological damage caused by oil spills and chemical sprayings whose consequences continue to be controversial. Additionally, we show the results of studies comprised of individuals occupationally exposed to toxic agents in two very different settings: flower plantation workers exposed to pesticide mixtures and X-ray exposure of hospital workers. The results from these studies confirm that genotoxicity studies can help evaluate current conditions and prevent further damage in the populations exposed to contaminants. As such, they are evidence of the need for biomonitoring employers at risk, stricter law enforcement regarding the use of pesticides, and increasingly conscientious oil extraction activities.

  5. Genotoxicity Studies Performed in the Ecuadorian Population

    PubMed Central

    Paz-y-Miño, César; Cumbal, Nadia; Sánchez, María Eugenia

    2012-01-01

    Genotoxicity studies in Ecuador have been carried out during the past two decades. The focuses of the research were mainly the area of environmental issues, where the populations have been accidentally exposed to contaminants and the area of occupational exposure of individuals at the workplace. This paper includes studies carried out in the population of the Amazon region, a zone known for its rich biodiversity as well as for the ecological damage caused by oil spills and chemical sprayings whose consequences continue to be controversial. Additionally, we show the results of studies comprised of individuals occupationally exposed to toxic agents in two very different settings: flower plantation workers exposed to pesticide mixtures and X-ray exposure of hospital workers. The results from these studies confirm that genotoxicity studies can help evaluate current conditions and prevent further damage in the populations exposed to contaminants. As such, they are evidence of the need for biomonitoring employers at risk, stricter law enforcement regarding the use of pesticides, and increasingly conscientious oil extraction activities. PMID:22496977

  6. Residual-QSAR. Implications for genotoxic carcinogenesis

    PubMed Central

    2011-01-01

    Introduction Both main types of carcinogenesis, genotoxic and epigenetic, were examined in the context of non-congenericity and similarity, respectively, for the structure of ligand molecules, emphasizing the role of quantitative structure-activity relationship ((Q)SAR) studies in accordance with OECD (Organization for Economic and Cooperation Development) regulations. The main purpose of this report involves electrophilic theory and the need for meaningful physicochemical parameters to describe genotoxicity by a general mechanism. Residual-QSAR Method The double or looping multiple linear correlation was examined by comparing the direct and residual structural information against the observed activity. A self-consistent equation of observed-computed activity was assumed to give maximum correlation efficiency for those situations in which the direct correlations gave non-significant statistical information. Alternatively, it was also suited to describe slow and apparently non-noticeable cancer phenomenology, with special application to non-congeneric molecules involved in genotoxic carcinogenesis. Application and Discussions The QSAR principles were systematically applied to a given pool of molecules with genotoxic activity in rats to elucidate their carcinogenic mechanisms. Once defined, the endpoint associated with ligand-DNA interaction was used to select variables that retained the main Hansch physicochemical parameters of hydrophobicity, polarizability and stericity, computed by the custom PM3 semiempirical quantum method. The trial and test sets of working molecules were established by implementing the normal Gaussian principle of activities that applies when the applicability domain is not restrained to the congeneric compounds, as in the present study. The application of the residual, self-consistent QSAR method and the factor (or average) method yielded results characterized by extremely high and low correlations, respectively, with the latter resembling

  7. Genotoxicity of dental resin polymerization initiators in vitro.

    PubMed

    Nomura, Y; Teshima, W; Kawahara, T; Tanaka, N; Ishibashi, H; Okazaki, M; Arizono, K

    2006-01-01

    The polymerization initiators for resins cured using visible light usually consist of a photosensitizer, primarily camphorquinone (CQ), and a reducing agent, which is often a tertiary amine (DMPT, DMAEMA), while the initiator used for self-curing resins consists of benzoyl peroxide (BPO) and a tertiary amine (DMPT). The genotoxicities of camphorquinone (CQ), benzoyl peroxide (BPO), dimethyl-para-toluidine (DMPT), 2-dimethylamino-ethyl-methacrylate (DMAEMA), and 1-allyl-2-thiourea (ATU) were examined using the bioluminescent bacterial genotoxicity test. 4-Nitroquinoline-N-oxide (4NQO) was prepared for comparison with these chemicals. Acetone solutions of the five polymerization initiators and 4NQO were prepared. Benzoyl peroxide (BPO), dimethyl-para-toluidine (DMPT), and 1-allyl-2-thiourea (ATU) showed significant genotoxic activity at 24 h in the bioluminescent bacterial genotoxicity test, at concentrations of approximately 5 microM, 4 mM, and 1 mM, respectively. 2-Dimethyloamino-ethyl-methacrylate (DMAEMA) did not have genotoxic activity and CQ had questionable genotoxic activity. In comparison, 4NQO had strong genotoxicity, at 4 microM, roughly the same as that of BPO. Therefore, BPO should be used carefully in clinical dentistry.

  8. Forced Degradation Studies of Ivabradine and In Silico Toxicology Predictions for Its New Designated Impurities.

    PubMed

    Pikul, Piotr; Jamrógiewicz, Marzena; Nowakowska, Joanna; Hewelt-Belka, Weronika; Ciura, Krzesimir

    2016-01-01

    All activities should aim to eliminate genotoxic impurities and/or protect the API against degradation. There is a necessity to monitor impurities from all classification groups, hence ivabradine forced degradation studies were performed. Ivabradine was proved to be quite durable active substance, but still new and with insufficient stability data. Increased temperature, acid, base, oxidation reagents and light were found to cause its degradation. Degradation products were determined with the usage of HPLC equipped with Q-TOF-MS detector. Calculations of pharmacological and toxicological properties were performed for six identified degradation products. Target prediction algorithm was applied on the basis of Hyperpolarization-activated cyclic nucleotide-gated cation channels, as well as more general parameters like logP and aqueous solubility. Ames test and five cytochromes activities were calculated for toxicity assessment for selected degradation products. Pharmacological activity of photodegradation product (UV4), which is known as active metabolite, was qualified and identified. Two other degradation compounds (Ox1 and N1), which were formed during degradation process, were found to be pharmacologically active. PMID:27199759

  9. Forced Degradation Studies of Ivabradine and In Silico Toxicology Predictions for Its New Designated Impurities

    PubMed Central

    Pikul, Piotr; Jamrógiewicz, Marzena; Nowakowska, Joanna; Hewelt-Belka, Weronika; Ciura, Krzesimir

    2016-01-01

    All activities should aim to eliminate genotoxic impurities and/or protect the API against degradation. There is a necessity to monitor impurities from all classification groups, hence ivabradine forced degradation studies were performed. Ivabradine was proved to be quite durable active substance, but still new and with insufficient stability data. Increased temperature, acid, base, oxidation reagents and light were found to cause its degradation. Degradation products were determined with the usage of HPLC equipped with Q-TOF-MS detector. Calculations of pharmacological and toxicological properties were performed for six identified degradation products. Target prediction algorithm was applied on the basis of Hyperpolarization-activated cyclic nucleotide-gated cation channels, as well as more general parameters like logP and aqueous solubility. Ames test and five cytochromes activities were calculated for toxicity assessment for selected degradation products. Pharmacological activity of photodegradation product (UV4), which is known as active metabolite, was qualified and identified. Two other degradation compounds (Ox1 and N1), which were formed during degradation process, were found to be pharmacologically active. PMID:27199759

  10. Large-scale genotoxicity assessments in the marine environment.

    PubMed

    Hose, J E

    1994-12-01

    There are a number of techniques for detecting genotoxicity in the marine environment, and many are applicable to large-scale field assessments. Certain tests can be used to evaluate responses in target organisms in situ while others utilize surrogate organisms exposed to field samples in short-term laboratory bioassays. Genotoxicity endpoints appear distinct from traditional toxicity endpoints, but some have chemical or ecotoxicologic correlates. One versatile end point, the frequency of anaphase aberrations, has been used in several large marine assessments to evaluate genotoxicity in the New York Bight, in sediment from San Francisco Bay, and following the Exxon Valdez oil spill.

  11. Large-scale genotoxicity assessments in the marine environment.

    PubMed

    Hose, J E

    1994-12-01

    There are a number of techniques for detecting genotoxicity in the marine environment, and many are applicable to large-scale field assessments. Certain tests can be used to evaluate responses in target organisms in situ while others utilize surrogate organisms exposed to field samples in short-term laboratory bioassays. Genotoxicity endpoints appear distinct from traditional toxicity endpoints, but some have chemical or ecotoxicologic correlates. One versatile end point, the frequency of anaphase aberrations, has been used in several large marine assessments to evaluate genotoxicity in the New York Bight, in sediment from San Francisco Bay, and following the Exxon Valdez oil spill. PMID:7713029

  12. Impurities in the Lithium Tokamak Experiment

    NASA Astrophysics Data System (ADS)

    Boyle, D. P.; Bell, R. E.; Kaita, R.; Majeski, R.; Biewer, T. M.; Gray, T. K.; Tritz, K.; Widmann, K.

    2014-10-01

    The Lithium Tokamak Experiment (LTX) is designed to study the low-recycling regime through the use of close-fitting, lithium-coated, heatable shell quadrants surrounding the plasma volume. Lithium coatings can getter and bury impurities, but they can also become covered by impurity compounds. Liquefied coatings can both dissolve impurity compounds and bring them to the surface, while sputtering and evaporation rates increase strongly with temperature. Here, we use spectroscopic measurements to assess the effects of varying wall conditions on plasma impurities, mainly Li, C, and O. A passive Doppler spectroscopy system measures toroidal and poloidal impurity profiles using fixed-wavelength and variable-wavelength visible spectrometers. In addition, survey and high-resolution extreme ultraviolet spectrometers detect emission from higher charge states. Preliminary results show that fresh Li coatings generally reduced C and O emission. C emission decreased sharply following the first solid Li coatings. Inverted toroidal profiles in a discharge with solid Li coatings show peaked Li III emissivity and temperature profiles. Recently, experiments with fresh liquid coatings led to especially strong O reduction. Results from these and additional experiments will be presented. Supported by US DOE Contracts DE-AC02-09CH11466 and DE-AC05-00OR22725.

  13. Gettering of metal impurities in silicon

    SciTech Connect

    Schroeter, W.; Spiecker, E.; Apel, M.

    1995-08-01

    Gettering means the removal of metallic impurities from the device-active area of the wafer by transport to a predesigned region-called gettering layer (GL). We introduce an interface at z = d{sub GL}, at which the effect of the gettering mechanism on the metal impurity distribution in the wafer is quantified, e.g. by specifying currents or by interfacial reactions of metal impurities, self interstitials etc. between GL and wafer. In response metal impurities will diffuse out of the wafer into the gettering layer. Following such a concept, in general three species of the metal impurity (M) are involved in gettering: M{sub p} {l_arrow} M{sub i} {l_arrow} M{sub GL}. M{sub p} denotes immobile species in the wafer, which are precipitated into suicides or segregated at extended defects or whose diffusivity is too small to contribute noticeably to transport during the gettering procedure - like many substitutional metal species.

  14. Micellar nanocarriers: pharmaceutical perspectives.

    PubMed

    Torchilin, V P

    2007-01-01

    Micelles, self-assembling nanosized colloidal particles with a hydrophobic core and hydrophilic shell are currently successfully used as pharmaceutical carriers for water-insoluble drugs and demonstrate a series of attractive properties as drug carriers. Among the micelle-forming compounds, amphiphilic copolymers, i.e., polymers consisting of hydrophobic block and hydrophilic block, are gaining an increasing attention. Polymeric micelles possess high stability both in vitro and in vivo and good biocompatibility, and can solubilize a broad variety of poorly soluble pharmaceuticals many of these drug-loaded micelles are currently at different stages of preclinical and clinical trials. Among polymeric micelles, a special group is formed by lipid-core micelles, i.e., micelles formed by conjugates of soluble copolymers with lipids (such as polyethylene glycol-phosphatidyl ethanolamine conjugate, PEG-PE). Polymeric micelles, including lipid-core micelles, carrying various reporter (contrast) groups may become the imaging agents of choice in different imaging modalities. All these micelles can also be used as targeted drug delivery systems. The targeting can be achieved via the enhanced permeability and retention (EPR) effect (into the areas with the compromised vasculature), by making micelles of stimuli-responsive amphiphilic block-copolymers, or by attaching specific targeting ligand molecules to the micelle surface. Immunomicelles prepared by coupling monoclonal antibody molecules to p-nitrophenylcarbonyl groups on the water-exposed termini of the micelle corona-forming blocks demonstrate high binding specificity and targetability. This review will discuss some recent trends in using micelles as pharmaceutical carriers. PMID:17109211

  15. Chemical process research and development in the 21st century: challenges, strategies, and solutions from a pharmaceutical industry perspective.

    PubMed

    Federsel, Hans-Jürgen

    2009-05-19

    reduction to under 10 years for the specific segment covering preclinical development through launch. This change puts enormous pressure on the entire organization, and the implication for PR&D is that the time allowed for conducting route design and scale-up has shrunk accordingly. Furthermore, molecular complexity has become extremely challenging in many instances, and demand steadily grows for process understanding and knowledge generation about low-level byproduct, which often must be controlled even at trace concentrations to meet regulatory specifications (especially in the case of potentially genotoxic impurities). In this Account, we paint a broad picture of the technical challenges the PR&D community is grappling with today, focusing on what measures have been taken over the years to create more efficiency and effectiveness. PMID:19338294

  16. [Adhesive cutaneous pharmaceutical forms].

    PubMed

    Gafiţanu, E; Matei, I; Mungiu, O C; Pavelescu, M; Mîndreci, I; Apostol, I; Ionescu, G

    1989-01-01

    The adhesive cutaneous pharmaceutical forms aimed to local action release the drug substance in view of a dermatological, traumatological, antirheumatic, cosmetic action. Two such preparations were obtained and their stability, consistency and pH were determined. The "in vitro" tests of their bioavailability revealed the dynamics of calcium ions release according to the associations of each preparation. The bioavailability determined by evaluating the pharmacological response demonstrated the antiinflammatory action obtained by the association of calcium ions with the components extracted from poplar muds. The therapeutical efficiency of the studied preparations has proved in the treatment of some sport injuries.

  17. Bolaamphiphiles: A Pharmaceutical Review

    PubMed Central

    Fariya, Mayur; Jain, Ankitkumar; Dhawan, Vivek; Shah, Sanket; Nagarsenker, Mangal S.

    2014-01-01

    The field of drug discovery is ever growing and excipients play a major role in it. A novel class of amphiphiles has been discussed in the review. The review focuses on natural as well as synthetic bolaamphiphiles, their chemical structures and importantly, their ability to self assemble rendering them of great use to pharmaceutical industry. Recent reports on their ability to be used in fabrication of suitable nanosized carriers for drug as well as genes to target site, has been discussed substantially to understand the potential of bolaamphiphiles in field of drug delivery. PMID:25671179

  18. Interaction-induced localization of mobile impurities in ultracold systems

    PubMed Central

    Li, Jian; An, Jin; Ting, C. S.

    2013-01-01

    The impurities, introduced intentionally or accidentally into certain materials, can significantly modify their characteristics or reveal their intrinsic physical properties, and thus play an important role in solid-state physics. Different from those static impurities in a solid, the impurities realized in cold atomic systems are naturally mobile. Here we propose an effective theory for treating some unique behaviors exhibited by ultracold mobile impurities. Our theory reveals the interaction-induced transition between the extended and localized impurity states, and also explains the essential features obtained from several previous models in a unified way. Based on our theory, we predict many intriguing phenomena in ultracold systems associated with the extended and localized impurities, including the formation of the impurity-molecules and impurity-lattices. We hope this investigation can open up a new avenue for the future studies on ultracold mobile impurities. PMID:24192986

  19. Interaction-induced localization of mobile impurities in ultracold systems

    NASA Astrophysics Data System (ADS)

    Li, Jian; An, Jin; Ting, C. S.

    2013-11-01

    The impurities, introduced intentionally or accidentally into certain materials, can significantly modify their characteristics or reveal their intrinsic physical properties, and thus play an important role in solid-state physics. Different from those static impurities in a solid, the impurities realized in cold atomic systems are naturally mobile. Here we propose an effective theory for treating some unique behaviors exhibited by ultracold mobile impurities. Our theory reveals the interaction-induced transition between the extended and localized impurity states, and also explains the essential features obtained from several previous models in a unified way. Based on our theory, we predict many intriguing phenomena in ultracold systems associated with the extended and localized impurities, including the formation of the impurity-molecules and impurity-lattices. We hope this investigation can open up a new avenue for the future studies on ultracold mobile impurities.

  20. Impurity and particle control for INTOR

    SciTech Connect

    Post, D.

    1985-02-01

    The INTOR impurity control system studies have been focused on the development of an impurity control system which would be able to provide the necessary heat removal and He pumping while satisfying the requirements for (1) minimum plasma contamination by impurities, (2) reasonable component lifetime (approx. 1 year), and (3) minimum size and cost. The major systems examined were poloidal divertors and pumped limiters. The poloidal divertor was chosen as the reference option since it offered the possibility of low sputtering rates due to the formation of a cool, dense plasma near the collector plates. Estimates of the sputtering rates associated with pumped limiters indicated that they would be too high for a reasonable system. Development of an engineering design concept was done for both the poloidal divertor and the pumped limiter.

  1. On charged impurity structures in liquid helium

    NASA Astrophysics Data System (ADS)

    Pelmenev, A. A.; Krushinskaya, I. N.; Bykhalo, I. B.; Boltnev, R. E.

    2016-03-01

    The thermoluminescence spectra of impurity-helium condensates (IHC) submerged in superfluid helium have been observed for the first time. Thermoluminescence of impurity-helium condensates submerged in superfluid helium is explained by neutralization reactions occurring in impurity nanoclusters. Optical spectra of excited products of neutralization reactions between nitrogen cations and thermoactivated electrons were rather different from the spectra observed at higher temperatures, when the luminescence due to nitrogen atom recombination dominates. New results on current detection during the IHC destruction are presented. Two different mechanisms of nanocluster charging are proposed to describe the phenomena observed during preparation and warm-up of IHC samples in bulk superfluid helium, and destruction of IHC samples out of liquid helium.

  2. Interaction between some common genotoxic agents.

    PubMed

    Beckman, L; Nordenson, I

    1986-01-01

    The clastogenic effects of arsenic, lead and sulphur dioxide and the protective effect of selenium were studied in short-term lymphocyte cultures. The three agents selected are the major toxic substances in emissions from copper smelters. Cells from non-smoking, healthy individuals were exposed to individual agents and combinations of the four agents (sodium arsenite, lead acetate, sodium sulphite and sodium selenite) and the cells were analysed for chromosome aberrations and sister chromatide exchanges. Selenium showed an antagonistic (protective) effect against the other agents. No synergistic effects were found, and the interactions between arsenic, lead and sulphur dioxide were mainly antagonistic. These rather unexpected findings indicate that mixed exposure from copper smelters, and other mixed exposures where arsenic, lead and sulphur dioxide are involved, may cause less genetic damage than expected and that an adequate dietary supplement of selenium may reduce the genotoxic effects of these agents. PMID:3793119

  3. Monitoring genotoxic exposure in uranium mines

    SciTech Connect

    Sram, R.J.; Vesela, D.; Vesely, D.

    1993-10-01

    Recent data from deep uranium mines in Czechoslovakia indicated that miners are exposed to other mutagenic factors in addition to radon daughter products. Mycotoxins were identified as a possible source of mutagens in these mines. Mycotoxins were examined in 38 samples from mines and in throat swabs taken from 116 miners and 78 controls. The following mycotoxins were identified from mines samples: aflatoxins B{sub 1} and G1, citrinin, citreoviridin, mycophenolic acid, and sterigmatocystin. Some mold strains isolated from mines and throat swabs were investigated for mutagenic activity by the SOS chromotest and Salmonella assay with strains TA100 and TA98. Mutagenicity was observed, especially with metabolic activation in citro. These data suggest that mycotoxins produced by molds in uranium mines are a new genotoxic factor im uranium miners. 17 refs., 4 tabs.

  4. Chromosome aberrations as bioindicators of environmental genotoxicity.

    PubMed

    Ibrulj, Slavica; Haverić, Sanin; Haverić, Anja

    2007-11-01

    Due to the exposure to various potentially genotoxic xenobiotics, derived from recent war activities such as NATO air strikes with antitank ammunition containing depleted uranium, we have evaluated chromosome aberrations in 84 peripheral blood samples from three local populations. One population sample included 30 individuals who lived in the Sarajevo area during and after the war (exposed to potential genotoxins), second population was presented with 26 employees of the tank repair facility in Hadzići (target of NATO air strikes), and 28 inhabitants of Posusje (not exposed to war-related activities) were treated as sample of control population. The mean of chromosome aberration frequencies for the population from Hadzići was significantly higher than the frequencies for the two other populations. Point bi-serial coefficient analysis did not reveal any relationship between the frequencies of chromosome aberrations and smoking habits or gender. Results suggest that depleted uranium could be a risk factor for human health.

  5. Genotoxicity testing of Maillard reaction products.

    PubMed

    Shibamoto, T

    1989-01-01

    Since the development of short-term genotoxicity tests such as the Ames assay, the mutagenicity of Maillard reaction products has been tested extensively. Some products have exhibited strong activity. For example, one of the earliest studies demonstrated some mutagenic activity in a dichloromethane extract of a D-glucose/ammonia Maillard model system. Many researchers have attempted to pinpoint the principal chemical(s) of mutagenicity of the Maillard products using various sugar-amino acid browning model systems over last two decades. However, no mutagenic individual Maillard product has been isolated and identified. Nitrite has been also used as a reactant in browning reaction model systems, primarily to investigate the formation of potentially mutagenic or carcinogenic N-nitroso compounds. Recently some potent mutagens isolated from pyrolyzed amino acids or proteins have begun to receive attention as Maillard reaction products. PMID:2675034

  6. Genotoxicity profile of azidothymidine in vitro.

    PubMed

    Zeller, Andreas; Koenig, Julie; Schmitt, Georg; Singer, Thomas; Guérard, Melanie

    2013-10-01

    Azidothymidine (Zidovudine, AZT) is part of the standard care of treatment for acquired immunodeficiency syndrome since many years. A great number of studies on the genotoxic potential of AZT have been published, but no comprehensive hypothesis yet explains all observations. We investigated a multitude of genotoxic endpoints, both in vitro and in vivo, with the goal to complete the picture. The mutagenic potential of AZT in bacteria was found to be restricted to strains with an "ochre" target sequence and could be abrogated both by thymidine supplementation and rat liver S9 mix. Single-strand breaks in mammalian cells were detected in the comet assay after short-term treatment (3h) with AZT, which did not induce micronuclei. The latter were mainly seen after prolonged exposure (24 and 48h) and are probably not directly related to AZT incorporation into DNA. Our data demonstrate that short-term exposure to low AZT concentrations does not induce biologically relevant micronucleation. Only treatment with high concentrations of AZT for prolonged time periods manifests in substantial micronucleus induction. Furthermore, we found that high concentrations of thymidine have no effect in the comet assay but increase micronucleus frequency in a manner very similar to AZT. These results lead us to the following hypothesis: AZT is triphosphorylated and then incorporated into DNA strands, leading to mutations and cytotoxicity. Cellular attempts to repair these DNA lesions as well as stalled replication forks due to chain termination are detectable with the comet assay. Increased micronucleus frequency is likely related to nucleotide pool imbalance. PMID:23811827

  7. THE GENOTOXICITY OF AMBIENT OUTDOOR AIR, A REVIEW: SALMONELLA MUTAGENICITY

    EPA Science Inventory

    The genotoxicity of ambient outdoor air, a review: Salmonella mutagenicity

    Abstract
    Mutagens in urban air pollution come from anthropogenic sources (especially combustion sources) and are products of airborne chemical reactions. Bacterial mutation tests have been used ...

  8. Titanium dioxide nanoparticles cause genotoxicity in human lung epithelial cells

    EPA Science Inventory

    The use of engineered nanoparticles in consumer products is steadily increasing. However, the health effects of exposure to these nanoparticles are not thoroughly understood. This study investigated the genotoxicity of six titanium dioxide and two cerium oxide nanoparticles of va...

  9. Undercompensated kondo impurity with quantum critical point

    PubMed

    Schlottmann

    2000-02-14

    The low-temperature properties of a magnetic impurity of spin S interacting with an electron gas via anisotropic spin exchange are studied via Bethe's ansatz. For S>1/2 the impurity is only partially compensated at T = 0, leaving an effective spin that is neither integer nor half integer. The entropy has an essential singularity at H = T = 0, and the susceptibility and the specific heat follow power laws of H and T with nonuniversal exponents, which are the consequence of a quantum critical point. The results for the generalization to an arbitrary number of channels are also reported. PMID:11017567

  10. Mapping itinerant electrons around Kondo impurities.

    PubMed

    Prüser, H; Wenderoth, M; Weismann, A; Ulbrich, R G

    2012-04-20

    We investigate single Fe and Co atoms buried below a Cu(100) surface using low temperature scanning tunneling spectroscopy. By mapping the local density of states of the itinerant electrons at the surface, the Kondo resonance near the Fermi energy is analyzed. Probing bulk impurities in this well-defined scattering geometry allows separating the physics of the Kondo system and the measuring process. The line shape of the Kondo signature shows an oscillatory behavior as a function of depth of the impurity as well as a function of lateral distance. The oscillation period along the different directions reveals that the spectral function of the itinerant electrons is anisotropic. PMID:22680744

  11. The physics of Kondo impurities in graphene.

    PubMed

    Fritz, Lars; Vojta, Matthias

    2013-03-01

    This article summarizes our understanding of the Kondo effect in graphene, primarily from a theoretical perspective. We shall describe different ways to create magnetic moments in graphene, either by adatom deposition or via defects. For dilute moments, the theoretical description is in terms of effective Anderson or Kondo impurity models coupled to graphene's Dirac electrons. We shall discuss in detail the physics of these models, including their quantum phase transitions and the effect of carrier doping, and confront this with existing experimental data. Finally, we will point out connections to other quantum impurity problems, e.g., in unconventional superconductors, topological insulators, and quantum spin liquids.

  12. The Pharmaceutical Commons

    PubMed Central

    Lezaun, Javier

    2015-01-01

    In the last decade, the organization of pharmaceutical research on neglected tropical diseases has undergone transformative change. In a context of perceived “market failure,” the development of new medicines is increasingly handled by public-private partnerships. This shift toward hybrid organizational models depends on a particular form of exchange: the sharing of proprietary assets in general and of intellectual property rights in particular. This article explores the paradoxical role of private property in this new configuration of global health research and development. Rather than a tool to block potential competitors, proprietary assets function as a lever to attract others into risky collaborative ventures; instead of demarcating public and private domains, the sharing of property rights is used to increase the porosity of that boundary. This reimagination of the value of property is connected to the peculiar timescape of global health drug development, a promissory orientation to the future that takes its clearest form in the centrality of “virtual” business models and the proliferation of strategies of deferral. Drawing on the anthropological literature on inalienable possessions, we reconsider property’s traditional exclusionary role and discuss the possibility that the new pharmaceutical “commons” proclaimed by contemporary global health partnerships might be the precursor of future enclosures. PMID:25866425

  13. Impurity Crystal in a Bose-Einstein Condensate

    SciTech Connect

    Roberts, David C.; Rica, Sergio

    2009-01-16

    We investigate the behavior of impurity fields immersed in a larger condensate field in various dimensions. We discuss the localization of a single impurity field within a condensate and note the effects of surface energy. We derive the functional form of the attractive condensate-mediated interaction between two impurities. Generalizing the analysis to N impurity fields, we show that within various parameter regimes a crystal of impurity fields can form spontaneously in the condensate. Finally, the system of condensate and crystallized impurity structure is shown to have nonclassical rotational inertia, which is characteristic of superfluidity; i.e., the system can be seen to exhibit supersolid behavior.

  14. Influence of impurities on the crystallization of dextrose monohydrate

    NASA Astrophysics Data System (ADS)

    Markande, Abhay; Nezzal, Amale; Fitzpatrick, John; Aerts, Luc; Redl, Andreas

    2012-08-01

    The effects of impurities on dextrose monohydrate crystallization were investigated. Crystal nucleation and growth kinetics in the presence of impurities were studied using an in-line focused beam reflectance monitoring (FBRM) technique and an in-line process refractometer. Experimental data were obtained from runs carried out at different impurity levels between 4 and 11 wt% in the high dextrose equivalent (DE) syrup. It was found that impurities have no significant influence on the solubility of dextrose in water. However, impurities have a clear influence on the nucleation and growth kinetics of dextrose monohydrate crystallization. Nucleation and growth rate were favored by low levels of impurities in the syrup.

  15. Genotoxicity of instant coffee: possible involvement of phenolic compounds.

    PubMed

    Duarte, M P; Laires, A; Gaspar, J; Leão, D; Oliveira, J S; Rueff, J

    1999-06-01

    Instant coffee exhibits direct genotoxic activity in the tester strains TA 98, 100, 102, 104 and YG 1024. In the Ames tester strain TA 100, the presence of S9 mix, S100 mix, S9 mix without cofactors led to a significant decrease of the genotoxicity observed. The decrease observed in the presence of S9 mix seems to be highly correlated with the catalase content of S9 mix. The genotoxicity of instant coffee detected in strain TA 100 was dependent on the pH, with higher genotoxic effects at pH values above neutrality. Also, dependent on the pH was the ability of some phenolic molecules present in coffee promoting the degradation of deoxyribose in the presence of Fe3+/EDTA. These results suggest that apart from other molecules present in instant coffee responsible for their genotoxicity in several short term assays, phenolic molecules could also be implicated in the genotoxicity of coffee, via reactive oxygen species arising from its auto-oxidation.

  16. The ecotoxicological significance of genotoxicity in marine invertebrates.

    PubMed

    Depledge, M H

    1998-03-13

    Attention is drawn to the goals of genetic ecotoxicology, in particular, the need to relate genotoxicity in individuals to population and community level consequences. The evidence for pollutant-induced genotoxicity in marine invertebrates is reviewed. Neoplasia is apparently rare in marine invertebrates and only limited evidence is available to suggest that chemical genotoxins act as causative agents. It is unknown why marine invertebrates exhibit low tumour incidences and are much more tolerant of ionising radiation than their vertebrate counterparts. The importance of the genotoxic disease syndrome is highlighted. Disentangling phenotypic manifestations of genotoxic damage and that due to direct metabolic toxicity provides a major challenge for the future. Further work is required to assess the significance of interspecific and interindividual variability in susceptibility to genotoxicity, especially with regard to the evolution of resistant populations and communities of marine organisms at contaminated sites. Only by addressing the issues highlighted above can proper risk assessments of genotoxic agents be performed to minimise threats to human and ecosystem health.

  17. An evaluation of the genotoxicity of the antitussive drug Dextromethorphan.

    PubMed

    Aardema, Marilyn J; Robison, Steven H; Gatehouse, David; Johnston, Gail

    2008-04-01

    Dextromethorphan (DMP) is an effective and widely used antitussive drug. While DMP has over a 50 year safe-marketing history, the only available genotoxicity data was an unpublished, negative Ames assay (Roche). Lack of a complete genotoxicity profile on DMP, specifically covering the chromosomal damage endpoint, prompted a regulatory request for an in vitro chromosome aberration assay. In accordance with EC and CPMP Guidance, we evaluated data for a number of chemicals with a structural relationship to DMP. DMP contains no structural alerts for genotoxicity or carcinogenicity using the Deductive Estimation of Risk from Existing Knowledge (DEREK) software tool, confirming the negative results obtained in the existing Ames assay. This is also consistent with the mostly negative genotoxicity and carcinogenicity data available on structurally related chemicals including morphine, codeine, nalbuphine, buprenorphine, naloxone, hydromorphone, levorphanol, and oxycodone. A state-of-the-science, in vitro chromosome aberration assay was also conducted, which demonstrated a lack of genotoxicity for DMP. The overall weight of evidence for DMP and its structural analogues, supports the conclusion that this class of phenanthrene-based chemicals, and DMP, in particular, are not genotoxic in vitro or in vivo, and do not represent a carcinogenic risk to patients.

  18. Method development for impurity profiling in SFC: The selection of a dissimilar set of stationary phases.

    PubMed

    Galea, Charlene; Mangelings, Debby; Heyden, Yvan Vander

    2015-01-01

    Supercritical fluid chromatography (SFC) is drawing considerable interest as separation technique in the pharmaceutical industry. The technique is already well established in chiral separations both analytically and on a preparative scale. The use of SFC as a technique for drug impurity profiling is examined here. To define starting conditions in method development for drug impurity profiling, a set of dissimilar stationary phases is screened in parallel. The possibility to select a set of dissimilar columns using the retention factors (k-values) for a set of 64 drugs measured on 27 columns in SFC was examined. Experiments were carried out at a back-pressure of 150 bar and 25 °C with a mobile phase consisting of CO2 and methanol with 0.1% isopropylamine (5-40% over 10 min) at a flow rate of 3 mL/min. These k-values were then used to calculate correlation coefficients on the one hand and to perform a principal component analysis on the other. The Kennard and Stone algorithm, besides dendrograms and correlation-coefficient colour maps were used to select a set of 6 dissimilar stationary phases. The stationary phase characterization results from this study were compared to those from previous studies found in the literature. Retention mechanisms for compounds possessing different properties were also evaluated. The dissimilarity of the selected subset of 6 stationary phases was validated using mixtures of compounds with similar properties and structures, as one can expect in a drug impurity profile. PMID:25630237

  19. Method development for impurity profiling in SFC: The selection of a dissimilar set of stationary phases.

    PubMed

    Galea, Charlene; Mangelings, Debby; Heyden, Yvan Vander

    2015-01-01

    Supercritical fluid chromatography (SFC) is drawing considerable interest as separation technique in the pharmaceutical industry. The technique is already well established in chiral separations both analytically and on a preparative scale. The use of SFC as a technique for drug impurity profiling is examined here. To define starting conditions in method development for drug impurity profiling, a set of dissimilar stationary phases is screened in parallel. The possibility to select a set of dissimilar columns using the retention factors (k-values) for a set of 64 drugs measured on 27 columns in SFC was examined. Experiments were carried out at a back-pressure of 150 bar and 25 °C with a mobile phase consisting of CO2 and methanol with 0.1% isopropylamine (5-40% over 10 min) at a flow rate of 3 mL/min. These k-values were then used to calculate correlation coefficients on the one hand and to perform a principal component analysis on the other. The Kennard and Stone algorithm, besides dendrograms and correlation-coefficient colour maps were used to select a set of 6 dissimilar stationary phases. The stationary phase characterization results from this study were compared to those from previous studies found in the literature. Retention mechanisms for compounds possessing different properties were also evaluated. The dissimilarity of the selected subset of 6 stationary phases was validated using mixtures of compounds with similar properties and structures, as one can expect in a drug impurity profile.

  20. Pharmaceutical study of Yashadabhasma

    PubMed Central

    Bhojashettar, Santhosh; Jadar, P. G.; Rao, V. Nageswara

    2012-01-01

    Background: Rasashastra is a branch which deals with the pharmaceutics of Rasaoushadhis. Bhasmas are one among such Rasaoushadhis which are known for their low doses and fast action. A verse from Rasaratnasamuchchaya says that the bhasma prepared by using Mercury as media is of best quality. Materials and Methods: Following this principle, Yashadabhasma (Zinc calx) was prepared by subjecting it to Samanya shodhana (general purification method for all metals), Vishesha shodhana (specific putification method for Zinc), Jarana (roasting) and Marana (incineration) with Parada(Mercury) as a media under Gajaputa (classical heating system with 1000 cowdung cakes). Results and Conclusion: Yellow colored Yashadabhasma which passed all the classical bhasmaparikshas (tests for properly prepared calx) was obtained after two putas. The bhasma did not pass Nishchandratva(free from shining particles) test after 1stputa but was passed after giving it 2ndputa. PMID:23284213

  1. Spectral properties of superconductors with ferromagnetically ordered magnetic impurities

    NASA Astrophysics Data System (ADS)

    Persson, Daniel; Shevtsov, Oleksii; Löfwander, Tomas; Fogelström, Mikael

    2015-12-01

    We present a comprehensive theoretical study of thermodynamic properties of superconductors with a dilute concentration of magnetic impurities, with focus on how the properties of the superconducting host change if the magnetic moments of the impurities order ferromagnetically. Scattering off the magnetic impurities leads to the formation of a band of Yu-Shiba-Rusinov states within the superconducting energy gap that drastically influences superconductivity. In the magnetically ordered system, the magnetization displays a sudden drop as a function of the impurity density or magnetic moment amplitude. The drop occurs as the spin-polarized impurity band crosses the Fermi level and is associated with a quantum phase transition first put forward by Sakurai for the single impurity case. Taking into account that the background magnetic field created by the ordered impurity moments enters as a Zeeman shift, we find that the superconducting phase transition changes from second order to first order for high enough impurity concentrations.

  2. Process and system for removing impurities from a gas

    DOEpatents

    Henningsen, Gunnar; Knowlton, Teddy Merrill; Findlay, John George; Schlather, Jerry Neal; Turk, Brian S

    2014-04-15

    A fluidized reactor system for removing impurities from a gas and an associated process are provided. The system includes a fluidized absorber for contacting a feed gas with a sorbent stream to reduce the impurity content of the feed gas; a fluidized solids regenerator for contacting an impurity loaded sorbent stream with a regeneration gas to reduce the impurity content of the sorbent stream; a first non-mechanical gas seal forming solids transfer device adapted to receive an impurity loaded sorbent stream from the absorber and transport the impurity loaded sorbent stream to the regenerator at a controllable flow rate in response to an aeration gas; and a second non-mechanical gas seal forming solids transfer device adapted to receive a sorbent stream of reduced impurity content from the regenerator and transfer the sorbent stream of reduced impurity content to the absorber without changing the flow rate of the sorbent stream.

  3. In-situ impurity measurements in PDX Edge plasma

    SciTech Connect

    Staib, P.; Dylla, H.F.; Rossnagel, S.M.

    1980-07-01

    The surface analysis station of PDX combines several surface analysis techniques (AES, XPS, SIMS) for in-situ measurement of impurity fluxes in the edge-plasma. The major impurities deposited on a sample surface during nondiverted PDX discharges are oxygen, titanium (limiter material) and chlorine. The impurity fluxes measured at different radial positions decreased by a factor of ten from the plasma edge to the wall. The sample surface collecting the impurity ions is located behind a circular aperture. The observed broadening of the deposition profile of Ti relative to the aperture diameter enables an estimate to be made of the ratio of charge state/energy of Ti ions in the edge plasma. Time-resolved analyses of the deposited impurities are presented which indicate that the time behavior for various impurities may be quite different for different impurity species. This aspect is discussed in relation to probable impurity release mechanisms.

  4. Distribution Coefficients of Impurities in Metals

    NASA Astrophysics Data System (ADS)

    Pearce, J. V.

    2014-04-01

    Impurities dissolved in very pure metals at the level of parts per million often cause an elevation or depression of the freezing temperature of the order of millikelvins. This represents a significant contribution to the uncertainty of standard platinum resistance thermometer calibrations. An important parameter for characterizing the behavior of impurities is the distribution coefficient , which is the ratio of the solid solubility to liquid solubility. A knowledge of for a given binary system is essential for contemporary methods of evaluating or correcting for the effect of impurities, and it is therefore of universal interest to have the most complete set of values possible. A survey of equilibrium values of (in the low concentration limit) reported in the literature for the International Temperature Scale of 1990 fixed points of Hg, Ga, In, Sn, Zn, Al, Au, Ag, and Cu is presented. In addition, thermodynamic calculations of using MTDATA are presented for 170 binary systems. In total, the combined values of from all available sources for 430 binary systems are presented. In addition, by considering all available values of for impurities in 25 different metal solvents (1300 binary systems) enough data are available to characterize patterns in the value of for a given impurity as a function of its position in the periodic table. This enables prediction of for a significant number of binary systems for which data and calculations are unavailable. By combining data from many sources, values of for solutes (atomic number from 1 to 94) in ITS-90 fixed points from Hg to Cu are suggested, together with some tentative predicted values where literature data and calculations are unavailable.

  5. Comparative pathophysiology, toxicology, and human cancer risk assessment of pharmaceutical-induced hibernoma

    SciTech Connect

    Radi, Zaher; Bartholomew, Phillip; Elwell, Michael; Vogel, W. Mark

    2013-12-15

    In humans, hibernoma is a very rare, benign neoplasm of brown adipose tissue (BAT) that typically occurs at subcutaneous locations and is successfully treated by surgical excision. No single cause has been accepted to explain these very rare human tumors. In contrast, spontaneous hibernoma in rats is rare, often malignant, usually occurs in the thoracic or abdominal cavity, and metastases are common. In recent years, there has been an increased incidence of spontaneous hibernomas in rat carcinogenicity studies, but overall the occurrence remains relatively low and highly variable across studies. There have only been four reported examples of pharmaceutical-induced hibernoma in rat carcinogenicity studies. These include phentolamine, an alpha-adrenergic antagonist; varenicline, a nicotine partial agonist; tofacitinib, a Janus kinase (JAK) inhibitor; and hydromorphone, an opiod analgesic. Potential non-genotoxic mechanisms that may contribute to the pathogenesis of BAT activation/proliferation and/or subsequent hibernoma development in rats include: (1) physiological stimuli, (2) sympathetic stimulation, (3) peroxisome proliferator-activated receptor (PPAR) agonism, and/or (4) interference or inhibition of JAK/Signal Transducer and Activator of Transcription (JAK/STAT) signaling. The evaluation of an apparent increase of hibernoma in rats from 2-year carcinogenicity studies of novel pharmaceutical therapeutics and its relevance to human safety risk assessment is complex. One should consider: the genotoxicity of the test article, dose/exposure and safety margins, and pathophysiologic and morphologic differences and similarities of hibernoma between rats and humans. Hibernomas observed to date in carcinogenicity studies of pharmaceutical agents do not appear to be relevant for human risk at therapeutic dosages. - Highlights: • Highly variable incidence of spontaneous hibernoma in carcinogenicity studies • Recent increase in the spontaneous incidence of hibernomas

  6. The Potts model on a Bethe lattice with nonmagnetic impurities

    SciTech Connect

    Semkin, S. V. Smagin, V. P.

    2015-10-15

    We have obtained a solution for the Potts model on a Bethe lattice with mobile nonmagnetic impurities. A method is proposed for constructing a “pseudochaotic” impurity distribution by a vanishing correlation in the arrangement of impurity atoms for the nearest sites. For a pseudochaotic impurity distribution, we obtained the phase-transition temperature, magnetization, and spontaneous magnetization jumps at the phase-transition temperature.

  7. A new derivatization reagent for LC-MS/MS screening of potential genotoxic alkylation compounds.

    PubMed

    van Wijk, A M; Niederländer, H A G; Siebum, A H G; Vervaart, M A T; de Jong, G J

    2013-02-23

    A screening method for trace analysis of potentially genotoxic alkylating compounds has been developed using butyl 1-(pyridin-4-yl) piperidine 4-carboxylate (BPPC) as a new, selective pre-column derivatization reagent for their subsequent analysis by hydrophilic interaction liquid chromatography (HILIC) hyphenated with tandem mass spectrometry (LC-MS/MS). The new derivatization reagent is a modification of 4-dimethylaminopyridine (4-DMAP) previously used for the determination of potentially genotoxic compounds. By using the new reagent the screening potential was enhanced without compromising reactivity. Derivatization at a high pH value was carried out and the reaction time at 60°C was 24h to anticipate for alkyl chlorides showing to be less reactive. The new reagent was designed to obtain reagent related fragmentation of the whole reagent as well as a side group of the reagent. Collision energies for detection of alkylating components derivatized using the new reagent are shown to be significantly more universal than with 4-DMAP. Neutral loss scanning on the fragmentation related to the build in side group remedies shortcomings in the screening for alkyl halides observed when using 4-DMAP. The new approach allows for screening of alkyl halides and alkyl sulfonates at trace levels down to 1 mg kg(-1) and target analysis at about a factor of 10 lower without a significant effect of the active pharmaceutical ingredient (API) matrix. The synthesis of the reagent, investigation of reactivity, the specificity of the fragmentation of derivatives and screening conditions in MS/MS analysis are described. PMID:23245244

  8. Genotoxic effects of zinc oxide nanoparticles.

    PubMed

    Heim, Julia; Felder, Eva; Tahir, Muhammad Nawaz; Kaltbeitzel, Anke; Heinrich, Ulf Ruediger; Brochhausen, Christoph; Mailänder, Volker; Tremel, Wolfgang; Brieger, Juergen

    2015-05-21

    The potential toxicity of nanoparticles has currently provoked public and scientific discussions, and attempts to develop generally accepted handling procedures for nanoparticles are under way. The investigation of the impact of nanoparticles on human health is overdue and reliable test systems accounting for the special properties of nanomaterials must be developed. Nanoparticular zinc oxide (ZnO) may be internalised through ambient air or the topical application of cosmetics, only to name a few, with unpredictable health effects. Therefore, we analysed the determinants of ZnO nanoparticle (NP) genotoxicity. ZnO NPs (15-18 nm in diameter) were investigated at concentrations of 0.1, 10 and 100 μg mL(-1) using the cell line A549. Internalised NPs were only infrequently detectable by TEM, but strongly increased Zn(2+) levels in the cytoplasm and even more in the nuclear fraction, as measured by atom absorption spectroscopy, indicative of an internalised zinc and nuclear accumulation. We observed a time and dosage dependent reduction of cellular viability after ZnO NP exposure. ZnCl2 exposure to cells induced similar impairments of cellular viability. Complexation of Zn(2+) with diethylene triamine pentaacetic acid (DTPA) resulted in the loss of toxicity of NPs, indicating the relevant role of Zn(2+) for ZnO NP toxicity. Foci analyses showed the induction of DNA double strand breaks (DSBs) by ZnO NPs and increased intracellular reactive oxygen species (ROS) levels. Treatment of the cells with the ROS scavenger N-acetyl-l-cysteine (NAC) resulted in strongly decreased intracellular ROS levels and reduced DNA damage. However, a slow increase of ROS after ZnO NP exposure and reduced but not quashed DSBs after NAC-treatment suggest that Zn(2+) may exert genotoxic activities without the necessity of preceding ROS-induction. Our data indicate that ZnO NP toxicity is a result of cellular Zn(2+) intake. Subsequently increased ROS-levels cause DNA damage. However, we found

  9. Use and practice of achiral and chiral supercritical fluid chromatography in pharmaceutical analysis and purification.

    PubMed

    Lemasson, Elise; Bertin, Sophie; West, Caroline

    2016-01-01

    The interest of pharmaceutical companies for complementary high-performance chromatographic tools to assess a product's purity or enhance this purity is on the rise. The high-throughput capability and economic benefits of supercritical fluid chromatography, but also the "green" aspect of CO2 as the principal solvent, render supercritical fluid chromatography very attractive for a wide range of pharmaceutical applications. The recent reintroduction of new robust instruments dedicated to supercritical fluid chromatography and the progress in stationary phase technology have also greatly benefited supercritical fluid chromatography. Additionally, it was shown several times that supercritical fluid chromatography could be orthogonal to reversed-phase high-performance liquid chromatography and could efficiently compete with it. Supercritical fluid chromatography is an adequate tool for small molecules of pharmaceutical interest: synthetic intermediates, active pharmaceutical ingredients, impurities, or degradation products. In this review, we first discuss about general chromatographic conditions for supercritical fluid chromatography analysis to better suit compounds of pharmaceutical interest. We also discuss about the use of achiral and chiral supercritical fluid chromatography for analytical purposes and the recent applications in these areas. The use of preparative supercritical fluid chromatography by pharmaceutical companies is also covered.

  10. Metal-based impurities in graphenes: application for electroanalysis.

    PubMed

    Chee, Sze Yin; Pumera, Martin

    2012-05-01

    We show here that metallic impurities presented in graphenes prepared from graphite can be usefully employed for electroanalysis. We demonstrate that cumene hydroperoxide electrochemical reduction on graphene containing iron-based impurities provides significantly larger voltammetric currents than the same experiment using iron oxide nanoparticles. This opens doors for turning metallic impurities into potentially useful components of graphene based electrochemical systems.

  11. Monte Carlo method for magnetic impurities in metals

    NASA Technical Reports Server (NTRS)

    Hirsch, J. E.; Fye, R. M.

    1986-01-01

    The paper discusses a Monte Carlo algorithm to study properties of dilute magnetic alloys; the method can treat a small number of magnetic impurities interacting wiith the conduction electrons in a metal. Results for the susceptibility of a single Anderson impurity in the symmetric case show the expected universal behavior at low temperatures. Some results for two Anderson impurities are also discussed.

  12. Silver nanoparticles: correlating nanoparticle size and cellular uptake with genotoxicity

    PubMed Central

    Butler, Kimberly S.; Peeler, David J.; Casey, Brendan J.; Dair, Benita J.; Elespuru, Rosalie K.

    2015-01-01

    The focus of this research was to develop a better understanding of the pertinent physico-chemical properties of silver nanoparticles (AgNPs) that affect genotoxicity, specifically how cellular uptake influences a genotoxic cell response. The genotoxicity of AgNPs was assessed for three potential mechanisms: mutagenicity, clastogenicity and DNA strand-break-based DNA damage. Mutagenicity (reverse mutation assay) was assessed in five bacterial strains of Salmonella typhimurium and Echerichia coli, including TA102 that is sensitive to oxidative DNA damage. AgNPs of all sizes tested (10, 20, 50 and 100nm), along with silver nitrate (AgNO3), were negative for mutagenicity in bacteria. No AgNPs could be identified within the bacteria cells using transmission electron microscopy (TEM), indicating these bacteria lack the ability to actively uptake AgNPs 10nm or larger. Clastogenicity (flow cytometry-based micronucleus assay) and intermediate DNA damage (DNA strand breaks as measured in the Comet assay) were assessed in two mammalian white blood cell lines: Jurkat Clone E6-1 and THP-1. It was observed that micronucleus and Comet assay end points were inversely correlated with AgNP size, with smaller NPs inducing a more genotoxic response. TEM results indicated that AgNPs were confined within intracellular vesicles of mammalian cells and did not penetrate the nucleus. The genotoxicity test results and the effect of AgNO3 controls suggest that silver ions may be the primary, and perhaps only, cause of genotoxicity. Furthermore, since AgNO3 was not mutagenic in the gram-negative bacterial Ames strains tested, the lack of bacterial uptake of the AgNPs may not be the major reason for the lack of genotoxicity observed. PMID:25964273

  13. Protein Crystal Growth Dynamics and Impurity Incorporation

    NASA Technical Reports Server (NTRS)

    Chernov, Alex A.; Thomas, Bill

    2000-01-01

    The general concepts and theories of crystal growth are proven to work for biomolecular crystallization. This allowed us to extract basic parameters controlling growth kinetics - free surface energy, alpha, and kinetic coefficient, beta, for steps. Surface energy per molecular site in thermal units, alpha(omega)(sup 2/3)/kT approx. = 1, is close to the one for inorganic crystals in solution (omega is the specific molecular volume, T is the temperature). Entropic restrictions on incorporation of biomolecules into the lattice reduce the incorporation rate, beta, by a factor of 10(exp 2) - 10(exp 3) relative to inorganic crystals. A dehydration barrier of approx. 18kcal/mol may explain approx. 10(exp -6) times difference between frequencies of adding a molecule to the lattice and Brownian attempts to do so. The latter was obtained from AFM measurements of step and kink growth rates on orthorhombic lysozyme. Protein and many inorganic crystals typically do not belong to the Kossel type, thus requiring a theory to account for inequivalent molecular positions within its unit cell. Orthorhombic lysozyme will serve as an example of how to develop such a theory. Factors deteriorating crystal quality - stress and strain, mosaicity, molecular disorder - will be reviewed with emphasis on impurities. Dimers in ferritin and lysozyme and acetylated lysozyme, are microheterogeneous i.e. nearly isomorphic impurities that are shown to be preferentially trapped by tetragonal lysozyme and ferritin crystals, respectively. The distribution coefficient, K defined as a ratio of the (impurity/protein) ratios in crystal and in solution is a measure of trapping. For acetylated lysoyzme, K = 2.15 or, 3.42 for differently acetylated forms, is independent of both the impurity and the crystallizing protein concentration. The reason is that impurity flux to the surface is constant while the growth rate rises with supersaturation. About 3 times lower dimer concentration in space grown ferritin and

  14. Genotoxicity of Graphene in Escherichia coli

    NASA Astrophysics Data System (ADS)

    Sharma, Ananya

    Rapid advances in nanotechnology necessitate assessment of the safety of nanomaterials in the resulting products and applications. One key nanomaterial attracting much interest in many areas of science and technology is graphene. Graphene is a one atom thick carbon allotrope arranged in a two-dimensional honeycomb lattice. In addition to being extremely thin, graphene has several extraordinary physical properties such as its exceptional mechanical strength, thermal stability, and high electrical conductivity. Graphene itself is relatively chemically inert and therefore pristine graphene must undergo a process called functionalization, which is combination of chemical and physical treatments that change the properties of graphene, to make it chemically active. Functionalization of graphene is of crucial importance as the end application of graphene depends on proper functionalization. In the field of medicine, graphene is currently a nanomaterial of high interest for building biosensors, DNA transistors, and probes for cancer detection. Despite the promising applications of graphene in several areas of biomedicine, there have been only few studies in recent years that focus on evaluating cytotoxicity of graphene on cells, and almost no studies that investigate how graphene exposure affects cellular genetic material. Therefore, in this study we used a novel approach to evaluate the genotoxicity, i.e., the effects of graphene on DNA, using Escherichia coli as a prokaryotic model organism.

  15. Mutagenicity and genotoxicity assessment of industrial wastewaters.

    PubMed

    Masood, Farhana; Malik, Abdul

    2013-10-01

    The genotoxicity of industrial wastewaters from Jajmau (Kanpur), was carried out by Ames Salmonella/microsome test, DNA repair-defective mutants, and Allium cepa anaphase-telophase test. Test samples showed maximum response with TA98 strain with and without metabolic activation. Amberlite resins concentrated wastewater samples were found to be more mutagenic as compared to those of liquid-liquid extracts (hexane and dichloromethane extracts). The damage in the DNA repair defective mutants in the presence of Amberlite resins concentrated water samples were found to be higher to that of liquid-liquid-extracted water samples at the dose level of 20 μl/ml culture. Among all the mutants, polA exhibited maximum decline with test samples. Mitotic index (MI) of root tip meristematic cells of A. cepa treated with 5, 10, 25, 50, and 100 % (v/v) wastewaters were significantly lower than the control. Complementary to the lower levels of MI, the wastewaters showed higher chromosomal aberration levels in all cases investigated. PMID:23640391

  16. Genotoxic effects of zinc oxide nanoparticles

    NASA Astrophysics Data System (ADS)

    Heim, Julia; Felder, Eva; Tahir, Muhammad Nawaz; Kaltbeitzel, Anke; Heinrich, Ulf Ruediger; Brochhausen, Christoph; Mailänder, Volker; Tremel, Wolfgang; Brieger, Juergen

    2015-05-01

    The potential toxicity of nanoparticles has currently provoked public and scientific discussions, and attempts to develop generally accepted handling procedures for nanoparticles are under way. The investigation of the impact of nanoparticles on human health is overdue and reliable test systems accounting for the special properties of nanomaterials must be developed. Nanoparticular zinc oxide (ZnO) may be internalised through ambient air or the topical application of cosmetics, only to name a few, with unpredictable health effects. Therefore, we analysed the determinants of ZnO nanoparticle (NP) genotoxicity. ZnO NPs (15-18 nm in diameter) were investigated at concentrations of 0.1, 10 and 100 μg mL-1 using the cell line A549. Internalised NPs were only infrequently detectable by TEM, but strongly increased Zn2+ levels in the cytoplasm and even more in the nuclear fraction, as measured by atom absorption spectroscopy, indicative of an internalised zinc and nuclear accumulation. We observed a time and dosage dependent reduction of cellular viability after ZnO NP exposure. ZnCl2 exposure to cells induced similar impairments of cellular viability. Complexation of Zn2+ with diethylene triamine pentaacetic acid (DTPA) resulted in the loss of toxicity of NPs, indicating the relevant role of Zn2+ for ZnO NP toxicity. Foci analyses showed the induction of DNA double strand breaks (DSBs) by ZnO NPs and increased intracellular reactive oxygen species (ROS) levels. Treatment of the cells with the ROS scavenger N-acetyl-l-cysteine (NAC) resulted in strongly decreased intracellular ROS levels and reduced DNA damage. However, a slow increase of ROS after ZnO NP exposure and reduced but not quashed DSBs after NAC-treatment suggest that Zn2+ may exert genotoxic activities without the necessity of preceding ROS-induction. Our data indicate that ZnO NP toxicity is a result of cellular Zn2+ intake. Subsequently increased ROS-levels cause DNA damage. However, we found evidence for

  17. Genotoxicity of drinking water from Chao Lake

    SciTech Connect

    Liu, Q.; Jiao, Q.C.; Huang, X.M.; Jiang, J.P.; Cui, S.Q.; Yao, G.H.; Jiang, Z.R.; Zhao, H.K.; Wang, N.Y.

    1999-02-01

    Genotoxic activity appears to originate primarily from reactions of chlorine with humic substances in the source waters. Comparisons of extracts of settled versus chlorinated water have confirmed that chlorinating during water treatment produces mutagenic activity in the mutagenicity tests. Present work on XAD-2 extracts of raw, chlorinated (treated), and settled water from the Chao Lake region of China has involved a battery of mutagenicity assays for various genetic endpoints: the Salmonella test, the sister-chromatid exchange (SCE) induction in Chinese hamster lung (CHL) cells, and the micronucleus (MN) induction in the peripheral blood erythrocytes of silver carp. Extracts of raw and treated water but not the settled water are mutagenic in the Salmonella assay. On the other hand, extracts of three water samples show activity in the SCE and MN assays, especially the raw and treated water. These data show that contamination and chlorinating contribute mutagens to drinking water and suggest that the mammalian assays may be more sensitive for detecting mutagenicity in aquatic environment than the Salmonella test.

  18. Assessment of hazardous wastes for genotoxicity

    SciTech Connect

    DeMarini, D.M.; Houk, V.S.

    1987-09-01

    The authors have evaluated a group of short-term bioassays to identify those that may be suitable for screening large numbers of diverse hazardous industrial wastes for genotoxicity. Fifteen wastes (and dichloromethane extracts of these wastes) from a variety of manufacturing processes were tested for mutagenicity in Salmonella typhimurium strains TA98 and TA100 with and without Aroclor 1254-induced rat-liver S9. Ten of these wastes were fed by gavage to F-344 male rats, and the raw urines were assayed for mutagenicity in the presence of beta-glucuronidase in strain TA98 with S9. Six of these urines were extracted by C18/methanol elution, incubated with beta-glucuronidase, and evaluated in strain TA98 with S9 and beta-glucuronidase. Fourteen of the wastes were examined for their ability to induce prophage lambda in Escherichia coli in a microsuspension assay. A second set of wastes, consisting of four industrial wastes, were evaluated in Salmonella and in a series of mammalian cell assays to measure mutagenicity, cytogenetic effects, and transformation.

  19. Genotoxic effects of zinc oxide nanoparticles

    NASA Astrophysics Data System (ADS)

    Heim, Julia; Felder, Eva; Tahir, Muhammad Nawaz; Kaltbeitzel, Anke; Heinrich, Ulf Ruediger; Brochhausen, Christoph; Mailänder, Volker; Tremel, Wolfgang; Brieger, Juergen

    2015-05-01

    The potential toxicity of nanoparticles has currently provoked public and scientific discussions, and attempts to develop generally accepted handling procedures for nanoparticles are under way. The investigation of the impact of nanoparticles on human health is overdue and reliable test systems accounting for the special properties of nanomaterials must be developed. Nanoparticular zinc oxide (ZnO) may be internalised through ambient air or the topical application of cosmetics, only to name a few, with unpredictable health effects. Therefore, we analysed the determinants of ZnO nanoparticle (NP) genotoxicity. ZnO NPs (15-18 nm in diameter) were investigated at concentrations of 0.1, 10 and 100 μg mL-1 using the cell line A549. Internalised NPs were only infrequently detectable by TEM, but strongly increased Zn2+ levels in the cytoplasm and even more in the nuclear fraction, as measured by atom absorption spectroscopy, indicative of an internalised zinc and nuclear accumulation. We observed a time and dosage dependent reduction of cellular viability after ZnO NP exposure. ZnCl2 exposure to cells induced similar impairments of cellular viability. Complexation of Zn2+ with diethylene triamine pentaacetic acid (DTPA) resulted in the loss of toxicity of NPs, indicating the relevant role of Zn2+ for ZnO NP toxicity. Foci analyses showed the induction of DNA double strand breaks (DSBs) by ZnO NPs and increased intracellular reactive oxygen species (ROS) levels. Treatment of the cells with the ROS scavenger N-acetyl-l-cysteine (NAC) resulted in strongly decreased intracellular ROS levels and reduced DNA damage. However, a slow increase of ROS after ZnO NP exposure and reduced but not quashed DSBs after NAC-treatment suggest that Zn2+ may exert genotoxic activities without the necessity of preceding ROS-induction. Our data indicate that ZnO NP toxicity is a result of cellular Zn2+ intake. Subsequently increased ROS-levels cause DNA damage. However, we found evidence for

  20. Genotoxicity and carcinogenicity risk of carbon nanotubes.

    PubMed

    Toyokuni, Shinya

    2013-12-01

    Novel materials are often commercialized without a complete assessment of the risks they pose to human health because such assessments are costly and time-consuming; additionally, sometimes the methodology needed for such an assessment does not exist. Carbon nanotubes have the potential for widespread application in engineering, materials science and medicine. However, due to the needle-like shape and high durability of multiwalled carbon nanotubes (MWCNTs), concerns have been raised that they may induce asbestos-like pathogenicity when inhaled. Indeed, experiments in rodents supported this hypothesis. Notably, the genetic alterations in MWCNT-induced rat malignant mesothelioma were similar to those induced by asbestos. Single-walled CNTs (SWCNTs) cause mitotic disturbances in cultured cells, but thus far, there has been no report that SWCNTs are carcinogenic. This review summarizes the recent noteworthy publications on the genotoxicity and carcinogenicity of CNTs and explains the possible molecular mechanisms responsible for this carcinogenicity. The nanoscale size and needle-like rigid structure of CNTs appear to be associated with their pathogenicity in mammalian cells, where carbon atoms are major components in the backbone of many biomolecules. Publishing adverse events associated with novel materials is critically important for alerting people exposed to such materials. CNTs still have a bright future with superb economic and medical merits. However, appropriate regulation of the production, distribution and secondary manufacturing processes is required, at least to protect the workers.

  1. Genotoxicity profile of fexinidazole--a drug candidate in clinical development for human African trypanomiasis (sleeping sickness).

    PubMed

    Tweats, David; Bourdin Trunz, Bernadette; Torreele, Els

    2012-09-01

    The parasitic disease human African trypanomiasis (HAT), also known as sleeping sickness, is a highly neglected fatal condition endemic in sub-Saharan Africa, which is poorly treated with medicines that are toxic, no longer effective or very difficult to administer. New, safe, effective and easy-to-use treatments are urgently needed. Many nitroimidazoles possess antibacterial and antiprotozoal activity and examples such as tinidazole are used to treat trichomoniasis and guardiasis, but concerns about toxicity including genotoxicity limit their usefulness. Fexinidazole, a 2-substituted 5-nitroimidazole rediscovered by the Drugs for Neglected Diseases initiative (DNDi) after extensive compound mining of public and pharmaceutical company databases, has the potential to become a short-course, safe and effective oral treatment, curing both acute and chronic HAT. This paper describes the genotoxicity profile of fexinidazole and its two active metabolites, the sulfoxide and sulfone derivatives. All the three compounds are mutagenic in the Salmonella/Ames test; however, mutagenicity is either attenuated or lost in Ames Salmonella strains that lack one or more nitroreductase(s). It is known that these enzymes can nitroreduce compounds with low redox potentials, whereas their mammalian cell counterparts cannot, under normal conditions. Fexinidazole and its metabolites have low redox potentials and all mammalian cell assays to detect genetic toxicity, conducted for this study either in vitro (micronucleus test in human lymphocytes) or in vivo (ex vivo unscheduled DNA synthesis in rats; bone marrow micronucleus test in mice), were negative. Thus, fexinidazole does not pose a genotoxic hazard to patients and represents a promising drug candidate for HAT. Fexinidazole is expected to enter Phase II clinical trials in 2012.

  2. Revision of OECD Guidelines for Genotoxicity Testing: Current Status and Next Steps

    EPA Science Inventory

    Over the past 30 years, assays have been developed to evaluate chemical genotoxicity. OECD Genotoxicity Test Guidelines (TG) describe assay procedures for regulatory safety testing. Since the last OECD TG revision (1997), there has been tremendous scientific and technological pro...

  3. METHYLATED ASIII COMPOUNDS AS POTENTIAL PROXIMATE/ULTIMATE GENOTOXIC METABOLITES OF INORGANIC ARSENIC

    EPA Science Inventory

    METHYLATED Asm COMPOUNDS AS POTENTIAL PROXIMATE/ULTIMATE GENOTOXIC METABOLITES OF INORGANIC ARSENIC.

    The methylation of inorganic arsenic has typically been viewed as a detoxification process. Genotoxicity tests have generally shown that arsenite has greater mutagenic p...

  4. Power Radiated from ITER and CIT by Impurities

    DOE R&D Accomplishments Database

    Cummings, J.; Cohen, S. A.; Hulse, R.; Post, D. E.; Redi, M. H.; Perkins, J.

    1990-07-01

    The MIST code has been used to model impurity radiation from the edge and core plasmas in ITER and CIT. A broad range of parameters have been varied, including Z{sub eff}, impurity species, impurity transport coefficients, and plasma temperature and density profiles, especially at the edge. For a set of these parameters representative of the baseline ITER ignition scenario, it is seen that impurity radiation, which is produced in roughly equal amounts by the edge and core regions, can make a major improvement in divertor operation without compromising core energy confinement. Scalings of impurity radiation with atomic number and machine size are also discussed.

  5. Impurities in Bose-Einstein Condensates: From Polaron to Soliton.

    PubMed

    Shadkhoo, Shahriar; Bruinsma, Robijn

    2015-09-25

    We propose that impurities in a Bose-Einstein condensate which is coupled to a transversely laser-pumped multimode cavity form an experimentally accessible and analytically tractable model system for the study of impurities solvated in correlated liquids and the breakdown of linear-response theory [corrected]. As the strength of the coupling constant between the impurity and the Bose-Einstein condensate is increased, which is possible through Feshbach resonance methods, the impurity passes from a large to a small polaron state, and then to an impurity-soliton state. This last transition marks the breakdown of linear-response theory.

  6. Power radiated from ITER and CIT by impurities

    SciTech Connect

    Cummings, J.; Cohen, S.A.; Hulse, R.; Post, D.E.; Redi, M.H.; Perkins, J.

    1990-07-01

    The MIST code has been used to model impurity radiation from the edge and core plasmas in ITER and CIT. A broad range of parameters have been varied, including Z{sub eff}, impurity species, impurity transport coefficients, and plasma temperature and density profiles, especially at the edge. For a set of these parameters representative of the baseline ITER ignition scenario, it is seen that impurity radiation, which is produced in roughly equal amounts by the edge and core regions, can make a major improvement in divertor operation without compromising core energy confinement. Scalings of impurity radiation with atomic number and machine size are also discussed. 22 refs., 16 figs.

  7. Evaluation of Cytotoxicity and Genotoxicity of Acacia aroma Leaf Extracts

    PubMed Central

    Mattana, C. M.; Cangiano, M. A.; Alcaráz, L. E.; Sosa, A.; Escobar, F.; Sabini, C.; Sabini, L.; Laciar, A. L.

    2014-01-01

    Acacia aroma, native plant from San Luis, Argentina, is commonly used as antiseptic and for healing of wounds. The present study was conducted to investigate the in vitro cytotoxicity and genotoxicity of hot aqueous extract (HAE) and ethanolic extract (EE) of A. aroma. The cytotoxic activity was assayed by neutral red uptake assay on Vero cell. Cell treatment with a range from 100 to 5000 μg/mL of HAE and EE showed that 500 μg/mL and 100 μg/mL were the maximum noncytotoxic concentrations, respectively. The CC50 was 658 μg/mL for EE and 1020 μg/mL for HAE. The genotoxicity was tested by the single-cell gel electrophoresis comet assay. The results obtained in the evaluation of DNA cellular damage exposed to varied concentrations of the HAE showed no significant genotoxic effect at range of 1–20 mg/mL. The EE at 20 mg/mL showed moderate genotoxic effect related to the increase of the DNA percentage contained in tail of the comet; DNA was classified in category 2. At concentrations below 5 mg/mL, the results of cytotoxicity and genotoxicity of aqueous and ethanolic extracts of Acacia aroma guarantee the safety at cell and genomic level. However further studies are needed for longer periods including animal models to confirm the findings. PMID:25530999

  8. Genotoxic risk in rubber manufacturing industry: a systematic review.

    PubMed

    Bolognesi, Claudia; Moretto, Angelo

    2014-10-15

    A large body of evidence from epidemiological studies among workers employed in the rubber manufacturing industry has indicated a significant excess cancer risk in a variety of sites. The International Agency for Research on Cancer has recently classified the "Occupational exposures in the rubber-manufacturing industry" as carcinogenic to humans (Group 1). A genotoxic mechanism for the increased cancer risk was suggested on the basis of the evidence from the scientific literature. Exposure assessment studies have shown that workers in the rubber manufacturing industry may be exposed to different airborne carcinogenic and/or genotoxic chemicals, such as certain aromatic amines, polycyclic aromatic hydrocarbons, N-nitrosamines, although the available information does not allow to establish a causal association of cancer or genotoxic risk with particular substances/classes of chemicals or specific jobs. The aim of this paper is to critically evaluate, by conducting a systematic review, the available biomonitoring studies using genotoxicity biomarkers in rubber manufacturing industry. This systematic review suggests that a genotoxic hazard may still be present in certain rubber manufacturing industries. A quantitative risk assessment needs further studies addressing the different, processes and chemicals in the rubber manufacturing industries.

  9. Environmental genotoxicity assessment of an urban stream using freshwater planarians.

    PubMed

    Prá, Daniel; Lau, Adriana Helena; Knakievicz, Tanise; Carneiro, Flávia Rosa; Erdtmann, Bernardo

    2005-08-01

    Pollution is a major concern in urban areas. Due to its biological significance, genotoxicity should be a main focus for pollution biomonitoring, due mainly to the increasing complexity of the chemical environment in which organisms are exposed. Diluvio's Basin (Porto Alegre, RS, Brazil) is a heavily polluted urban ecosystem impacted by urban wastewater. Planarians are useful organism for evaluating environmental genotoxicity because of their high sensitivity, low cost, high proliferative rate and also because of their basal evolutionary position in relation to complex metazoans. Comet assay is a powerful and highly sensitive method of evaluating primary DNA lesions. Based on the unique features of planarians and the current environmental state of Diluvio's Basin, the aim of this work was to evaluate the genotoxic potential of this body of water using comet assay in planarians. Planarians were exposed to the water for 13 days in a laboratory and comet assay was performed in order to screen possible DNA damages. The results indicated an increasing gradient of damage towards basin's mouth. Such a gradient could be related to the gradual increase of pollutants among the different sample sites. Moreover, there seems to be a correlation between the urbanization gradient that exists within the watershed and the genotoxicity. Historical physical-chemical data was also gathered and examined for possible correlations with genotoxicity. Comet assay in planarians is a very promising test for environmental monitoring studies. Its application should be expanded.

  10. Evaluation of genotoxicity testing of FDA approved large molecule therapeutics.

    PubMed

    Sawant, Satin G; Fielden, Mark R; Black, Kurt A

    2014-10-01

    Large molecule therapeutics (MW>1000daltons) are not expected to enter the cell and thus have reduced potential to interact directly with DNA or related physiological processes. Genotoxicity studies are therefore not relevant and typically not required for large molecule therapeutic candidates. Regulatory guidance supports this approach; however there are examples of marketed large molecule therapeutics where sponsors have conducted genotoxicity studies. A retrospective analysis was performed on genotoxicity studies of United States FDA approved large molecule therapeutics since 1998 identified through the Drugs@FDA website. This information was used to provide a data-driven rationale for genotoxicity evaluations of large molecule therapeutics. Fifty-three of the 99 therapeutics identified were tested for genotoxic potential. None of the therapeutics tested showed a positive outcome in any study except the peptide glucagon (GlucaGen®) showing equivocal in vitro results, as stated in the product labeling. Scientific rationale and data from this review indicate that testing of a majority of large molecule modalities do not add value to risk assessment and support current regulatory guidance. Similarly, the data do not support testing of peptides containing only natural amino acids. Peptides containing non-natural amino acids and small molecules in conjugated products may need to be tested.

  11. Evaluation of cytotoxicity and genotoxicity of Acacia aroma leaf extracts.

    PubMed

    Mattana, C M; Cangiano, M A; Alcaráz, L E; Sosa, A; Escobar, F; Sabini, C; Sabini, L; Laciar, A L

    2014-01-01

    Acacia aroma, native plant from San Luis, Argentina, is commonly used as antiseptic and for healing of wounds. The present study was conducted to investigate the in vitro cytotoxicity and genotoxicity of hot aqueous extract (HAE) and ethanolic extract (EE) of A. aroma. The cytotoxic activity was assayed by neutral red uptake assay on Vero cell. Cell treatment with a range from 100 to 5000 μg/mL of HAE and EE showed that 500 μg/mL and 100 μg/mL were the maximum noncytotoxic concentrations, respectively. The CC50 was 658 μg/mL for EE and 1020 μg/mL for HAE. The genotoxicity was tested by the single-cell gel electrophoresis comet assay. The results obtained in the evaluation of DNA cellular damage exposed to varied concentrations of the HAE showed no significant genotoxic effect at range of 1-20 mg/mL. The EE at 20 mg/mL showed moderate genotoxic effect related to the increase of the DNA percentage contained in tail of the comet; DNA was classified in category 2. At concentrations below 5 mg/mL, the results of cytotoxicity and genotoxicity of aqueous and ethanolic extracts of Acacia aroma guarantee the safety at cell and genomic level. However further studies are needed for longer periods including animal models to confirm the findings.

  12. Genotoxicity of retroviral hematopoietic stem cell gene therapy

    PubMed Central

    Trobridge, Grant D

    2012-01-01

    Introduction Retroviral vectors have been developed for hematopoietic stem cell (HSC) gene therapy and have successfully cured X-linked severe combined immunodeficiency (SCID-X1), adenosine deaminase deficiency (ADA-SCID), adrenoleukodystrophy, and Wiskott-Aldrich syndrome. However, in HSC gene therapy clinical trials, genotoxicity mediated by integrated vector proviruses has led to clonal expansion, and in some cases frank leukemia. Numerous studies have been performed to understand the molecular basis of vector-mediated genotoxicity with the aim of developing safer vectors and safer gene therapy protocols. These genotoxicity studies are critical to advancing HSC gene therapy. Areas covered This review provides an introduction to the mechanisms of retroviral vector genotoxicity. It also covers advances over the last 20 years in designing safer gene therapy vectors, and in integration site analysis in clinical trials and large animal models. Mechanisms of retroviral-mediated genotoxicity, and the risk factors that contribute to clonal expansion and leukemia in HSC gene therapy are introduced. Expert opinion Continued research on virus–host interactions and next-generation vectors should further improve the safety of future HSC gene therapy vectors and protocols. PMID:21375467

  13. Substitutional impurity in the graphene quantum dots

    NASA Astrophysics Data System (ADS)

    Sierański, K.; Szatkowski, J.

    2015-09-01

    The process of formation of the localized defect states due to substitutional impurity in sp2-bonded graphene quantum dot is considered using a simple tight-binding-type calculation. We took into account the interaction of the quantum dot atoms surrounding the substitutional impurity from the second row of elements. To saturate the external dangling sp2 orbitals of the carbon additionally 18 hydrogen atoms were introduced. The chemical formula of the quantum dot is H18C51X, where X is the symbol of substitutional atom. The position of the localized levels is determined relative to the host-atoms (C) εp energies. We focused on the effect of substitutional doping by the B, N and O on the eigenstate energies and on the total energy change of the graphene dots including for O the effect of lattice distorsion. We conclude that B, N, and O can form stable substitutional defects in graphene quantum dot.

  14. Extrinsic germanium Blocked Impurity Bank (BIB) detectors

    NASA Technical Reports Server (NTRS)

    Krabach, Timothy N.; Huffman, James E.; Watson, Dan M.

    1989-01-01

    Ge:Ga blocked-impurity-band (BIB) detectors with long wavelength thresholds greater than 190 microns and peak quantum efficiencies of 4 percent, at an operating temperature of 1.8 K, have been fabricated. These proof of concept devices consist of a high purity germanium blocking layer epitaxially grown on a Ga-doped Ge substrate. This demonstration of BIB behavior in germanium enables the development of far infrared detector arrays similar to the current silicon-based devices. Present efforts are focussed on improving the chemical vapor deposition process used to create the blocking layer and on the lithographic processing required to produce monolithic detector arrays in germanium. Approaches to test the impurity levels in both the blocking and active layers are considered.

  15. Spin pumping through magnetic impurity effect

    NASA Astrophysics Data System (ADS)

    Deng, Wei-Yin; Sheng, Li; Xing, Ding-Yu

    2015-08-01

    We propose a simple adiabatic quantum spin pump to generate pure spin current. The spin pump is driven by an ac gate voltage and a time-dependent magnetic impurity potential. It is found that the total pumped spin per cycle exhibits oscillations, whose magnitude decays exponentially with changing strength of the impurity potential. The proposed method may be useful for spintronic applications. Project supported by the State Key Program for Basic Research of China (Grant Nos. 2015CB921202, 2014CB921103, 2011CB922103, and 2010CB923400), the National Natural Science Foundation of China (Grant Nos. 11225420, 11174125, and 91021003), and the Priority Academic Program Development of Jiangsu Higher Education Institutions.

  16. Bound States in Boson Impurity Models

    NASA Astrophysics Data System (ADS)

    Shi, Tao; Wu, Ying-Hai; González-Tudela, A.; Cirac, J. I.

    2016-04-01

    The formation of bound states involving multiple particles underlies many interesting quantum physical phenomena, such as Efimov physics or superconductivity. In this work, we show the existence of an infinite number of such states for some boson impurity models. They describe free bosons coupled to an impurity and include some of the most representative models in quantum optics. We also propose a family of wave functions to describe the bound states and verify that it accurately characterizes all parameter regimes by comparing its predictions with exact numerical calculations for a one-dimensional tight-binding Hamiltonian. For that model, we also analyze the nature of the bound states by studying the scaling relations of physical quantities, such as the ground-state energy and localization length, and find a nonanalytical behavior as a function of the coupling strength. Finally, we discuss how to test our theoretical predictions in experimental platforms, such as photonic crystal structures and cold atoms in optical lattices.

  17. Reducing pharmaceutical risk.

    PubMed

    Spilker, B

    1998-08-01

    This article describes several types of risk encountered in drug discovery, development and marketing, as well as the overall business risks in the pharmaceutical industry. Discovery risk refers to the risk companies face if they are partly or totally dependent on discovering new drugs; many avenues are presented for companies to pursue in order to decrease discovery risk. Development risk is defined as the risk that drug discoveries that enter development will not reach the market and become commercially viable drugs. To decrease development risk, it is possible to pursue one or more of the approaches presented. Significant marketing risks for a company include that the sales forecasts will not be met, the positioning of a drug may not be correct or optimal and the sales force is not performing adequately. At the corporate level there are numerous major risks involved in pursuing the specific mission, objectives, strategies and tactics of the overall company as well as those in the functional areas. Many aspects of the company's business can be adjusted or changed to decrease corporate risk. Selected issues concerning risk include venture capital funds, the appetite for risk within a company and the influence of senior and middle level managers' personalities on risk.

  18. Pharmaceutical prospects of phytoestrogens.

    PubMed

    Usui, Takeshi

    2006-02-01

    Interest in the physiologic and pharmacologic role of bioactive compounds present in plants has increased dramatically over the last decade. Of particular interest in relation to human health are the classes of compounds known as the phytoestrogens, which embody several groups of non-steroidal estrogens, including isoflavones and lignans that are widely distributed within nature. The impact of dietary phytoestrogens on normal biologic processes was first recognized in sheep. Observations of sheep grazing on fields rich in clover and cheetahs fed high soy diets in zoos suggested that flavonoids and related phytochemicals can affect mammalian health. Endogenous estrogens have an important role not only in the hypothalamic-pituitary-gonadal axis, but also in various non-gonadal systems, such as cardiovascular systems, bone, and central nervous systems, and lipid metabolism. There have been several clinical studies of hormone replacement therapy (HRT) in post-menopausal women to examine whether HRT has beneficial effects on the cardiovascular system, bone fractures, lipid metabolism, and Alzheimer's disease. In addition, estrogen contributes to the development of some estrogen-dependent cancers, such as breast cancer and prostate cancer and the number of patients with these cancers is increasing in developed countries. Although recent mega-studies showed negative results for classical HRT in the prevention of some of these diseases, the molecules that interact with estrogen receptors are candidate drugs for various diseases, including hormone-dependent cancers. This review focuses on the molecular properties and pharmaceutical potential of phytoestrogens.

  19. Reducing pharmaceutical risk.

    PubMed

    Spilker, B

    1998-08-01

    This article describes several types of risk encountered in drug discovery, development and marketing, as well as the overall business risks in the pharmaceutical industry. Discovery risk refers to the risk companies face if they are partly or totally dependent on discovering new drugs; many avenues are presented for companies to pursue in order to decrease discovery risk. Development risk is defined as the risk that drug discoveries that enter development will not reach the market and become commercially viable drugs. To decrease development risk, it is possible to pursue one or more of the approaches presented. Significant marketing risks for a company include that the sales forecasts will not be met, the positioning of a drug may not be correct or optimal and the sales force is not performing adequately. At the corporate level there are numerous major risks involved in pursuing the specific mission, objectives, strategies and tactics of the overall company as well as those in the functional areas. Many aspects of the company's business can be adjusted or changed to decrease corporate risk. Selected issues concerning risk include venture capital funds, the appetite for risk within a company and the influence of senior and middle level managers' personalities on risk. PMID:15616620

  20. Impurities: Curse and blessing for crystal growers

    NASA Astrophysics Data System (ADS)

    Fox, Donald K.; Mazelsky, R.

    1990-11-01

    The indespensability of high-quality source materials research and development has been established for many years. However, because contributors to this field are diverse and communication of research results is often fragmented, transfer of the new knowledge is very slow. This paper describes how increasing source purity has improved the quality of several crystals, and how the addition of controlled impurities has decreased the defect density in these crystals. Experimental evidence is presented in this paper.

  1. Prioritizing pharmaceuticals in municipal wastewater

    EPA Science Inventory

    Oral presentation at SETAC North America 32nd annual meeting, describing our prioritization of active pharmaceutical ingredients (APIs), based on estimates of risks posed by API residues originating from municipal wastewater. Goals of this project include prioritization of APIs f...

  2. Recognizing misleading pharmaceutical marketing online.

    PubMed

    De Freitas, Julian; Falls, Brian A; Haque, Omar S; Bursztajn, Harold J

    2014-01-01

    In light of decision-making psychology, this article details how drug marketing operates across established and novel web domains and identifies some common misleading trends and influences on prescribing and patient-initiated medication requests. The Internet has allowed pharmaceutical marketing to become more salient than ever before. Although the Internet's growth has improved the dissemination of pharmaceutical information, it has also led to the increased influence of misleading pharmaceutical marketing. Such mismarketing is of concern, especially in psychiatry, since psychotropics generate considerable revenue for drug companies. In a climate of resource-limited drug regulation and time-strapped physicians, we recommend improving both independent monitoring and consumer awareness of Internet-enabled, potentially misleading, pharmaceutical marketing influences.

  3. Effect of impurities and processing on silicon solar cells. Volume 1: Characterization methods for impurities in silicon and impurity effects data base

    NASA Technical Reports Server (NTRS)

    Hopkins, R. H.; Davis, J. R.; Rohatgi, A.; Campbell, R. B.; Blais, P. D.; Rai-Choudhury, P.; Stapleton, R. E.; Mollenkopf, H. C.; Mccormick, J. R.

    1980-01-01

    Two major topics are treated: methods to measure and evaluate impurity effects in silicon and comprehensive tabulations of data derived during the study. Discussions of deep level spectroscopy, detailed dark I-V measurements, recombination lifetime determination, scanned laser photo-response, conventional solar cell I-V techniques, and descriptions of silicon chemical analysis are presented and discussed. The tabulated data include lists of impurity segregation coefficients, ingot impurity analyses and estimated concentrations, typical deep level impurity spectra, photoconductive and open circuit decay lifetimes for individual metal-doped ingots, and a complete tabulation of the cell I-V characteristics of nearly 200 ingots.

  4. Impurity scattering and Friedel oscillations in monolayer black phosphorus

    NASA Astrophysics Data System (ADS)

    Zou, Yong-Lian; Song, Juntao; Bai, Chunxu; Chang, Kai

    2016-07-01

    We study the impurity scattering effect in black phosphorene (BP) in this work. For a single impurity, we calculate the impurity-induced local density of states (LDOS) in momentum space numerically based on a tight-binding Hamiltonian. In real space, we calculate the LDOS and Friedel oscillation analytically. The LDOS shows strong anisotropy in BP. Many impurities in BP are investigated using the T -matrix approximation when the density is low. Midgap states appear in the band gap with peaks in the DOS. The peaks of midgap states are dependent on the impurity potential. For finite positive potential, the impurity tends to bind negative charge carriers and vice versa. The infinite-impurity-potential problem is related to chiral symmetry in BP.

  5. What drives success for specialty pharmaceuticals?

    PubMed

    Gudiksen, Mark; Fleming, Edd; Furstenthal, Laura; Ma, Philip

    2008-07-01

    Specialty pharmaceuticals have become increasingly important in the global pharmaceutical landscape. Numerous large pharmaceutical companies are moving towards developing therapies for specialty markets, which are attractive owing to factors including the established commercial track record and lower commercial infrastructure costs. In this article, we analyse the key drivers of commercial success and failure for specialty pharmaceuticals.

  6. [Pharmaceutical chemistry of general anaesthetics].

    PubMed

    Szász, György; Takácsné, Novák Krisztina

    2004-01-01

    The paper represents the first part of a planned series of reviews about pharmaceutical chemistry of drugs acting on the central nervous system. The authorial aim and editorial concepts are the same were followed in a former series of papers about pharmaceutical chemistry of agents effecting the heart, blood circulation and vegetative nervous system. Consequently, general anaesthetics are discussed in the present paper through the chapters "history, preparation; structure-properties-activity; application; analysis".

  7. Cross-type spectrum rearrangement in graphene with weakly bound impurity centres: an impurity band with anomalous dispersion.

    PubMed

    Skrypnyk, Yuriy V; Loktev, Vadim M

    2013-05-15

    It is demonstrated that an anomalous dispersion region appears in the energy spectrum of charge carriers in graphene on increasing the concentration of weakly bound impurity centres. The corresponding spectrum rearrangement evolves in the neighbourhood of the impurity resonance energy and is of the cross type. The opening of the anomalous dispersion region in the impure graphene is accompanied by a doubling of the number of Dirac points in its electron spectrum. The stated spectrum rearrangement unfolds in a threshold manner, i.e. it takes place when the impurity concentration exceeds a certain critical value, which is determined by the mutual spatial overlap of individual impurity states.

  8. Evaluation of subchronic genotoxic potential of Swarna Makshika Bhasma

    PubMed Central

    Savalgi, Pavan B.; Patgiri, Biswajyoti; Thakkar, Jalaram H.; Ravishankar, B.; Gupta, Varun B.

    2012-01-01

    Extremely diminutive published information is available on the mutagenic activity of Ayurvedic Bhasmas. Genotoxicity of few Bhasmas were reported on single maximum dose, but no reference is available on the sub-chronic level. Hence the present study was carried to generate and evaluate genotoxic potentials of Swarna Makshika Bhasma (mineral preparation) administered at therapeutic dose for 14 days. Chromosomal aberrations and abnormal sperm assay parameters were taken in this study. Cyclophosphamide (CP) was taken as positive group and results were compared. The results revealed a lack of generation of structural deformity in above parameters by tested drugs compared to CP treated group. Observed data indicate that the Bhasmas tested were non-genotoxic under the experimental conditions. PMID:23723652

  9. Genotoxicity of Superparamagnetic Iron Oxide Nanoparticles in Granulosa Cells

    PubMed Central

    Pöttler, Marina; Staicu, Andreas; Zaloga, Jan; Unterweger, Harald; Weigel, Bianca; Schreiber, Eveline; Hofmann, Simone; Wiest, Irmi; Jeschke, Udo; Alexiou, Christoph; Janko, Christina

    2015-01-01

    Nanoparticles that are aimed at targeting cancer cells, but sparing healthy tissue provide an attractive platform of implementation for hyperthermia or as carriers of chemotherapeutics. According to the literature, diverse effects of nanoparticles relating to mammalian reproductive tissue are described. To address the impact of nanoparticles on cyto- and genotoxicity concerning the reproductive system, we examined the effect of superparamagnetic iron oxide nanoparticles (SPIONs) on granulosa cells, which are very important for ovarian function and female fertility. Human granulosa cells (HLG-5) were treated with SPIONs, either coated with lauric acid (SEONLA) only, or additionally with a protein corona of bovine serum albumin (BSA; SEONLA-BSA), or with dextran (SEONDEX). Both micronuclei testing and the detection of γH2A.X revealed no genotoxic effects of SEONLA-BSA, SEONDEX or SEONLA. Thus, it was demonstrated that different coatings of SPIONs improve biocompatibility, especially in terms of genotoxicity towards cells of the reproductive system. PMID:26540051

  10. Monitoring hospital wastewaters for their probable genotoxicity and mutagenicity.

    PubMed

    Sharma, Pratibha; Mathur, N; Singh, A; Sogani, M; Bhatnagar, P; Atri, R; Pareek, S

    2015-01-01

    Cancer is a leading cause of death worldwide. Excluding the genetic factors, environmental factors, mainly the pollutants, have been implicated in the causation of the majority of cancers. Wastewater originated from health-care sectors such as hospitals may carry vast amounts of carcinogenic and genotoxic chemicals to surface waters or any other source of drinking water, if discharged untreated. Humans get exposed to such contaminants through a variety of ways including drinking water. The aim of the present study was, thus, to monitor the genotoxic and mutagenic potential of wastewaters from three big hospitals located in Jaipur (Rajasthan), India. One of them was operating an effluent treatment plant (ETP) for treatment of its wastewater and therefore both the untreated and treated effluents from this hospital were studied for their genotoxicity. Two short-term bacterial bioassays namely the Salmonella fluctuation assay and the SOS chromotest were used for the purpose. Results of fluctuation assay revealed the highly genotoxic nature of all untreated effluent samples with mutagenicity ratios (MR) up to 23.13 ± 0.18 and 42.25 ± 0.35 as measured with Salmonella typhimurium strains TA98 and TA100, respectively. As determined with the chromotest, all untreated effluents produced significant induction factors (IF) ranging from 3.29 ± 1.11 to 13.35 ± 3.58 at higher concentrations. In contrast, treated effluent samples were found to be slightly genotoxic in fluctuation test only with an MR = 3.75 ± 0.35 for TA100 at 10 % concentration. Overall, the results indicated that proper treatment of hospital wastewaters may render the effluents safe for disposal contrary to the untreated ones, possessing high genotoxic potential. PMID:25487460

  11. Motion of a Distinguishable Impurity in the Bose Gas: Arrested Expansion Without a Lattice and Impurity Snaking

    NASA Astrophysics Data System (ADS)

    Robinson, Neil J.; Caux, Jean-Sébastien; Konik, Robert M.

    2016-04-01

    We consider the real-time dynamics of an initially localized distinguishable impurity injected into the ground state of the Lieb-Liniger model. Focusing on the case where integrability is preserved, we numerically compute the time evolution of the impurity density operator in regimes far from analytically tractable limits. We find that the injected impurity undergoes a stuttering motion as it moves and expands. For an initially stationary impurity, the interaction-driven formation of a quasibound state with a hole in the background gas leads to arrested expansion—a period of quasistationary behavior. When the impurity is injected with a finite center-of-mass momentum, the impurity moves through the background gas in a snaking manner, arising from a quantum Newton's cradlelike scenario where momentum is exchanged back and forth between the impurity and the background gas.

  12. Motion of a distinguishable Impurity in the Bose gas: Arrested expansion without a lattice and impurity snaking

    DOE PAGESBeta

    Neil J. Robinson; Caux, Jean -Sebastien; Konik, Robert M.

    2016-04-07

    We consider the real-time dynamics of an initially localized distinguishable impurity injected into the ground state of the Lieb-Liniger model. Focusing on the case where integrability is preserved, we numerically compute the time evolution of the impurity density operator in regimes far from analytically tractable limits. We find that the injected impurity undergoes a stuttering motion as it moves and expands. For an initially stationary impurity, the interaction-driven formation of a quasibound state with a hole in the background gas leads to arrested expansion—a period of quasistationary behavior. In conclusion, when the impurity is injected with a finite center-of-mass momentum,more » the impurity moves through the background gas in a snaking manner, arising from a quantum Newton’s cradlelike scenario where momentum is exchanged back and forth between the impurity and the background gas.« less

  13. Motion of a Distinguishable Impurity in the Bose Gas: Arrested Expansion Without a Lattice and Impurity Snaking.

    PubMed

    Robinson, Neil J; Caux, Jean-Sébastien; Konik, Robert M

    2016-04-01

    We consider the real-time dynamics of an initially localized distinguishable impurity injected into the ground state of the Lieb-Liniger model. Focusing on the case where integrability is preserved, we numerically compute the time evolution of the impurity density operator in regimes far from analytically tractable limits. We find that the injected impurity undergoes a stuttering motion as it moves and expands. For an initially stationary impurity, the interaction-driven formation of a quasibound state with a hole in the background gas leads to arrested expansion-a period of quasistationary behavior. When the impurity is injected with a finite center-of-mass momentum, the impurity moves through the background gas in a snaking manner, arising from a quantum Newton's cradlelike scenario where momentum is exchanged back and forth between the impurity and the background gas. PMID:27104716

  14. Validated HPLC method for quantifying permethrin in pharmaceutical formulations.

    PubMed

    García, E; García, A; Barbas, C

    2001-03-01

    An isocratic HPLC method for permethrin determination in raw material and pharmaceutical presentations as lotion and shampoo has been developed and validated following ICH recommendations. Cis and trans- isomers, impurities and degradation products are well separated. The chromatographic analysis were performed on a 4 microm particle C-18 Nova-Pak (Waters, Madrid, Spain) column (15 x 0.39 cm) kept in a Biorad column oven at 35 degrees C. Mobile phase consisted of methanol--water (78:22, v/v) at a flow rate of 1 ml/min. UV detection was performed at 272 nm and peaks were identified with retention times as compared with standards and confirmed with characteristic spectra using the photodiode array detector.

  15. [Environmental quality of Volturno river with toxic and genotoxic findings].

    PubMed

    Parrella, A; Isidori, M; Lavorgna, M; Dell'Aquila, A

    2003-01-01

    In order to assess the environmental quality of Volturno river in Southern Italy, the Extended Biotic Index, chemical and microbiological parameters were determined in nine sampling points as provided for D. Lgs. 152/99. Furthermore, this study reported toxicity of surface waters and pore waters from sediments and genotoxicity of pore waters to improve the definition of the ecological condition of the investigated watercourse. Results showed that toxicity and genotoxicity testing contributed to assess environmental quality and pore waters are an useful tool to combine investigations. PMID:12838830

  16. Genotoxic effects of arsenic: prevention by functional food-jaggery.

    PubMed

    Singh, Nrashant; Kumar, D; Raisuddin, S; Sahu, Anand P

    2008-09-18

    Arsenic contamination in groundwater is global human health hazard. There is no effective remedial action of chronic arsenicosis, however, a well-nourished diet can modulate the onset of adverse health effects and the delayed effect of arsenic in drinking water. In the present work, genotoxic effects induced by arsenic through parenteral administration and ameliorate by jaggery. Chromosomal aberrations were more pronounced in arsenic treated mice, while supplementation of jaggery with arsenic reduced the incidence of the aberrations. The outcome of study showed that Jaggery the natural functional food has the efficiency to encounter the genotoxic effects induced by arsenic.

  17. Mutagenicity and genotoxicity of sorbic acid-amine reaction products.

    PubMed

    Ferrand, C; Marc, F; Fritsch, P; Cassand, P; de Saint Blanquat, G

    2000-11-01

    Sorbic acid (E200) and its salts (potassium and calcium sorbate: E202 and E203) are allowed for use as preservatives in numerous processed foods. Sorbic acid had a conjugated system of double bonds which makes it susceptible to nucleophilic attack, sometimes giving mutagenic products. Under conditions typical of food processing (50-80 degrees C), we analysed the cyclic derivatives resulting from a double addition reaction between sorbic acid and various amines. Mutagenesis studies, involving Ames' test and genotoxicity studies with HeLa cells and plasmid DNA, showed that none of the products studied presented either mutagenic or genotoxic activities.

  18. Genotoxic and mutagenic effects of guarana (Paullinia cupana) in prokaryotic organisms.

    PubMed

    da Fonseca, C A; Leal, J; Costa, S S; Leitão, A C

    1994-05-01

    Aqueous extracts of Paullinia cupana (guarana), a species that belongs to the Sapindaceae family, were analyzed for the presence of genotoxic activities in bacterial cells. The extracts of guarana were genotoxic as assessed by lysogenic induction in Escherichia coli and they were also able to induce mutagenesis in Salmonella typhimurium. Addition of S9 microsomal fraction, catalase, superoxide dismutase or thiourea counteracted the genotoxic activity of guarana, suggesting that oxygen reactive species play an essential role in the genotoxicity of aqueous guarana extracts. The genotoxic activity in the extracts was related to the presence of a molecular complex formed by caffeine and a flavonoid (catechin or epicatechin) in the presence of potassium.

  19. Quality investigation of hydroxyprogesterone caproate active pharmaceutical ingredient and injection

    PubMed Central

    Chollet, John L.; Jozwiakowski, Michael J.

    2012-01-01

    The purpose of this study was to investigate the quality of hydroxyprogesterone caproate (HPC) active pharmaceutical ingredient (API) sources that may be used by compounding pharmacies, compared to the FDA-approved source of the API; and to investigate the quality of HPC injection samples obtained from compounding pharmacies in the US, compared to the FDA-approved product (Makena®). Samples of API were obtained from every source confirmed to be an original manufacturer of the drug for human use, which were all companies in China that were not registered with FDA. Eight of the ten API samples (80%) did not meet the impurity specifications required by FDA for the API used in the approved product. One API sample was found to not be HPC at all; additional laboratory testing showed that it was glucose. Thirty samples of HPC injection obtained from com pounding pharmacies throughout the US were also tested, and eight of these samples (27%) failed to meet the potency requirement listed in the USP monograph for HPC injection and/or the HPLC assay. Sixteen of the thirty injection samples (53%) exceeded the impurity limit setforthe FDA-approved drug product. These results confirm the inconsistency of compounded HPC Injections and suggest that the risk-benefit ratio of using an unapproved compounded preparation, when an FDA-approved drug product is available, is not favorable. PMID:22329865

  20. SIGNALING TO THE P53 TUMOR SUPPRESSOR THROUGH PATHWAYS ACTIVATED BY GENOTOXIC AND NON-GENOTOXIC STRESSES.

    SciTech Connect

    ANDERSON,C.W.APPELLA,E.

    2002-07-01

    The p53 tumor suppressor is a tetrameric transcription factor that is post-translational modified at {approx}18 different sites by phosphorylation, acetylation, or sumoylation in response to various cellular stress conditions. Specific posttranslational modifications, or groups of modifications, that result from the activation of different stress-induced signaling pathways are thought to modulate p53 activity to regulate cell fate by inducing cell cycle arrest, apoptosis, or cellular senescence. Here we review the posttranslational modifications to p53 and the pathways that produce them in response to both genotoxic and non-genotoxic stresses.

  1. Virtual pharmaceutical companies: collaborating flexibly in pharmaceutical development.

    PubMed

    Forster, Simon P; Stegmaier, Julia; Spycher, Rene; Seeger, Stefan

    2014-03-01

    Research and development (R&D) collaborations represent one approach chosen by the pharmaceutical industry to tackle current challenges posed by declining internal R&D success rates and fading of the blockbuster model. In recent years, a flexible concept to collaborate in R&D has emerged: virtual pharmaceutical companies (VPCs). These differ from other R&D companies, such as biotech start-ups, collaborating with big pharmaceutical companies, because they solely comprise experienced teams of managers. VPCs have only been described anecdotally in literature. Thus, we present here the characteristics of a VPC and suggest how big pharma can leverage the concept of VPCs by introducing five possible modes of collaboration. We find that one mode, investing, is particularly promising for big pharma. PMID:24291787

  2. Virtual pharmaceutical companies: collaborating flexibly in pharmaceutical development.

    PubMed

    Forster, Simon P; Stegmaier, Julia; Spycher, Rene; Seeger, Stefan

    2014-03-01

    Research and development (R&D) collaborations represent one approach chosen by the pharmaceutical industry to tackle current challenges posed by declining internal R&D success rates and fading of the blockbuster model. In recent years, a flexible concept to collaborate in R&D has emerged: virtual pharmaceutical companies (VPCs). These differ from other R&D companies, such as biotech start-ups, collaborating with big pharmaceutical companies, because they solely comprise experienced teams of managers. VPCs have only been described anecdotally in literature. Thus, we present here the characteristics of a VPC and suggest how big pharma can leverage the concept of VPCs by introducing five possible modes of collaboration. We find that one mode, investing, is particularly promising for big pharma.

  3. Entanglement in quantum impurity problems is nonperturbative

    NASA Astrophysics Data System (ADS)

    Saleur, H.; Schmitteckert, P.; Vasseur, R.

    2013-08-01

    We study the entanglement entropy of a region of length 2L with the remainder of an infinite one-dimensional gapless quantum system in the case where the region is centered on a quantum impurity. The coupling to this impurity is not scale invariant, and the physics involves a crossover between weak- and strong-coupling regimes. While the impurity contribution to the entanglement has been computed numerically in the past, little is known analytically about it, since in particular the methods of conformal invariance cannot be applied because of the presence of a crossover length. We show in this paper that the small coupling expansion of the entanglement entropy in this problem is quite generally plagued by strong infrared divergences, implying a nonperturbative dependence on the coupling. The large coupling expansion turns out to be better behaved, thanks to powerful results from the boundary CFT formulation and, in some cases, the underlying integrability of the problem. However, it is clear that this expansion does not capture well the crossover physics. In the integrable case—which includes problems such as an XXZ chain with a modified link, the interacting resonant level model or the anisotropic Kondo model—a nonperturbative approach is in principle possible using form factors. We adapt in this paper the ideas of Cardy [J. Stat. Phys.JSTPBS0022-471510.1007/s10955-007-9422-x 130, 129 (2008)] and Castro-Alvaredo and Doyon [J. Stat. Phys.JSTPBS0022-471510.1007/s10955-008-9664-2 134, 105 (2009)] to the gapless case and show that, in the rather simple case of the resonant level model, and after some additional renormalizations, the form-factors approach yields remarkably accurate results for the entanglement all the way from short to large distances. This is confirmed by detailed comparison with numerical simulations. Both our form factor and numerical results are compatible with a nonperturbative form at short distance.

  4. Evaluating additives and impurities in zinc electrowinning

    NASA Astrophysics Data System (ADS)

    Gonzalez-Dominguez, J. A.; Lew, R. W.

    1995-01-01

    The zinc electrowinning (EW) process is very sensitive to the presence of impurities. There is only one EW plant in the world that we know of that operates at moderate current efficiency and deposition times without using any additives. All the others must use them continuously. Additives allow zinc EW to occur at high current efficiencies while suppressing excessive acid mist formation. The study of the electrochemical effects of additives in zinc EW is not straightforward. This article presents a review of the experimental techniques currently used at Cominco Research: Cyclic voltammetry, Hull cells, laboratory and mini-cell electrowinning techniques are all described and their relationship to the industrial operation is discussed.

  5. Enhanced ionized impurity scattering in nanowires

    NASA Astrophysics Data System (ADS)

    Oh, Jung Hyun; Lee, Seok-Hee; Shin, Mincheol

    2013-06-01

    The electronic resistivity in silicon nanowires is investigated by taking into account scattering as well as the donor deactivation from the dielectric mismatch. The effects of poorly screened dopant atoms from the dielectric mismatch and variable carrier density in nanowires are found to play a crucial role in determining the nanowire resistivity. Using Green's function method within the self-consistent Born approximation, it is shown that donor deactivation and ionized impurity scattering combined with the charged interface traps successfully to explain the increase in the resistivity of Si nanowires while reducing the radius, measured by Björk et al. [Nature Nanotech. 4, 103 (2009)].

  6. Macromolecule Crystal Quality Improvement in Microgravity: The Role of Impurities

    NASA Technical Reports Server (NTRS)

    Judge, Russell A.; Snell, Edward H.; Pusey, Marc L.; Sportiello, Michael G.; Todd, Paul; Bellamy, Henry; Borgstahl, Gloria E.; Pokros, Matt; Cassanto, John M.

    2000-01-01

    While macromolecule impurities may affect crystal size and morphology the over-riding question is; "How do macromolecule impurities effect crystal X-ray quality and diffraction resolution?" In the case of chicken egg white lysozyme, crystals can be grown in the presence of a number of impurities without affecting diffraction resolution. One impurity however, the lysozyme dimer, does negatively impact the X-ray crystal properties. Crystal quality improvement as a result of better partitioning of this impurity during crystallization in microgravity has been reported'. In our recent experimental work dimer partitioning was found to be not significantly different between the two environments. Mosaicity analysis of pure crystals showed a reduced mosaicity and increased signal to noise for the microgravity grown crystals. Dimer incorporation however, did greatly reduce the resolution limit in both ground and microgravity grown crystals. These results indicate that impurity effects in microgravity are complex and may rely on the conditions or techniques employed.

  7. Genotoxicity of refinery waste assessed by some DNA damage tests.

    PubMed

    Gupta, Amit Kumar; Ahmad, Irshad; Ahmad, Masood

    2015-04-01

    Refinery waste effluent is well known to contain polycyclic aromatic hydrocarbons, phenols and heavy metals as potentially genotoxic substances. The aim of the present study was to assess the genotoxic potential of Mathura refinery wastewater (MRWW) by various in vitro tests including the single cell gel electrophoresis, plasmid nicking assay and S1 nuclease assay. Treatment of human lymphocytes to different MRWW concentrations (0.15×, 0.3×, 0.5× and 0.78×) caused the formation of comets of which the mean tail lengths increased proportionately and differed significantly from those of unexposed controls. The toxic effect of MRWW on DNA was also studied by plasmid nicking assay and S1 nuclease assay. Strand breaks formation in the MRWW treated pBR322 plasmid confirmed its genotoxic effect. Moreover, a dose dependent increase in cleavage of calf thymus DNA in S1 nuclease assay was also suggestive of the DNA damaging potential of MRWW. A higher level of ROS generation in the test water sample was recorded which might be contributing to its genotoxicity. Interaction between the constituents of MRWW and calf thymus DNA was also ascertained by UV-visible spectroscopy.

  8. Review of genotoxicity biomonitoring studies of glyphosate-based formulations.

    PubMed

    Kier, Larry D

    2015-03-01

    Abstract Human and environmental genotoxicity biomonitoring studies involving exposure to glyphosate-based formulations (GBFs) were reviewed to complement an earlier review of experimental genotoxicity studies of glyphosate and GBFs. The environmental and most of the human biomonitoring studies were not informative because there was either a very low frequency of GBF exposure or exposure to a large number of pesticides without analysis of specific pesticide effects. One pesticide sprayer biomonitoring study indicated there was not a statistically significant relationship between frequency of GBF exposure reported for the last spraying season and oxidative DNA damage. There were three studies of human populations in regions of GBF aerial spraying. One study found increases for the cytokinesis-block micronucleus endpoint but these increases did not show statistically significant associations with self-reported spray exposure and were not consistent with application rates. A second study found increases for the blood cell comet endpoint at high exposures causing toxicity. However, a follow-up to this study 2 years after spraying did not indicate chromosomal effects. The results of the biomonitoring studies do not contradict an earlier conclusion derived from experimental genotoxicity studies that typical GBFs do not appear to present significant genotoxic risk under normal conditions of human or environmental exposures.

  9. Genistein genotoxicity: Critical considerations of in vitro exposure dose

    SciTech Connect

    Klein, Catherine B. King, Audrey A.

    2007-10-01

    The potential health benefits of soy-derived phytoestrogens include their reported utility as anticarcinogens, cardioprotectants and as hormone replacement alternatives in menopause. Although there is increasing popularity of dietary phytoestrogen supplementation and of vegetarian and vegan diets among adolescents and adults, concerns about potential detrimental or other genotoxic effects persist. While a variety of genotoxic effects of phytoestrogens have been reported in vitro, the concentrations at which such effects occurred were often much higher than the physiologically relevant doses achievable by dietary or pharmacologic intake of soy foods or supplements. This review focuses on in vitro studies of the most abundant soy phytoestrogen, genistein, critically examining dose as a crucial determinant of cellular effects. In consideration of levels of dietary genistein uptake and bioavailability we have defined in vitro concentrations of genistein > 5 {mu}M as non-physiological, and thus 'high' doses, in contrast to much of the previous literature. In doing so, many of the often-cited genotoxic effects of genistein, including apoptosis, cell growth inhibition, topoisomerase inhibition and others become less obvious. Recent cellular, epigenetic and microarray studies are beginning to decipher genistein effects that occur at dietarily relevant low concentrations. In toxicology, the well accepted principle of 'the dose defines the poison' applies to many toxicants and can be invoked, as herein, to distinguish genotoxic versus potentially beneficial in vitro effects of natural dietary products such as genistein.

  10. Genotoxicity of Swimming Pool Water and Carcinogenicity of Drinking Water

    EPA Science Inventory

    Among the 11 disinfection by-products (DBPs) in drinking water that are regulated by the U.S. EPA, (a) 2 DBPs (chloroaceticacid and chlorite) are not carcinogenic-in either of2 species; (b) chlorite is not carcinogenic in 3 rodent assays and has never been tested for genotoxicity...

  11. Genotoxicity of Swimming Pool Water and Carcinogenicity of Drinking Water**

    EPA Science Inventory

    Among the 11 disinfection by-products (DBPs) in drinking water that are regulated by the U.S. EPA, (a) 2 DBPs (chloroaceticacid and chlorite) are not carcinogenic-in either of2 species; (b) chlorite is not carcinogenic in 3 rodent assays and has never been tested for genotoxicity...

  12. Genistein genotoxicity: critical considerations of in vitro exposure dose.

    PubMed

    Klein, Catherine B; King, Audrey A

    2007-10-01

    The potential health benefits of soy-derived phytoestrogens include their reported utility as anticarcinogens, cardioprotectants and as hormone replacement alternatives in menopause. Although there is increasing popularity of dietary phytoestrogen supplementation and of vegetarian and vegan diets among adolescents and adults, concerns about potential detrimental or other genotoxic effects persist. While a variety of genotoxic effects of phytoestrogens have been reported in vitro, the concentrations at which such effects occurred were often much higher than the physiologically relevant doses achievable by dietary or pharmacologic intake of soy foods or supplements. This review focuses on in vitro studies of the most abundant soy phytoestrogen, genistein, critically examining dose as a crucial determinant of cellular effects. In consideration of levels of dietary genistein uptake and bioavailability we have defined in vitro concentrations of genistein >5 microM as non-physiological, and thus "high" doses, in contrast to much of the previous literature. In doing so, many of the often-cited genotoxic effects of genistein, including apoptosis, cell growth inhibition, topoisomerase inhibition and others become less obvious. Recent cellular, epigenetic and microarray studies are beginning to decipher genistein effects that occur at dietarily relevant low concentrations. In toxicology, the well accepted principle of "the dose defines the poison" applies to many toxicants and can be invoked, as herein, to distinguish genotoxic versus potentially beneficial in vitro effects of natural dietary products such as genistein. PMID:17688899

  13. Genotoxicity of refinery waste assessed by some DNA damage tests.

    PubMed

    Gupta, Amit Kumar; Ahmad, Irshad; Ahmad, Masood

    2015-04-01

    Refinery waste effluent is well known to contain polycyclic aromatic hydrocarbons, phenols and heavy metals as potentially genotoxic substances. The aim of the present study was to assess the genotoxic potential of Mathura refinery wastewater (MRWW) by various in vitro tests including the single cell gel electrophoresis, plasmid nicking assay and S1 nuclease assay. Treatment of human lymphocytes to different MRWW concentrations (0.15×, 0.3×, 0.5× and 0.78×) caused the formation of comets of which the mean tail lengths increased proportionately and differed significantly from those of unexposed controls. The toxic effect of MRWW on DNA was also studied by plasmid nicking assay and S1 nuclease assay. Strand breaks formation in the MRWW treated pBR322 plasmid confirmed its genotoxic effect. Moreover, a dose dependent increase in cleavage of calf thymus DNA in S1 nuclease assay was also suggestive of the DNA damaging potential of MRWW. A higher level of ROS generation in the test water sample was recorded which might be contributing to its genotoxicity. Interaction between the constituents of MRWW and calf thymus DNA was also ascertained by UV-visible spectroscopy. PMID:24836934

  14. THE GENOTOXICITY OF PRIORITY POLYCYCLIC AROMATIC HYDROCARBONS IN COMPLEX MIXTURES

    EPA Science Inventory

    Risk assessment of complex environmental samples suffers from difficulty in identifying toxic components, inadequacy of available toxicity data, and a paucity of knowledge about the behavior of geno(toxic) substances in complex mixtures. Lack of information about the behavior of ...

  15. Mercury-induced genotoxicity in marine diatom (Chaetoceros tenuissimus).

    PubMed

    Sarker, Subhodeep; Desai, Somashekhar R; Verlecar, Xivanand N; Sarker, Munmun Saha; Sarkar, A

    2016-02-01

    In this paper, we present an evaluation of genotoxic responses in marine diatom, Chaetoceros tenuissimus, isolated from Kandla Creek (lat 23.03° N, long 70.22° E), Gujarat, India, in terms of impairment of DNA integrity as a function of their exposure to elevated levels of mercury (Hg) under laboratory conditions. DNA integrity in C. tenuissimus was determined by partial alkaline unwinding assay. To our knowledge, this is the first such genotoxicity study to be conducted on marine diatom cultures towards understanding the relationship between Hg toxicity and DNA damage. Furthermore, we studied the impact of Hg on the growth of C. tenuissimus as a function of their exposure to enhanced levels of Hg in terms of decreasing chlorophyll a (chl a) concentrations. The data show the genotoxic effect of Hg on the growth of C. tenuissimus as well as DNA integrity to a great extent. Based on the results of our investigations, it is suggested that C. tenuissimus can be used as sentinel species for bio-monitoring of pollution due to genotoxic contaminants.

  16. Evaluation of Genotoxic Pressure along the Sava River

    PubMed Central

    Kračun-Kolarević, Margareta; Kostić, Jovana; Simonović, Predrag; Simić, Vladica; Milošković, Aleksandra; Reischer, Georg; Farnleitner, Andreas; Gačić, Zoran; Milačič, Radmila; Zuliani, Tea; Vidmar, Janja; Pergal, Marija; Piria, Marina; Paunović, Momir; Vuković-Gačić, Branka

    2016-01-01

    In this study we have performed a comprehensive genotoxicological survey along the 900 rkm of the Sava River. In total, 12 sites were chosen in compliance with the goals of GLOBAQUA project dealing with the effects of multiple stressors on biodiversity and functioning of aquatic ecosystems. The genotoxic potential was assessed using a complex battery of bioassays performed in prokaryotes and aquatic eukaryotes (freshwater fish). Battery comprised evaluation of mutagenicity by SOS/umuC test in Salmonella typhimurium TA1535/pSK1002. The level of DNA damage as a biomarker of exposure (comet assay) and biomarker of effect (micronucleus assay) and the level of oxidative stress as well (Fpg—modified comet assay) was studied in blood cells of bleak and spirlin (Alburnus alburnus/Alburnoides bipunctatus respectively). Result indicated differential sensitivity of applied bioassays in detection of genotoxic pressure. The standard and Fpg—modified comet assay showed higher potential in differentiation of the sites based on genotoxic potential in comparison with micronucleus assay and SOS/umuC test. Our data represent snapshot of the current status of the river which indicates the presence of genotoxic potential along the river which can be traced to the deterioration of quality of the Sava River by communal and industrial wastewaters. The major highlight of the study is that we have provided complex set of data obtained from a single source (homogeneity of analyses for all samples). PMID:27631093

  17. Evaluation of Genotoxic Pressure along the Sava River.

    PubMed

    Kolarević, Stoimir; Aborgiba, Mustafa; Kračun-Kolarević, Margareta; Kostić, Jovana; Simonović, Predrag; Simić, Vladica; Milošković, Aleksandra; Reischer, Georg; Farnleitner, Andreas; Gačić, Zoran; Milačič, Radmila; Zuliani, Tea; Vidmar, Janja; Pergal, Marija; Piria, Marina; Paunović, Momir; Vuković-Gačić, Branka

    2016-01-01

    In this study we have performed a comprehensive genotoxicological survey along the 900 rkm of the Sava River. In total, 12 sites were chosen in compliance with the goals of GLOBAQUA project dealing with the effects of multiple stressors on biodiversity and functioning of aquatic ecosystems. The genotoxic potential was assessed using a complex battery of bioassays performed in prokaryotes and aquatic eukaryotes (freshwater fish). Battery comprised evaluation of mutagenicity by SOS/umuC test in Salmonella typhimurium TA1535/pSK1002. The level of DNA damage as a biomarker of exposure (comet assay) and biomarker of effect (micronucleus assay) and the level of oxidative stress as well (Fpg-modified comet assay) was studied in blood cells of bleak and spirlin (Alburnus alburnus/Alburnoides bipunctatus respectively). Result indicated differential sensitivity of applied bioassays in detection of genotoxic pressure. The standard and Fpg-modified comet assay showed higher potential in differentiation of the sites based on genotoxic potential in comparison with micronucleus assay and SOS/umuC test. Our data represent snapshot of the current status of the river which indicates the presence of genotoxic potential along the river which can be traced to the deterioration of quality of the Sava River by communal and industrial wastewaters. The major highlight of the study is that we have provided complex set of data obtained from a single source (homogeneity of analyses for all samples). PMID:27631093

  18. Genotoxicity of complex mixtures: CHO cell mutagenicity assay

    SciTech Connect

    Frazier, M.E.; Samuel, J.E.

    1985-02-01

    A Chinese hamster ovary (CHO) mammalian cell assay was used to evaluate the genotoxicity of complex mixtures (synthetic fuels). The genotoxicity (mutagenic potency) of the mixtures increased as the temperature of their boiling range increased. Most of the genotoxicity in the 750/sup 0/F+ boiling-range materials was associated with the neutral polycyclic aromatic hydrocarbon (PAH) fractions. Chemical analysis data indicate that the PAH fractions of high-boiling coal liquids contain a number of known chemical carcinogens, including five- and six-ring polyaromatics (e.g., benzo(a)pyrene) as well as four- and five-ring alkyl-substituted PAH (e.g., methylchrysene and dimethylbenzanthracenes); concentrations are a function of boiling point (bp). In vitro genotoxicity was also detected in fractions of nitrogen-containing polyaromatic compounds, as well as in those with aliphatics of hydroxy-containing PAH. Mutagenic activity of some fractions was detectable in the CHO assay in the absence of an exogenous metabolic activation system; in some instances, addition of exogenous enzymes and cofactors inhibited expression of the direct-acting mutagenic potential of the fraction. These data indicate that the organic matrix of the chemical fraction determines whether, and to what degree, various mutagens are expressed in the CHO assay. Therefore, the results of biological assays of these mixtures must be correlated with chemical analyses for proper interpretation of these data. 29 references, 16 figures, 4 tables.

  19. Linking genotoxic responses and reproductive success in ecotoxicology.

    PubMed Central

    Anderson, S L; Wild, G C

    1994-01-01

    The potential of genotoxicity biomarkers as predictors of detrimental environmental effects, such as altered reproductive success of wild organisms, must be rigorously determined. Recent research to evaluate relationships between genotoxic responses and indicators of reproductive success in model animals is described from an ecotoxicological perspective. Genotoxicity can be correlated with reproductive effects such as gamete loss due to cell death; embryonic mortality; and heritable mutations in a range of model animals including polychaete worms, nematodes, sea urchins, amphibians, and fish. In preliminary studies, the polychaete worm, Neanthes arenaceodentata, and the nematode, Caenorhabditis elegans, have also shown the potential for cumulative DNA damage in gametes. If DNA repair capacity is limited in gametes, then selected life history traits such as long and synchronous periods of gametogenesis may confer vulnerability to genotoxic substances in chronic exposures. Recommendations for future research include strategic development of animal models that can be used to elucidate multiple mechanisms of effect (multiend point) at varying levels of biological organization (multilevel). PMID:7713042

  20. Mutagenicity and genotoxicity of coal fly ash water leachate

    SciTech Connect

    Chakraborty, R.; Mukherjee, A.

    2009-03-15

    Fly ash is a by-product of coal-fired electricity generation plants. The prevalent practice of disposal is as slurry of ash and water to storage or ash ponds located near power stations. This has lain to waste thousands of hectares of land all over the world. Since leaching is often the cause of off-site contamination and pathway of introduction into the human environment, a study on the genotoxic effects of fly ash leachate is essential. Leachate prepared from the fly ash sample was analyzed for metal content, and tested for mutagenicity and genotoxicity. Analyses of metals show predominance of the metals - sodium, silicon, potassium, calcium, magnesium, iron, manganese, zinc, and sulphate. The Ames Salmonella mutagenicity assay, a short-term bacterial reverse mutation assay, was conducted on two-tester strains of Salmonella typhimurium strains TA97a and TA102. For genotoxicity, the alkaline version of comet assay on fly ash leachate was carried in vitro on human blood cells and in vivo on Nicotiana plants. The leachate was directly mutagenic and induced significantconcentration-dependent increases in DNA damage in whole blood cells, lymphocytes, and in Nicotiana plants. The comet parameters show increases in tail DNA percentage (%), tail length (mu m), and olive tail moment (arbitrary units). Our results indicate that leachate from fly ash dumpsites has the genotoxic potential and may lead to adverse effects on vegetation and on the health of exposed human populations.

  1. Linking genotoxic responses and reproductive success in ecotoxicology

    SciTech Connect

    Anderson, S.L.; Wild, G.C.

    1994-12-01

    The potential of genotoxicity biomarkers as predictors of detrimental environmental effects, such as altered reproductive success of wild organisms, must be rigorously determined. Recent research to evaluate relationships between genotoxic responses and indicators of reproductive success in model animals is described from an ecotoxicological perspective. Genotoxicity can be correlated with reproductive effects such as gamete loss due to cell death; embryonic mortality; and heritable mutations in a range of model animals including polychaete worms, nematodes, sea urchins, amphibians, and fish. In preliminary studies, the polychaete worm, Neanthes arenaceodentata, and the nematode, Caenorhabditis elegans, have also shown the potential for cumulative DNA damage in gametes. If DNA repair capacity is limited in gametes, then selected life history traits such as long and synchronous periods of gametogenesis may confer vulnerability to genotoxic substances in chronic exposures. Recommendations for future research include strategic development of animal models that can be used to elucidate multiple mechanisms of effect (multiend point) at varying levels of biological organization (multilevel). 27 refs., 2 tabs.

  2. GENOTOXICITY STUDIES OF SODIUM DICHLOROACETATE AND SODIUM TRICHLOROACETATE

    EPA Science Inventory

    The genotoxic properties of sodium dichloroacetate (DCA) and sodium trichloroacetate (TCA)were evaluated in several short-term in vitro and in vivo assays. Neither compound was mutagenic in tester strain TA102 in the Salmonella mutagenicity assay. Both DCA and TCA were weak induc...

  3. Updated recommended lists of genotoxic and non-genotoxic chemicals for assessment of the performance of new or improved genotoxicity tests.

    PubMed

    Kirkland, David; Kasper, Peter; Martus, Hans-Jörg; Müller, Lutz; van Benthem, Jan; Madia, Federica; Corvi, Raffaella

    2016-01-01

    In 2008 we published recommendations on chemicals that would be appropriate to evaluate the sensitivity and specificity of new/modified mammalian cell genotoxicity tests, in particular to avoid misleading positive results. In light of new data it is appropriate to update these lists of chemicals. An expert panel was convened and has revised the recommended chemicals to fit the following different sets of characteristics: • Group 1: chemicals that should be detected as positive in in vitro mammalian cell genotoxicity tests. Chemicals in this group are all in vivo genotoxins at one or more endpoints, either due to DNA-reactive or non DNA-reactive mechanisms. Many are known carcinogens with a mutagenic mode of action, but a sub-class of probable aneugens has been introduced. • Group 2: chemicals that should give negative results in in vitro mammalian cell genotoxicity tests. Chemicals in this group are usually negative in vivo and non-DNA-reactive. They are either non-carcinogenic or rodent carcinogens with a non-mutagenic mode of action. • Group 3: chemicals that should give negative results in in vitro mammalian cell genotoxicity tests, but have been reported to induce gene mutations in mouse lymphoma cells, chromosomal aberrations or micronuclei, often at high concentrations or at high levels of cytotoxicity. Chemicals in this group are generally negative in vivo and negative in the Ames test. They are either non-carcinogenic or rodent carcinogens with an accepted non-mutagenic mode of action. This group contains comments as to any conditions that can be identified under which misleading positive results are likely to occur. This paper, therefore, updates these three recommended lists of chemicals and describes how these should be used for any test evaluation program. PMID:26774663

  4. Renormalization-group calculation of excitation properties for impurity models

    NASA Astrophysics Data System (ADS)

    Yoshida, M.; Whitaker, M. A.; Oliveira, L. N.

    1990-05-01

    The renormalization-group method developed by Wilson to calculate thermodynamical properties of dilute magnetic alloys is generalized to allow the calculation of dynamical properties of many-body impurity Hamiltonians. As a simple illustration, the impurity spectral density for the resonant-level model (i.e., the U=0 Anderson model) is computed. As a second illustration, for the same model, the longitudinal relaxation rate for a nuclear spin coupled to the impurity is calculated as a function of temperature.

  5. Multichannel Kondo impurity dynamics in a Majorana device.

    PubMed

    Altland, A; Béri, B; Egger, R; Tsvelik, A M

    2014-08-15

    We study the multichannel Kondo impurity dynamics realized in a mesoscopic superconducting island connected to metallic leads. The effective "impurity spin" is nonlocally realized by Majorana bound states and strongly coupled to lead electrons by non-Fermi liquid correlations. We explore the spin dynamics and its observable ramifications near the low-temperature fixed point. The topological protection of the system raises the perspective to observe multichannel Kondo impurity dynamics in experimentally realistic environments.

  6. Analysis of the effects of impurities in silicon

    NASA Technical Reports Server (NTRS)

    Wohlgemuth, J.; Giuliano, M. N.

    1980-01-01

    A solar cell fabrication and analysis program was conducted to determine the effects on the resultant solar cell efficiency of impurities intentionally incorporated into silicon. It was found that certain impurities such as titanium, tantalum, and vanadium were bad, even in very small concentrations. Cell performance appeared relatively tolerable to impurities such as copper, carbon, calcium, chromium, iron and nickel (in the concentration levels which were considered).

  7. Chemistry in the Pharmaceutical Industry

    NASA Astrophysics Data System (ADS)

    Poindexter, Graham S.; Pendri, Yadagiri; Snyder, Lawrence B.; Yevich, Joseph P.; Deshpande, Milind

    This chapter will discuss the role of chemistry within the pharmaceutical industry. Although the focus will be upon the industry within the United States, much of the discussion is equally relevant to pharmaceutical companies based in other first world nations such as Japan and those in Europe. The major objective of the pharmaceutical industry is the discovery, development, and marketing of efficacious and safe drugs for the treatment of human disease. Of course drug companies do not exist as altruistic, charitable organizations but like other share-holder owned corporations within our capitalistic society must achieve profits in order to remain viable and competitive. Thus, there exists a conundrum between the dual goals of enhancing the quality and duration of human life and that of increasing stock-holder equity. Much has been written and spoken in the lay media about the high prices of prescription drugs and the hardships this places upon the elderly and others of limited income.

  8. Numerical Simulation of mobile BEC-impurity interaction

    NASA Astrophysics Data System (ADS)

    Lausch, Tobias; Grusdt, Fabian; Fleischhauer, Michael; Widera, Artur

    2016-05-01

    Cooling atoms to temperatures, where quantum effects become dominant, has become a standard in cold atom experiments. Especially interactions of quantum baths such as fermi gases and the implementation of impurities, which form fermi polarons, have been studied theoretically and experimentally in detail. However, detailed experiments on the bose polaron and the interaction between impurities and a bose gas are still elusive. We consider a model, where we immerse a single impurity into a BEC, which is described by Bogoliubov approximation. From the master equation, we derived the impurity's momentum resolved scattering and cooling dynamics for numerical simulations. Such cooling processes should enable momentum resolved radio-frequency spectroscopy of the BEC polaron.

  9. Impurity Gettering Effect of Te Inclusions in Cdznte Single Crystals

    SciTech Connect

    Yang, G.; Bolotnikov, A; Cui, Y; Camarda, G; Hossain, A; James, R

    2009-01-01

    The local impurity distribution in Te inclusions of CdZnTe (CZT) crystal was investigated by the time-of-flight secondary ion mass spectrometry (Tof-SIMS) technique. Direct evidence of impurity gettering in Te inclusions has been observed for the first time. The impurity gettering in Te inclusions originated from the diffusion mechanism during crystal growth and segregation mechanism during crystal cooling. This phenomenon is meaningful, because it reveals how Te inclusions affect CZT properties and provides a possible approach to reduce the impurities in CZT by the way of removing Te inclusions.

  10. Impurity-induced conductance anomaly in zigzag carbon nanotubes

    NASA Astrophysics Data System (ADS)

    Chang, Po-Yao; Huang, Wen-Min; Lin, Hsiu-Hau

    2009-02-01

    Impurities in carbon nanotubes give rise to rich physics due to the honeycomb lattice structure. We concentrate on the conductance through a point-like defect in metallic zigzag carbon nanotube via the Landauer-Büttiker approach. At low bias, the conductance is suppressed due to the presence of an additional impurity state existing only on one of the sublattices. In consequence, the suppression is exactly half of the perfect conductance without impurity. Furthermore, there exists a transport resonance at larger bias where the perfect conductance is recovered as if the impurity were absent. Implications of these conductance anomalies are elaborated and experimental detections in realistic carbon nanotubes are also discussed.

  11. Topological state engineering by potential impurities on chiral superconductors

    NASA Astrophysics Data System (ADS)

    Kaladzhyan, Vardan; Röntynen, Joel; Simon, Pascal; Ojanen, Teemu

    2016-08-01

    In this work we consider the influence of potential impurities deposited on top of two-dimensional chiral superconductors. As discovered recently, magnetic impurity lattices on an s -wave superconductor may give rise to a rich topological phase diagram. We show that a similar mechanism takes place in chiral superconductors decorated by nonmagnetic impurities, thus avoiding the delicate issue of magnetic ordering of adatoms. We illustrate the method by presenting the theory of potential impurity lattices embedded on chiral p -wave superconductors. While a prerequisite for the topological state engineering is a chiral superconductor, the proposed procedure results in vistas of nontrivial descendant phases with different Chern numbers.

  12. The World Bank and pharmaceuticals.

    PubMed

    Falkenberg, T; Tomson, G

    2000-03-01

    Within less than a decade the World Bank has become the largest single source of finance (loans) for health in low and middle income countries as well as a major player in the field of pharmaceuticals. Often 20-50% of the recurrent government health budget in developing countries is used to procure drugs. Drugs are among the most salient and cost-effective elements of health care and often a key factor for the success of a health sector reform. However, pharmaceuticals are frequently being used irrationally, mainly due to market imperfections in health care, such as information asymmetries, leading to serious health problems and a heavy financial burden on the health system. Lending priorities set by the World Bank could be used to promote public health sector reform, leading to the rational use of affordable and available drugs of good quality in developing countries. This report provides the first analysis of World Bank activity in the pharmaceutical sector worldwide. The analysis of 77 staff appraisal reports, describing the planning phase of World Bank country projects, shows that 16% of the total World Bank health, nutrition and population budget, or approximately US$1.3 billion, has been committed to loans or credits supporting pharmaceutical activities in the programme countries between 1989-95. Roughly US$1.05 billion has been committed to procurement of drugs and medical equipment. Only 5% of the total pharmaceutical sector lending is committed to software components such as drug policy work and rational use of drugs. No more than 45% of the projects were developed in collaboration with pharmaceutical expertise. The World Bank is recommended to improve its pharmaceutical sector involvement by promoting drug policy research and development including national and international dialogue on pharmaceutical issues to ensure rational use of both drugs and loans. In this, the World Bank has an advantage given its experience from working with both the private and

  13. The World Bank and pharmaceuticals.

    PubMed

    Falkenberg, T; Tomson, G

    2000-03-01

    Within less than a decade the World Bank has become the largest single source of finance (loans) for health in low and middle income countries as well as a major player in the field of pharmaceuticals. Often 20-50% of the recurrent government health budget in developing countries is used to procure drugs. Drugs are among the most salient and cost-effective elements of health care and often a key factor for the success of a health sector reform. However, pharmaceuticals are frequently being used irrationally, mainly due to market imperfections in health care, such as information asymmetries, leading to serious health problems and a heavy financial burden on the health system. Lending priorities set by the World Bank could be used to promote public health sector reform, leading to the rational use of affordable and available drugs of good quality in developing countries. This report provides the first analysis of World Bank activity in the pharmaceutical sector worldwide. The analysis of 77 staff appraisal reports, describing the planning phase of World Bank country projects, shows that 16% of the total World Bank health, nutrition and population budget, or approximately US$1.3 billion, has been committed to loans or credits supporting pharmaceutical activities in the programme countries between 1989-95. Roughly US$1.05 billion has been committed to procurement of drugs and medical equipment. Only 5% of the total pharmaceutical sector lending is committed to software components such as drug policy work and rational use of drugs. No more than 45% of the projects were developed in collaboration with pharmaceutical expertise. The World Bank is recommended to improve its pharmaceutical sector involvement by promoting drug policy research and development including national and international dialogue on pharmaceutical issues to ensure rational use of both drugs and loans. In this, the World Bank has an advantage given its experience from working with both the private and

  14. Somatic cell genotoxicity at the glycophorin A locus in humans

    SciTech Connect

    Jensen, R.H.; Grant, S.G.; Langlois, R.G.; Bigbee, W.L.

    1990-12-28

    We have developed an assay for detecting variant erythrocytes that occur as a result of in vivo allele loss at the glycophorin A (GPA) locus on chromosome 4 in humans. This gene codes for an erythroid- specific cell surface glycoprotein, and with our assay we are able to detect rare variant erythrocytes that have lost expression of one of the two GPA alleles. Two distinctly different variant cell types are detected with this assay. One variant cell type (called N{O}) is hemizygous. Our assay also detects homozygous variant erythrocytes that have lost expression of the GPA(M) allele and express the GPA(N) allele at twice the heterozygous level. The results of this assay are an enumeration of the frequency of N{O} and NN variant cell types for each individual analyzed. These variant cell frequencies provide a measure of the amount of somatic cell genotoxicity that has occurred at the GPA locus. Such genotoxicity could be the result of (1) reactions of toxic chemicals to which the individual has been exposed, or (2) high energy radiation effects on erythroid precursor cells, or (3) errors in DNA replication or repair in these cells of the bone marrow. Thus, the GPA-based variant cell frequency can serve as a biodosimeter that indicates the amount of genotoxic exposure each individual has received. Because two very different kinds of variant cells are enumerated, different kinds of genotoxicity should be distinguishable. Results of the GPA somatic genotoxicity assay may also provide valuable information for cancer-risk estimation on each individual. 16 refs.

  15. Genotoxicity in native fish associated with agricultural runoff events

    USGS Publications Warehouse

    Whitehead, A.; Kuivila, K.M.; Orlando, J.L.; Kotelevtsev, S.; Anderson, S.L.

    2004-01-01

    The primary objective of the present study was to test whether agricultural chemical runoff was associated with in-stream genotoxicity in native fish. Using Sacramento sucker (Catostomus occidentalis), we combined field-caging experiments in an agriculturally dominated watershed with controlled laboratory exposures to field-collected water samples, and we coupled genotoxicity biomarker measurements in fish with bacterial mutagenicity analysis of water samples. We selected DNA strand breakage as a genotoxicity biomarker and Ames Salmonella mutagenicity tests as a second, supporting indicator of genotoxicity. Data from experiments conducted during rainfall runoff events following winter application of pesticides in 2000 and 2001 indicated that DNA strand breaks were significantly elevated in fish exposed to San Joaquin River (CA, USA) water (38.8, 28.4, and 53.6% DNA strand breakage in year 2000 field, year 2000 lab, and year 2001 field exposures, respectively) compared with a nearby reference site (15.4, 8.7, and 12.6% DNA strand breakage in year 2000 field, year 2000 lab, and year 2001 field exposures, respectively). Time-course measurements in field experiments supported a linkage between induction of DNA strand breakage and the timing of agricultural runoff. San Joaquin River water also caused significant reversion mutation in two Ames Salmonella tester strains. Salmonella mutagenicity corroborated in-stream effects, further strengthening a causal relationship between runoff events and genotoxicity. Potentially responsible agents are discussed in the context of timing of runoff events in the field, concordance between laboratory and field exposures, pesticide application patterns in the drainage, and analytical chemistry data.

  16. Appropriate In Vitro Methods for Genotoxicity Testing of Silver Nanoparticles

    PubMed Central

    Kim, Ha Ryong; Park, Yong Joo; Shin, Da Young; Oh, Seung Min

    2013-01-01

    Objectives We investigated the genotoxic effects of 40-59 nm silver nanoparticles (Ag-NPs) by bacterial reverse mutation assay (Ames test), in vitro comet assay and micronucleus (MN) assay. In particular, we directly compared the effect of cytochalasin B (cytoB) and rat liver homogenate (S9 mix) in the formation of MN by Ag-NPs. Methods Before testing, we confirmed that Ag-NPs were completely dispersed in the experimental medium by sonication (three times in 1 minute) and filtration (0.2 µm pore size filter), and then we measured their size in a zeta potential analyzer. After that the genotoxicity were measured and especially, S9 mix and with and without cytoB were compared one another in MN assay. Results Ames test using Salmonella typhimurium TA98, TA100, TA1535 and TA1537 strains revealed that Ag-NPs with or without S9 mix did not display a mutagenic effect. The genotoxicity of Ag-NPs was also evaluated in a mammalian cell system using Chinese hamster ovary cells. The results revealed that Ag-NPs stimulated DNA breakage and MN formation with or without S9 mix in a dose-dependent manner (from 0.01 µg/mL to 10 µg/mL). In particular, MN induction was affected by cytoB. Conclusions All of our findings, with the exception of the Ames test results, indicate that Ag-NPs show genotoxic effects in mammalian cell system. In addition, present study suggests the potential error due to use of cytoB in genotoxic test of nanoparticles. PMID:23440978

  17. Studies of impurity behavior in TFTR

    SciTech Connect

    Hill, K.W.; Bitter, M.; Bretz, N.L.; Diesso, M.; Efthimion, P.C.; Von Goeler, S.; Kiraly, J.; Ramsey, A.T.; Sauthoff, N.R.; Schivell, J.

    1986-03-01

    Central medium- and low-Z impurity concentrations and Z/sub eff/ have been measured by x-ray spectrometry in Tokamak Fusion Test Reactor discharges during three periods of operation. These were the (1) start-up period, (2) ohmic heating, and (3) ohmic heating portion of the two neutral beam periods, distinguished mainly by different vacuum vessel internal hardware and increasing plasma current and toroidal field capability. Plasma parameters spanned minor radius a = 0.41 - 0.83 m, major radius R = 2.1 - 3.1 m, current I/sub p = 0.25 - 2.0 MA, line-averaged electron density n-bar/sub e/ = 0.9 - 4.0 x 10/sup 19/ m/sup -3/, and toroidal magnetic field B/sub T/ = 1.8 - 4.0 T. The metal impurities came mostly from the limiter. At low densities titanium or nickel approached 1% of n/sub e/ during operation on a TiC-coated graphite or Inconel limiter, respectively. Lower levels of Cr, Fe, and Ni (less than or equal to0.1%) were observed with a graphite limiter at similarly low densities; these elements were removed mainly from stainless steel or Inconel hardware within the vacuum vessel during pulse discharge cleaning or plasma operation on an Inconel limiter and then deposited on the graphite limiter. Hardware closest to the graphite limiter contributed most to the deposits.

  18. Particle fueling and impurity control in PDX

    SciTech Connect

    Fonck, R.J.; Bell, M.; Bol, K.; Budny, R.; Couture, P.; Darrow, D.; Dylla, H.; Goldston, R.; Grek, B.; Hawryluk, R.

    1984-12-01

    Fueling requirements and impurity levels in neutral-beam-heated discharges in the PDX tokamak have been compared for plasmas formed with conventional graphite rail limiters, a particle scoop limiter, and an open or closed poloidal divertor. Gas flows necessary to obtain a given density are highest for diverted discharges and lowest for the scoop limiter. Hydrogen pellet injection provides an efficient alternate fueling technique, and a multiple pellet injector has produced high density discharges for an absorbed neutral beam power of up to 600 kW, above which higher speeds or more massive pellets are required for penetration to the plasma core. Power balance studies indicate that 30 to 40% of the total input power is radiated while approx. 15% is absorbed by the limiting surface, except in the open divertor case, where 60% flows to the neutralizer plate. In all operating configurations, Z/sub eff/ usually rises at the onset of neutral beam injection. Both open divertor plasmas and those formed on a well conditioned water-cooled limiter have Z/sub eff/ less than or equal to 2 at the end of neutral injection. A definitive comparison of divertors and limiters for impurity control purposes requires longer beam pulses or higher power levels than available on present machines.

  19. Particle fueling and impurity control in PDX

    NASA Astrophysics Data System (ADS)

    Fonck, R. J.; Bell, M.; Bol, K.; Budny, R.; Couture, P.; Darrow, D.; Dylla, H.; Goldston, R.; Grek, B.; Hawryluk, R.; Ida, K.; Jaehnig, K.; Johnson, D.; Kaita, R.; Kaye, S.; Kugel, H.; Leblanc, B.; Mansfield, D.; Mcbride, T.; Mcguire, K.; Milora, S.; Mueller, D.; Okabayashi, M.; Owens, D.; Post, D.; Reusch, M.; Schmidt, G.; Sesnic, S.; Takahashi, H.; Tenney, F.; Ulrickson, M.

    1984-12-01

    Fueling requirements and impurity levels in neutral-beam-heated discharges in the PDX tokamak have been compared for plasmas formed with conventional graphite rail limiters, a particle scoop limiter, and an open or closed poloidal divertor. Gas flows necessary to obtain a given density are highest for diverted discharges and lowest for the scoop limiter. Hydrogen pellet injection provides an efficient alternative fueling technique, and a multiple pellet injector has produced high density discharges for an absorbed neutral beam power of up to 600 kW, above which higher speeds or more massive pellets are required for penetration to the plasma core. Power balance studies indicate that 30-40% of the total input power is radiated while ~15% is absorbed by the limiting surface, except in the open divertor case, where 60% flows to the neutralizer plate. In all operating configurations, Zeff usually rises at the onset of neutral beam injection. Both open divertor pl;asmas and those formed on a well conditioned water-cooled limiter have Zeff ⪅ 2 at the end of neutral injection. A definitive comparison of divertors and limiters for impurity control purposes requires longer beam pulses or higher power levels than available on present machines.

  20. Endocrine-Active Pharmaceuticals: An Environmental Concern?

    EPA Science Inventory

    Recently, there has been growing interest in pharmaceuticals that are specifically designed to have endocrine activity, such as the estrogens used in birth control pills, exerting unintended effects on fish and other aquatic organisms. These pharmaceuticals may not be persistent...

  1. Patrick Couvreur: inspiring pharmaceutical innovation.

    PubMed

    Stanwix, Hannah

    2014-05-01

    Patrick Couvreur speaks to Hannah Stanwix, Managing Comissioning Editor: Professor Patrick Couvreur received his pharmacy degree from the Université Catholique de Louvain (Louvain-la-Neuve, Belgium) in 1972. He holds a PhD in pharmaceutical technology from the same university and completed a postdoctoral fellowship at the Eidgenössische Technische Hochschule (Zürich, Switzerland). Since 1984, Professor Couvreur has been Full Professor of Pharmacy at the Paris-Sud University (Paris, France) and was holder of the Chair of Innovation Technologique at the prestigious Collège de France (Paris, France). He has published more than 450 peer-reviewed articles and has an H-index of 73, with over 19,000 citations. Professor Coureur has been recognized by numerous national and international awards, including the 2004 Pharmaceutical Sciences World Congress Award, the prestigious Host Madsen Medal, the Prix Galien, the European Pharmaceutical Scientist Award 2011 from the European Federation of Pharmaceutical Sciences, the Médaille de l'Innovation from the Centre National de la Recherche Scientifique, and recently the European Inventor Award 2013 from the European Patent Office.

  2. Pharmaceutical care in smoking cessation.

    PubMed

    Marín Armero, Alicia; Calleja Hernandez, Miguel A; Perez-Vicente, Sabina; Martinez-Martinez, Fernando

    2015-01-01

    As a determining factor in various diseases and the leading known cause of preventable mortality and morbidity, tobacco use is the number one public health problem in developed countries. Facing this health problem requires authorities and health professionals to promote, via specific programs, health campaigns that improve patients' access to smoking cessation services. Pharmaceutical care has a number of specific characteristics that enable the pharmacist, as a health professional, to play an active role in dealing with smoking and deliver positive smoking cessation interventions. The objectives of the study were to assess the efficacy of a smoking cessation campaign carried out at a pharmaceutical care center and to evaluate the effects of pharmaceutical care on patients who decide to try to stop smoking. The methodology was an open, analytical, pre-post intervention, quasi-experimental clinical study performed with one patient cohort. The results of the study were that the promotional campaign for the smoking cessation program increased the number of patients from one to 22, and after 12 months into the study, 43.48% of the total number of patients achieved total smoking cessation. We can conclude that advertising of a smoking cessation program in a pharmacy increases the number of patients who use the pharmacy's smoking cessation services, and pharmaceutical care is an effective means of achieving smoking cessation. PMID:25678779

  3. Electron microscopy of pharmaceutical systems.

    PubMed

    Klang, Victoria; Valenta, Claudia; Matsko, Nadejda B

    2013-01-01

    During the last decades, the focus of research in pharmaceutical technology has steadily shifted towards the development and optimisation of nano-scale drug delivery systems. As a result, electron microscopic methods are increasingly employed for the characterisation of pharmaceutical systems such as nanoparticles and microparticles, nanoemulsions, microemulsions, solid lipid nanoparticles, different types of vesicles, nanofibres and many more. Knowledge of the basic properties of these systems is essential for an adequate microscopic analysis. Classical transmission and scanning electron microscopic techniques frequently have to be adapted for an accurate analysis of formulation morphology, especially in case of hydrated colloidal systems. Specific techniques such as environmental scanning microscopy or cryo preparation are required for their investigation. Analytical electron microscopic techniques such as electron energy-loss spectroscopy or energy-dispersive X-ray spectroscopy are additional assets to determine the elemental composition of the systems, but are not yet standard tools in pharmaceutical research. This review provides an overview of pharmaceutical systems of interest in current research and strategies for their successful electron microscopic analysis. Advantages and limitations of the different methodological approaches are discussed and recent findings of interest are presented. PMID:22921788

  4. Pharmaceutical care in smoking cessation

    PubMed Central

    Marín Armero, Alicia; Calleja Hernandez, Miguel A; Perez-Vicente, Sabina; Martinez-Martinez, Fernando

    2015-01-01

    As a determining factor in various diseases and the leading known cause of preventable mortality and morbidity, tobacco use is the number one public health problem in developed countries. Facing this health problem requires authorities and health professionals to promote, via specific programs, health campaigns that improve patients’ access to smoking cessation services. Pharmaceutical care has a number of specific characteristics that enable the pharmacist, as a health professional, to play an active role in dealing with smoking and deliver positive smoking cessation interventions. The objectives of the study were to assess the efficacy of a smoking cessation campaign carried out at a pharmaceutical care center and to evaluate the effects of pharmaceutical care on patients who decide to try to stop smoking. The methodology was an open, analytical, pre–post intervention, quasi-experimental clinical study performed with one patient cohort. The results of the study were that the promotional campaign for the smoking cessation program increased the number of patients from one to 22, and after 12 months into the study, 43.48% of the total number of patients achieved total smoking cessation. We can conclude that advertising of a smoking cessation program in a pharmacy increases the number of patients who use the pharmacy’s smoking cessation services, and pharmaceutical care is an effective means of achieving smoking cessation. PMID:25678779

  5. Career pathways in research: pharmaceutical.

    PubMed

    Kenkre, J E; Foxcroft, D R

    The pharmaceutical pathway is the final article in this series on career pathways and highlights opportunities for nurses within associated industries. This pathway shows that nurses can use their nursing qualifications, combined with their knowledge, skills and expertise, to develop a career within another sphere of employment.

  6. Pharmaceutical crystallization with nanocellulose organogels.

    PubMed

    Ruiz-Palomero, Celia; Kennedy, Stuart R; Soriano, M Laura; Jones, Christopher D; Valcárcel, Miguel; Steed, Jonathan W

    2016-06-14

    Carboxylated nanocellulose forms organogels at 0.3 wt% in the presence of a cationic surfactant. The resulting gels can be used as novel crystallization media for pharmaceutical solid form control, resulting in isolation a new sulfapyridine solvate, morphology modification and crystallization of an octadecylammonium salt of sulfamethoxazole. PMID:27168091

  7. Distribution profile of gadolinium in gadolinium chelate-treated renally-impaired rats: role of pharmaceutical formulation.

    PubMed

    Fretellier, Nathalie; Salhi, Mariem; Schroeder, Josef; Siegmund, Heiko; Chevalier, Thibaut; Bruneval, Patrick; Jestin-Mayer, Gaëlle; Delaloge, Francette; Factor, Cécile; Mayer, Jean-François; Fabicki, Jean-Michel; Robic, Caroline; Bonnemain, Bruno; Idée, Jean-Marc; Corot, Claire

    2015-05-25

    While not acutely toxic, chronic hepatic effect of certain gadolinium chelates (GC), used as contrast agent for magnetic resonance imaging, might represent a risk in renally-impaired patients due to free gadolinium accumulation in the liver. To answer this question, this study investigated the consequences of the presence of small amounts of either a soluble gadolinium salt ("free" Gd) or low-stability chelating impurity in the pharmaceutical solution of gadoteric acid, a macrocyclic GC with high thermodynamic and kinetic stabilities, were investigated in renally-impaired rats. Renal failure was induced by adding 0.75% adenine in the diet for three weeks. The pharmaceutical and commercial solution of gadoteric acid was administered (5 daily intravenous injections of 2.5 mmol Gd/kg) either alone or after being spiked with either "free" gadolinium (i.e., 0.04% w/v) or low-stability impurity (i.e., 0.06 w/v). Another GC, gadodiamide (low thermodynamic and kinetic stabilities) was given as its commercial solution at a similar dose. Non-chelated gadolinium was tested at two doses (0.005 and 0.01 mmol Gd/kg) as acetate salt. Gadodiamide induced systemic toxicity (mortality, severe epidermal and dermal lesions) and substantial tissue Gd retention. The addition of very low amounts of "free", non-chelated gadolinium or low thermodynamic stability impurity to the pharmaceutical solution of the thermodynamically stable GC gadoteric acid resulted in substantial capture of metal by the liver, similar to what was observed in "free" gadolinium salt-treated rats. Relaxometry studies strongly suggested the presence of free and soluble gadolinium in the liver. Electron microscopy examinations revealed the presence of free and insoluble gadolinium deposits in hepatocytes and Kupffer cells of rats treated with gadoteric acid solution spiked with low-stability impurity, free gadolinium and gadodiamide, but not in rats treated with the pharmaceutical solution of gadoteric acid. The

  8. Microwave-assisted digestion using nitric acid for heavy metals and sulfated ash testing in active pharmaceutical ingredients.

    PubMed

    Pluhácek, T; Hanzal, J; Hendrych, J; Milde, D

    2016-04-01

    The monitoring of inorganic impurities in active pharmaceutical ingredients plays a crucial role in the quality control of the pharmaceutical production. The heavy metals and residue on ignition/sulfated ash methods employing microwave-assisted digestion with concentrated nitric acid have been demonstrated as alternatives to inappropriate compendial methods recommended in United States Pharmacopoeia (USP) and European Pharmacopoeia (Ph. Eur.). The recoveries using the heavy metals method ranged between 89% and 122% for nearly all USP and Ph. Eur. restricted elements as well as the recoveries of sodium sulfate spikes were around 100% in all tested matrices. The proposed microwave-assisted digestion method allowed simultaneous decomposition of 15 different active pharmaceutical ingredients with sample weigh up to 1 g. The heavy metals and sulfated ash procedures were successfully applied to the determination of heavy metals and residue on ignition/sulfated ash content in mycophenolate mofetil, nicergoline and silymarin. PMID:27209695

  9. Impurity transport through a strongly interacting bosonic quantum gas

    SciTech Connect

    Johnson, T. H.; Clark, S. R.; Bruderer, M.; Jaksch, D.

    2011-08-15

    Using near-exact numerical simulations, we study the propagation of an impurity through a one-dimensional Bose lattice gas for varying bosonic interaction strengths and filling factors at zero temperature. The impurity is coupled to the Bose gas and confined to a separate tilted lattice. The precise nature of the transport of the impurity is specific to the excitation spectrum of the Bose gas, which allows one to measure properties of the Bose gas nondestructively, in principle, by observing the impurity; here we focus on the spatial and momentum distributions of the impurity as well as its reduced density matrix. For instance, we show it is possible to determine whether the Bose gas is commensurately filled as well as the bandwidth and gap in its excitation spectrum. Moreover, we show that the impurity acts as a witness to the crossover of its environment from the weakly to the strongly interacting regime, i.e., from a superfluid to a Mott insulator or Tonks-Girardeau lattice gas, and the effects on the impurity in both of these strongly interacting regimes are clearly distinguishable. Finally, we find that the spatial coherence of the impurity is related to its propagation through the Bose gas.

  10. Tight-Binding Description of Impurity States in Semiconductors

    ERIC Educational Resources Information Center

    Dominguez-Adame, F.

    2012-01-01

    Introductory textbooks in solid state physics usually present the hydrogenic impurity model to calculate the energy of carriers bound to donors or acceptors in semiconductors. This model treats the pure semiconductor as a homogeneous medium and the impurity is represented as a fixed point charge. This approach is only valid for shallow impurities…

  11. 40 CFR 158.340 - Discussion of formation of impurities.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... require an expanded discussion of information on impurities: (1) From other possible chemical reactions... why they may be present. The discussion should be based on established chemical theory and on what the... range of levels) of these impurities. (iii) The intended reactions and side reactions which may occur...

  12. Removal of polar impurities from diesel and jet fuel

    SciTech Connect

    Diaz, Z.; Miller, J.H.

    1990-04-03

    This patent describes a process for the removal of polar impurities in diesel or jet fuel. It comprises: treating the diesel or jet fuel with a non-ionic macroreticular cross-linked acrylic aliphatic ester resin to effect removal of the polar impurities.

  13. Genotoxic and developmental effects in sea urchins are sensitive indicators of effects of genotoxic chemicals

    SciTech Connect

    Anderson, S.L. . Energy and Environment Division); Hose, J.E. . Dept. of Biology); Knezovich, J.P. . Health and Ecological Assessment Division)

    1994-07-01

    Purple sea urchin (Strongylocentrotus purpuratus) gametes and embryos were exposed to three known mutagenic chemicals (phenol, benzidine,and pentachlorophenol) over concentration ranges bracketing the effect levels for fertilization success. Normal development and cytogenetic effects (anaphase aberrations) were assessed after the cultures were allowed to develop for 48 h. Using radiolabeled chemicals, the authors also characterized concentrations in the test water as well as doses in the embryos following 2- and 48-h exposures. The authors observed dose responses for all chemicals and all responses, except for phenol, which showed no significant effect on development. Fertilization success was never the most sensitive end point. anaphase aberrations were the most sensitive response for phenol, with an LOEC of 2.5 mg/L exposure concentration. Anaphase aberrations and development were equivalent in sensitivity for benzidine within the tested dose range, and an LOEC of <0.1 mg/L was observed. Development was the most sensitive reasons for pentachlorophenol (LOEC 1 mg/L). the LOEC values for this study were generally lower than comparable data for aquatic life or human health protection. The authors conclude that genotoxicity and development evaluations should be included in environmental management applications and that tests developed primarily for human health protection do not reliably predict the effects of toxic substances on aquatic life.

  14. Viscoelasticity of colloidal polycrystals doped with impurities

    NASA Astrophysics Data System (ADS)

    Louhichi, Ameur; Tamborini, Elisa; Oberdisse, Julian; Cipelletti, Luca; Ramos, Laurence

    2015-09-01

    We investigate how the microstructure of a colloidal polycrystal influences its linear visco-elasticity. We use thermosensitive copolymer micelles that arrange in water in a cubic crystalline lattice, yielding a colloidal polycrystal. The polycrystal is doped with a small amount of nanoparticles, of size comparable to that of the micelles, which behave as impurities and thus partially segregate in the grain boundaries. We show that the shear elastic modulus only depends on the packing of the micelles and varies neither with the presence of nanoparticles nor with the crystal microstructure. By contrast, we find that the loss modulus is strongly affected by the presence of nanoparticles. A comparison between rheology data and small-angle neutron-scattering data suggests that the loss modulus is dictated by the total amount of nanoparticles in the grain boundaries, which in turn depends on the sample microstructure.

  15. Viscoelasticity of colloidal polycrystals doped with impurities.

    PubMed

    Louhichi, Ameur; Tamborini, Elisa; Oberdisse, Julian; Cipelletti, Luca; Ramos, Laurence

    2015-09-01

    We investigate how the microstructure of a colloidal polycrystal influences its linear visco-elasticity. We use thermosensitive copolymer micelles that arrange in water in a cubic crystalline lattice, yielding a colloidal polycrystal. The polycrystal is doped with a small amount of nanoparticles, of size comparable to that of the micelles, which behave as impurities and thus partially segregate in the grain boundaries. We show that the shear elastic modulus only depends on the packing of the micelles and varies neither with the presence of nanoparticles nor with the crystal microstructure. By contrast, we find that the loss modulus is strongly affected by the presence of nanoparticles. A comparison between rheology data and small-angle neutron-scattering data suggests that the loss modulus is dictated by the total amount of nanoparticles in the grain boundaries, which in turn depends on the sample microstructure. PMID:26465473

  16. The Mg impurity in nitride alloys

    SciTech Connect

    Zvanut, M. E.; Willoughby, W. R.; Sunay, U. R.; Koleske, D. D.; Allerman, A. A.; Wang, Ke; Araki, Tsutomu; Nanishi, Yasushi

    2014-02-21

    Although several magnetic resonance studies address the Mg acceptor in GaN, there are few reports on Mg doping in the alloys, where hole production depends strongly on the Al or In content. Our electron paramagnetic resonance (EPR) measurements of the p-type alloys suggest that the Mg impurity retains the axial symmetry, characteristic of a p-type dopant in both alloys; however, In and Al produce additional, different characteristics of the acceptor. In InGaN, the behavior is consistent with a lowering of the acceptor level and increasing hole density as In concentration increases. For AlGaN, the amount of neutral Mg decreases with increasing Al content, which is attributed to different kinetics of hydrogen diffusion thought to occur in samples with higher Al mole fraction.

  17. Light-absorbing impurities in Arctic snow

    NASA Astrophysics Data System (ADS)

    Doherty, S. J.; Warren, S. G.; Grenfell, T. C.; Clarke, A. D.; Brandt, R. E.

    2010-12-01

    Absorption of radiation by ice is extremely weak at visible and near-ultraviolet wavelengths, so small amounts of light-absorbing impurities in snow can dominate the absorption of solar radiation at these wavelengths, reducing the albedo relative to that of pure snow, contributing to the surface energy budget and leading to earlier snowmelt. In this study Arctic snow is surveyed for its content of light-absorbing impurities, expanding and updating the 1983-1984 survey of Clarke and Noone. Samples were collected in Alaska, Canada, Greenland, Svalbard, Norway, Russia, and the Arctic Ocean during 1998 and 2005-2009, on tundra, glaciers, ice caps, sea ice, frozen lakes, and in boreal forests. Snow was collected mostly in spring, when the entire winter snowpack is accessible for sampling. Sampling was carried out in summer on the Greenland Ice Sheet and on the Arctic Ocean, of melting glacier snow and sea ice as well as cold snow. About 1200 snow samples have been analyzed for this study. The snow is melted and filtered; the filters are analyzed in a specially designed spectrophotometer system to infer the concentration of black carbon (BC), the fraction of absorption due to non-BC light-absorbing constituents and the absorption Ångstrom exponent of all particles. This is done using BC calibration standards having a mass absorption efficiency of 6.0 m2 g-1 at 550 nm and by making an assumption that the absorption Angstrom exponent for BC is 1.0 and for non-BC light-absorbing aerosol is 5.0. The reduction of snow albedo is primarily due to BC, but other impurities, principally brown (organic) carbon, are typically responsible for ~40% of the visible and ultraviolet absorption. The meltwater from selected snow samples was saved for chemical analysis to identify sources of the impurities. Median BC amounts in surface snow are as follows (nanograms of carbon per gram of snow): Greenland 3, Arctic Ocean snow 7, melting sea ice 8, Arctic Canada 8, subarctic Canada 14

  18. Copper thiocyanate: polytypes, defects, impurities, and surfaces.

    PubMed

    Tsetseris, Leonidas

    2016-07-27

    Copper thiocyanate (CuSCN) is an established solid state dye in solar cells and has emerged as a key material for applications in transparent conductors and solution-processed thin film transistors. Here we report the results of density-functional theory calculations on several fundamental properties related to the performance of CuSCN in the above-mentioned systems. We describe the structural and electronic properties of CuSCN phases and show that the material is prone to polytypism. We also perform a systematic study on various defects and hydrogen impurities and determine their effect on the electronic properties of the host system, particularly with respect to doping. Finally, we show that non-polar surfaces have low formation energies, suggesting easy cleavage along certain directions. PMID:27248787

  19. A validated stability-indicative UPLC method for nilotinib hydrochloride for the determination of process-related and degradation impurities.

    PubMed

    Kondra, Sudhakar Babu; Madireddy, Venkataramanna; Chilukuri, Mohanareddy; Papadasu, Narayanareddy; Jonnalagadda, Latha

    2014-09-01

    A novel stability-indicating ultra performance liquid chromatographic (UPLC) method has been developed for quantitative determination of nilotinib hydrochloride in active pharmaceutical ingredients along with four impurities (imp-1, imp-2, imp-3 and imp-4). The method is applicable to the quantification of related compounds and assay of nilotinib hydrochloride drug. Efficient chromatographic separation was achieved on a Shim-pack XR-ODS II, 75 × 3.0 mm, 1.8-µm column with a gradient mobile phase combination. Quantification was carried at 260 nm at a flow rate of 0.6 mL min(-1). Stress degradation conditions were established for nilotinib hydrochloride by subjecting it to acid, base, oxidation, humidity, thermal and photolysis. The stress samples were assayed against a qualified reference standard and the mass balance was found close to 97.0%. The developed UPLC method was validated according to the present International Conference on Harmonisation guidelines for specificity, detection limit, quantitation limit, linearity, accuracy, precision, intermediate precision and robustness. The resolution between nilotinib hydrochloride and four potential impurities is found to be >2.0. Regression analysis shows as r value (correlation coefficient) of >0.999 for nilotinib hydrochloride and four potential impurities.

  20. Development, validation and comparison of UHPSFC and UHPLC methods for the determination of agomelatine and its impurities.

    PubMed

    Plachká, Kateřina; Chrenková, Lucia; Douša, Michal; Nováková, Lucie

    2016-06-01

    Agomelatine is one of the newest antidepressants. Due to a different mechanism of action it offers a completely new approach in the treatment of depressive disorders. Two chromatographic methods for determination of agomelatine and its impurities were developed. The separations on UHPSFC system were accomplished using stationary phase based on BEH 2-EP and gradient elution with CO2 and methanol containing 20mM ammonium formate and 5% of water. The UHPLC separations were performed on stationary phase BEH Shield RP18. The mixture of acetonitrile and methanol in ratio 1:1 and ammonium acetate buffer pH 9.5 were used as mobile phase. Both developed methods were properly validated in terms of linearity, sensitivity (LOD, LOQ), accuracy and precision according to ICH guidelines. The UHPSFC method was linear in the range 0.25-70μg/ml for all analytes with method accuracy ≥97.4% and ≥100.2% and method intra-day precision RSD ≤2.4 and ≤0.8 for impurities and API (active pharmaceutical ingredient), respectively. The UHPLC method was linear in the range 0.1-10μg/ml for all analytes except three impurities for which the linear range was larger 0.1-25μg/ml. Method accuracy ≥95.7% and ≥95.2% and method intra-day precision RSD ≤2.6 and ≤1.5 were found for impurities and API, respectively. The measurement of tablet samples was performed and the selected parameters of the methods were compared. In conclusion, both methods were appropriate for the determination of agomelatine and its impurities in pharmaceutical quality control (QC), although the UHPSFC method was found as more convenient especially in the method development phase. The advantages of newly developed UHPSFC-PDA (photo diode array detector) method were its environmental friendliness due to the mobile phase used, a very good resolution, selectivity and high speed of analysis (total time of separation was 4.1min). PMID:27131147

  1. Single atom impurity in a single molecular transistor

    SciTech Connect

    Ray, S. J.

    2014-10-21

    The influence of an impurity atom on the electrostatic behaviour of a Single Molecular Transistor was investigated through Ab-initio calculations in a double-gated geometry. The charge stability diagram carries unique signature of the position of the impurity atom in such devices which together with the charging energy of the molecule could be utilised as an electronic fingerprint for the detection of such impurity states in a nano-electronic device. The two gated geometry allows additional control over the electrostatics as can be seen from the total energy surfaces (for a specific charge state), which is sensitive to the positions of the impurity. These devices which are operational at room temperature can provide significant advantages over the conventional silicon based single dopant devices functional at low temperature. The present approach could be a very powerful tool for the detection and control of individual impurity atoms in a single molecular device and for applications in future molecular electronics.

  2. The effect of secondary impurities on solar cell performance

    NASA Technical Reports Server (NTRS)

    Hill, D. E.; Gutsche, H. W.; Wang, M. S.; Gupta, K. P.; Tucker, W. F.; Dowdy, J. D.; Crepin, R. J.

    1976-01-01

    Czochralski and float zone sigle crystals of silicon were doped with the primary impurities B or P so that a resistivity of 0.5 ohm cm resulted, and in addition doped with certain secondary impurities including Al, C, Cr, Cu, Fe, Mg, Mn, Na, Ni, O, Ti, V, and Zr. The actual presence of these impurities was confirmed by analysis of the crystals. Solar cell performance was evaluated and found to be degraded most significantly by Ti, V, and Zr and to some extent by most of the secondary impurities considered. These results are of significance to the low cost silicon program, since any such process would have to yield at least tolerable levels of these impurities.

  3. [Impurity removal technology of Tongan injection in liquid preparation process].

    PubMed

    Yang, Xu-fang; Wang, Xiu-hai; Bai, Wei-rong; Kang, Xiao-dong; Liu, Jun-chao; Wu, Yun; Xiao, Wei

    2015-08-01

    In order to effectively remove the invalid impurities in Tongan injection, optimize the optimal parameters of the impurity removal technology of liquid mixing process, in this paper, taking Tongan injection as the research object, with the contents of celandine alkali, and sinomenine, solids reduction efficiency, and related substances inspection as the evaluation indexes, the removal of impurities and related substances by the combined process of refrigeration, coction and activated carbon adsorption were investigated, the feasibility of the impurity removal method was definited and the process parameters were optimized. The optimized process parameters were as follows: refrigerated for 36 h, boiled for 15 min, activated carbon dosage of 0.3%, temperature 100 degrees C, adsorption time 10 min. It can effectively remove the tannin, and other impurities, thus ensure the quality and safety of products.

  4. Impurity effect on surface states of Bi (111) ultrathin films

    NASA Astrophysics Data System (ADS)

    Zhu, Kai; Tian, Dai; Wu, Lin; Xu, Jianli; Jin, Xiaofeng

    2016-08-01

    The surface impurity effect on the surface-state conductivity and weak antilocalization (WAL) effect has been investigated in epitaxial Bi (111) films by magnetotransport measurements at low temperatures. The surface-state conductivity is significantly reduced by the surface impurities of Cu, Fe, and Co. The magnetotransport data demonstrate that the observed WAL is robust against deposition of nonmagnetic impurities, but it is quenched by the deposition of magnetic impurities which break the time reversal symmetry. Our results help to shed light on the effect of surface impurities on the electron and spin transport properties of a 2D surface electron systems. Project supported by the National Basic Research Program of China (Grants Nos. 2015CB921400 and 2011CB921802) and the National Natural Science Foundation of China (Grants Nos. 11374057, 11434003, and 11421404).

  5. Spectroscopic Analysis of Impurity Precipitates in CdS Films

    SciTech Connect

    Webb, J. D.; Keane, J.; Ribelin, R.; Gedvilas, L.; Swartzlander, A.; Ramanathan, K.; Albin, D. S.; Noufi, R.

    1999-10-31

    Impurities in cadmium sulfide (CdS) films are a concern in the fabrication of copper (indium, gallium) diselenide (CIGS) and cadmium telluride (CdTe) photovoltaic devices. Devices incorporating chemical-bath-deposited (CBD) CdS are comparable in quality to devices incorporating purer CdS films grown using vacuum deposition techniques, despite the higher impurity concentrations typically observed in the CBD CdS films. In this paper, we summarize and review the results of Fourier transform infrared (FTIR), Auger, electron microprobe, and X-ray photoelectron spectroscopic (XPS) analyses of the impurities in CBD CdS films. We show that these impurities differ as a function of substrate type and film deposition conditions. We also show that some of these impurities exist as 10{sup 2} micron-scale precipitates.

  6. Impurity transport due to electromagnetic drift wave turbulence

    NASA Astrophysics Data System (ADS)

    Moradi, S.; Pusztai, I.; Mollén, A.; Fülöp, T.

    2012-03-01

    Finite β effects on impurity transport are studied through local linear gyrokinetic simulations with GYRO [J. Candy and E. Belli, General Atomics Report No. GA-A26818, 2011]; in particular, we investigate the parametric dependences of the impurity peaking factor (zero-flux density gradient) and the onset of the kinetic ballooning modes (KBMs). We find that electromagnetic effects even at low β can have significant impact on the impurity transport. The KBM instability threshold depends on the plasma parameters, particularly strongly on plasma shape. We have shown that magnetic geometry significantly influences the results, and the commonly used s-α model overestimates the KBM growth rates and ITG stabilization at high β. In the β range, where the KBM is the dominant instability the impurity peaking factor is strongly reduced, with very little dependence on β and the impurity charge.

  7. Pharmaceuticals: pharmaceutical cost controls--2005. End of Year Issue Brief.

    PubMed

    Seay, Melicia; Varma, Priya

    2005-12-31

    The enactment of the Omnibus Budget Reconciliation Act of 1990 (OBRA '90) gave states the option of offering pharmaceutical benefits within their Medicaid programs. But the law placed restrictions on states' flexibility to control what prescriptions they would cover and required the states to reimburse outpatient prescription drugs from manufacturers that signed rebate agreements with the U.S. Department of Health and Human Services. Forty-nine states--Arizona is excluded, based on its program structure--and the District of Columbia currently offer prescription drug coverage under the Medicaid Drug Rebate Program. During the past four years, states all over the country have been plagued with revenue shortfalls in their state Medicaid budgets. While the fiscal situation improved for most states in the 2004 legislative session, many states still face budget pressures in 2005. Compounding existing budget pressures are threats from the Bush Administration to shift increased costs of the Medicaid program on to the states. All things considered, the economic pressure of funding Medicaid is at the top of legislative agendas in 2005. As in previous years, states are attempting to reduce costs to their Medicaid programs by seeking savings in their pharmaceutical programs. Prescription drug costs are highly attributed as a contributing factor to the fiscal climate of state Medicaid programs. Currently, prescription drug spending outpaces that of every other category of health care and drug prices are rising faster than inflation. In response, states are instituting a variety of pharmaceutical cost control measures such as creating preferred drug lists (PDLs), negotiating supplemental rebates, forming bulk purchasing pools, promoting generic drug substitution and implementing price controls. As prescription drug cost containment tools have gained acceptance and momentum, they continue to be controversial. This issue brief explores the debate, history, methodology, utilization

  8. Acetaminophen metabolism, cytotoxicity, and genotoxicity in rat primary hepatocyte cultures

    SciTech Connect

    Milam, K.M.; Byard, J.L.

    1985-06-30

    Acetaminophen (APAP) metabolism, cytotoxicity, and genotoxicity were measured in primary cultures of rat hepatocytes. Although 3 mM APAP caused a slight increase in cellular release of lactate dehydrogenase into the culture medium, cellular glutathione concentration (an index of APAP metabolism) was reduced by 50%. APAP at 7 mM was significantly more toxic to these hepatocytes and had a similar but more marked effect on glutathione concentrations. In spite of its cytotoxicity, neither dose of APAP stimulated DNA repair synthesis when monitored by the rate of incorporation of (/sup 3/H)thymidine into DNA following exposure to APAP. Thus, although APAP has been shown to be both hepato- and nephrotoxic in several in vivo and in vitro systems, the reactive toxic metabolite of APAP is not genotoxic in rat primary hepatocyte cultures.

  9. Hexavalent chromium is cytotoxic and genotoxic to American alligator cells.

    PubMed

    Wise, Sandra S; Wise, Catherine; Xie, Hong; Guillette, Louis J; Zhu, Cairong; Wise, John Pierce; Wise, John Pierce

    2016-02-01

    Metals are a common pollutant in the aquatic ecosystem. With global climate change, these levels are anticipated to rise as lower pH levels allow sediment bound metals to be released. The American alligator (Alligator mississippiensis) is an apex predator in the aquatic ecosystem and is considered a keystone species; as such it serves as a suitable monitor for localized pollution. One metal of increasing concern is hexavalent chromium (Cr(VI)). It is present in the aquatic environment and is a known human carcinogen and reproductive toxicant. We measured the cytotoxicity and genotoxicity of Cr(VI) in American alligator cells derived from scute tissue. We found that particulate and soluble Cr(VI) are both cytotoxic and genotoxic to alligator cells in a concentration-dependent manner. These data suggest that alligators may be used as a model for assessing the effects of environmental Cr(VI) contamination as well as for other metals of concern. PMID:26730726

  10. DNA and protein adducts as markers of genotoxicity.

    PubMed

    Farmer, Peter B

    2004-04-01

    Determination of the interaction products (adducts) of a carcinogen with DNA or protein indicates the amount of genotoxic material that has reached the tissue under study and provides a valuable biomarker of exposure for molecular epidemiological studies. DNA adducts may also give further information with regard to the mutagenic significance of the exposure. The sensitivity and applicability of the analytical methods for the detection and quantification of carcinogen adducts has greatly increased in recent years, and DNA damage levels as low as one adduct per 10(8) nucleotides can now routinely be measured. The discovery of many types of endogenously-produced damage of DNA and protein has demonstrated previously unsuspected sources of genotoxicity, the biological consequences of which are so far not known.

  11. In vitro genotoxicity assessment of caffeic, cinnamic and ferulic acids.

    PubMed

    Maistro, E L; Angeli, J P F; Andrade, S F; Mantovani, M S

    2011-06-14

    Phenols are a large and diverse class of compounds, many of which occur naturally in a variety of food plants; they exhibit a wide range of biological effects, including antibacterial, anti-inflammatory, antiallergic, hepatoprotective, antithrombotic, antiviral, anticarcinogenic, and vasodilatory actions. We examined the genotoxic and clastogenic potential of three phenolic compounds: caffeic, cinnamic and ferulic acids, using the comet and micronucleus assays in vitro. Drug-metabolizing rat hepatoma tissue cells (HTCs) were used. Three different concentrations (50, 500 and 1500 μM) of these phenolic acids were tested on the HTCs for 24 h. The caffeic, cinnamic and ferulic acids were not genotoxic by the comet assay (P > 0.05). However, the micronucleus test showed an increase in the frequency of micronucleated cells for the three compounds, indicating that these substances have clastogenic effects in HTC.

  12. Hexavalent chromium is cytotoxic and genotoxic to American alligator cells.

    PubMed

    Wise, Sandra S; Wise, Catherine; Xie, Hong; Guillette, Louis J; Zhu, Cairong; Wise, John Pierce; Wise, John Pierce

    2016-02-01

    Metals are a common pollutant in the aquatic ecosystem. With global climate change, these levels are anticipated to rise as lower pH levels allow sediment bound metals to be released. The American alligator (Alligator mississippiensis) is an apex predator in the aquatic ecosystem and is considered a keystone species; as such it serves as a suitable monitor for localized pollution. One metal of increasing concern is hexavalent chromium (Cr(VI)). It is present in the aquatic environment and is a known human carcinogen and reproductive toxicant. We measured the cytotoxicity and genotoxicity of Cr(VI) in American alligator cells derived from scute tissue. We found that particulate and soluble Cr(VI) are both cytotoxic and genotoxic to alligator cells in a concentration-dependent manner. These data suggest that alligators may be used as a model for assessing the effects of environmental Cr(VI) contamination as well as for other metals of concern.

  13. Nuclear PTEN controls DNA repair and sensitivity to genotoxic stress

    PubMed Central

    Bassi, C; Ho, J; Srikumar, T; Dowling, RJO; Gorrini, C; Miller, SJ; Mak, TW; Neel, BG; Raught, B; Stambolic, V

    2016-01-01

    Loss of function of the Phosphatase and tensin homologue deleted on chromosome 10 (PTEN) tumor suppressor gene is associated with many human cancers. In the cytoplasm, PTEN antagonizes the Phosphatidylinositol 3′ kinase (PI3K) signaling pathway. PTEN also accumulates in the nucleus, where its function remains poorly understood. We demonstrate that SUMOylation (SUMO) of PTEN controls its nuclear localization. In cells exposed to genotoxic stress, SUMO-PTEN was rapidly excluded from the nucleus dependent on the protein kinase Ataxia telangiectasia mutated (ATM). Cells lacking nuclear PTEN were hypersensitive to DNA damage, while PTEN-deficient cells were susceptible to killing by a combination of genotoxic stress and a small molecule PI3K inhibitor both in vitro and in vivo. Our findings may have implications for individualized therapy for patients with PTEN-deficient tumors. PMID:23888040

  14. Toxicity and genotoxicity of wastewater from gasoline stations.

    PubMed

    Oliveira-Martins, Cynthia R; Grisolia, Cesar K

    2009-10-01

    The toxicity and genotoxicity of wastewater from eight gasoline stations in Brasília, Brazil's capital city, was studied by assessing chromosomal aberrations, chromosomal malsegregation and the mitotic index in Alliumcepa root cells, and the occurrence of micronucleus and nuclear abnormalities in peripheral erythrocytes of tilapia fish (Oreochromis niloticus). The content of gasoline station effluents was also analyzed based on several physico-chemical parameters. None of the wastewater samples was genotoxic to A. cepa root cells, although cell proliferation was significantly inhibited, especially at the highest concentrations. Likewise, no micronuclei were observed in O. niloticus peripheral erythrocytes, even after exposure to high concentrations, but there was an increase in the number of nuclear abnormalities and fish mortality. These results show that although the effluent from gasoline stations is processed by an oil/water separation system before being discharged into the main sewage system, the wastewater still contains toxic compounds.

  15. Toxicity and genotoxicity of wastewater from gasoline stations

    PubMed Central

    2009-01-01

    The toxicity and genotoxicity of wastewater from eight gasoline stations in Brasília, Brazil's capital city, was studied by assessing chromosomal aberrations, chromosomal malsegregation and the mitotic index in Alliumcepa root cells, and the occurrence of micronucleus and nuclear abnormalities in peripheral erythrocytes of tilapia fish (Oreochromis niloticus). The content of gasoline station effluents was also analyzed based on several physico-chemical parameters. None of the wastewater samples was genotoxic to A. cepa root cells, although cell proliferation was significantly inhibited, especially at the highest concentrations. Likewise, no micronuclei were observed in O. niloticus peripheral erythrocytes, even after exposure to high concentrations, but there was an increase in the number of nuclear abnormalities and fish mortality. These results show that although the effluent from gasoline stations is processed by an oil/water separation system before being discharged into the main sewage system, the wastewater still contains toxic compounds. PMID:21637464

  16. Studies on the potential for genotoxic carcinogenicity of fragrances and other chemicals.

    PubMed

    Rosenkranz, H S; Zhang, Y P; Klopman, G

    1998-08-01

    The potential of fragrances, physiological chemicals, natural products and a group of randomly selected chemicals to induce cancers by a genotoxic mechanism (i.e. "genotoxic" carcinogenesis) was compared using structure-activity relationships (SAR) models. Fragrances are significantly less likely to induce genotoxic carcinogenicity than randomly selected chemicals or natural products. With respect to the latter potential, fragrances were indistinguishable from normal mammalian physiological constituents.

  17. CHROMATOGRAPHIC TECHNIQUES IN PHARMACEUTICAL ANALYSIS IN POIAND: HISTORY AND THE PRESENCE ON THE BASIS OF PAPERS PUBLISHED IN SELECTED POLISH PHARMACEUTICAL JOURNALS IN XX CENTURY.

    PubMed

    Bilek, Maciej; Namieśnik, Jacek

    2016-01-01

    For a long time, chromatographic techniques and techniques related to them have stimulated the development of new procedures in the field of pharmaceutical analysis. The newly developed methods, characterized by improved metrological parameters, allow for more accurate testing of, among others, the composition of raw materials, intermediates and final products. The chromatographic techniques also enable studies on waste generated in research laboratories and factories producing pharmaceuticals and parapharmaceuticals. Based on the review of reports published in Polish pharmaceutical journals, we assessed the impact of chromatographic techniques on the development of pharmaceutical analysis. The first chromatographic technique used in pharmaceutical analysis was a so-called capillary analysis. It was applied in the 1930s to control the identity of pharmaceutical formulations. In the 1940s and 1950s, the chromatographic techniques were mostly a subject of review publications, while their use in experimental work was rare. Paper chromatography and thin layer chromatography were introduced in the 1960s and 1970s, respectively. These new analytical tools have contributed to the intensive development of research in the field of phytochemistry and the analysis of herbal medicines. The development of colunm chromatography-based techniques, i.e., gas chromatography and high performance liquid chromatography took place in the end of 20th century. Both aforementioned techniques were widely applied in pharmaceutical analysis, for example, to assess the stability of drugs, test for impurities and degradation products as well as in pharmacokinetics studies. The first decade of 21" century was the time of new detection methods in gas and liquid chromatography. The information sources used to write this article were Polish pharmaceutical journals, both professional and scientific, originating from the interwar and post-war period, i.e., "Kronika Farmaceutyczna", "Farmacja Wsp

  18. CHROMATOGRAPHIC TECHNIQUES IN PHARMACEUTICAL ANALYSIS IN POIAND: HISTORY AND THE PRESENCE ON THE BASIS OF PAPERS PUBLISHED IN SELECTED POLISH PHARMACEUTICAL JOURNALS IN XX CENTURY.

    PubMed

    Bilek, Maciej; Namieśnik, Jacek

    2016-01-01

    For a long time, chromatographic techniques and techniques related to them have stimulated the development of new procedures in the field of pharmaceutical analysis. The newly developed methods, characterized by improved metrological parameters, allow for more accurate testing of, among others, the composition of raw materials, intermediates and final products. The chromatographic techniques also enable studies on waste generated in research laboratories and factories producing pharmaceuticals and parapharmaceuticals. Based on the review of reports published in Polish pharmaceutical journals, we assessed the impact of chromatographic techniques on the development of pharmaceutical analysis. The first chromatographic technique used in pharmaceutical analysis was a so-called capillary analysis. It was applied in the 1930s to control the identity of pharmaceutical formulations. In the 1940s and 1950s, the chromatographic techniques were mostly a subject of review publications, while their use in experimental work was rare. Paper chromatography and thin layer chromatography were introduced in the 1960s and 1970s, respectively. These new analytical tools have contributed to the intensive development of research in the field of phytochemistry and the analysis of herbal medicines. The development of colunm chromatography-based techniques, i.e., gas chromatography and high performance liquid chromatography took place in the end of 20th century. Both aforementioned techniques were widely applied in pharmaceutical analysis, for example, to assess the stability of drugs, test for impurities and degradation products as well as in pharmacokinetics studies. The first decade of 21" century was the time of new detection methods in gas and liquid chromatography. The information sources used to write this article were Polish pharmaceutical journals, both professional and scientific, originating from the interwar and post-war period, i.e., "Kronika Farmaceutyczna", "Farmacja Wsp

  19. A validated stability-indicating LC method for acetazolamide in the presence of degradation products and its process-related impurities.

    PubMed

    Srinivasu, Prabha; Subbarao, Devarakonda V; Vegesna, Raju V K; Sudhakar Babu, K

    2010-05-01

    The objective of the current study was to develop a validated, specific and stability-indicating reverse phase liquid chromatographic method for the quantitative determination of acetazolamide and its related substances. The determination was done for an active pharmaceutical ingredient, its pharmaceutical dosage form in the presence of degradation products, and its process-related impurities. The drug was subjected to stress conditions of hydrolysis (acid and base), oxidation, photolysis and thermal degradation as per International Conference on Harmonization (ICH) prescribed stress conditions to show the stability-indicating power of the method. Significant degradation was observed during acid and base hydrolysis, and the major degradant was identified by LC-MS, FTIR and (1)H/(13)C NMR spectral analysis. The chromatographic conditions were optimized using an impurity-spiked solution and the generated samples were used for forced degradation studies. In the developed HPLC method, the resolution between acetazolamide and, its process-related impurities (namely imp-1, imp-2, imp-3, imp-4 and its degradation products) was found to be greater than 2. The chromatographic separation was achieved on a C18, 250mmx4.6mm, 5microm column. The LC method employed a linear gradient elution, and the detection wavelength was set at 254nm. The stress samples were assayed against a qualified reference standard and the mass balance was found to be close to 99.6%. The developed RP-LC method was validated with respect to linearity, accuracy, precision and robustness.

  20. Cell cycle control, checkpoint mechanisms, and genotoxic stress.

    PubMed Central

    Shackelford, R E; Kaufmann, W K; Paules, R S

    1999-01-01

    The ability of cells to maintain genomic integrity is vital for cell survival and proliferation. Lack of fidelity in DNA replication and maintenance can result in deleterious mutations leading to cell death or, in multicellular organisms, cancer. The purpose of this review is to discuss the known signal transduction pathways that regulate cell cycle progression and the mechanisms cells employ to insure DNA stability in the face of genotoxic stress. In particular, we focus on mammalian cell cycle checkpoint functions, their role in maintaining DNA stability during the cell cycle following exposure to genotoxic agents, and the gene products that act in checkpoint function signal transduction cascades. Key transitions in the cell cycle are regulated by the activities of various protein kinase complexes composed of cyclin and cyclin-dependent kinase (Cdk) molecules. Surveillance control mechanisms that check to ensure proper completion of early events and cellular integrity before initiation of subsequent events in cell cycle progression are referred to as cell cycle checkpoints and can generate a transient delay that provides the cell more time to repair damage before progressing to the next phase of the cycle. A variety of cellular responses are elicited that function in checkpoint signaling to inhibit cyclin/Cdk activities. These responses include the p53-dependent and p53-independent induction of Cdk inhibitors and the p53-independent inhibitory phosphorylation of Cdk molecules themselves. Eliciting proper G1, S, and G2 checkpoint responses to double-strand DNA breaks requires the function of the Ataxia telangiectasia mutated gene product. Several human heritable cancer-prone syndromes known to alter DNA stability have been found to have defects in checkpoint surveillance pathways. Exposures to several common sources of genotoxic stress, including oxidative stress, ionizing radiation, UV radiation, and the genotoxic compound benzo[a]pyrene, elicit cell cycle

  1. In vivo genotoxicity of estragole in male F344 rats.

    PubMed

    Ding, Wei; Levy, Dan D; Bishop, Michelle E; Pearce, Mason G; Davis, Kelly J; Jeffrey, Alan M; Duan, Jian-Dong; Williams, Gary M; White, Gene A; Lyn-Cook, Lascelles E; Manjanatha, Mugimane G

    2015-05-01

    Estragole, a naturally occurring constituent of various herbs and spices, is a rodent liver carcinogen which requires bio-activation. To further understand the mechanisms underlying its carcinogenicity, genotoxicity was assessed in F344 rats using the comet, micronucleus (MN), and DNA adduct assays together with histopathological analysis. Oxidative damage was measured using human 8-oxoguanine-DNA-N-glycosylase (hOGG1) and EndonucleaseIII (EndoIII)-modified comet assays. Results with estragole were compared with the structurally related genotoxic carcinogen, safrole. Groups of seven-week-old male F344 rats received corn oil or corn oil containing 300, 600, or 1,000 mg/kg bw estragole and 125, 250, or 450 mg/kg bw safrole by gavage at 0, 24, and 45 hr and terminated at 48 hr. Estragole-induced dose-dependent increases in DNA damage following EndoIII or hOGG1 digestion and without enzyme treatment in liver, the cancer target organ. No DNA damage was detected in stomach, the non-target tissue for cancer. No elevation of MN was observed in reticulocytes sampled from peripheral blood. Comet assays, both without digestion or with either EndoIII or hOGG1 digestion, also detected DNA damage in the liver of safrole-dosed rats. No DNA damage was detected in stomach, nor was MN elevated in peripheral blood following dosing with safrole suggesting that, as far both safrole and estragole, oxidative damage may contribute to genotoxicity. Taken together, these results implicate multiple mechanisms of estragole genotoxicity. DNA damage arises from chemical-specific interaction and is also mediated by oxidative species.

  2. Defining a Genotoxic Profile with Mouse Embryonic Stem Cells

    PubMed Central

    Kim, Tae Moon; Rebel, Vivienne I.; Hasty, Paul

    2014-01-01

    Many genotoxins are found in the environment from synthetic to natural, yet very few have been studied in depth. This means we fail to understand many molecules that damage DNA, we do not understand the type of damage they cause and the repair pathways required to correct their lesions. It is surprising so little is known about the vast majority of genotoxins since they have potential to cause disease from developmental defects to cancer to degenerative ailments. By contrast some of these molecules have commercial and medical potential and some can be weaponized. Therefore, we need a systematic method to efficiently generate a genotoxic profile for these agents. A genotoxic profile would include the type of damage the genotoxin causes, the pathways used to repair the damage and the resultant mutations if repair fails. Mouse embryonic stem (ES) cells are well suited for identifying pathways and mutations. Mouse ES cells are genetically tractable and many DNA repair mutant cells are available. ES cells have a high mitotic index and form colonies so experiments can be completed quickly and easily. Furthermore, ES cells have robust DNA repair pathways to minimize genetic mutations at a particularly vulnerable time in life, early development when a mutation in a single cell could ultimately contribute to a large fraction of the individual. After an initial screen, other types of cells and mouse models can be used to complement the analysis. This review discusses the merging field of genotoxic screens in mouse ES cells that can be used to discover and study potential genotoxic activity for chemicals commonly found in our environment. PMID:23598974

  3. Induction of microtubule damage in Allium cepa meristematic cells by pharmaceutical formulations of thiabendazole and griseofulvin.

    PubMed

    Andrioli, Nancy B; Soloneski, Sonia; Larramendy, Marcelo L; Mudry, Marta D

    2014-09-15

    Microtubules (MT) are formed by the assembly of α- and β-tubulins and MT-associated proteins. We characterized the effects of pharmaceutical formulations containing the microtubule disruptors thiabendazole (TBZ) and griseofulvin (GF) on the mitotic machinery of plant (A. cepa) meristematic cells. GF concentrations between 10 and 250 μg/ml were tested. GF induced mitotic index inhibition and genotoxic effects, including chromosome fragments, bridges, lagged chromosomes, C-metaphases, tripolar cell division, disorganized anaphases and nuclear abnormalities in interphase cells. Efects on the mitotic machinery were studied by direct immunofluorescence with β-tubulin labeling and by DNA counterstaining with 4',6-diamidino-2-phenylindole (DAPI). Exposure of meristematic root cells to TBZ or GF, 100 μg/ml, caused microtubular damage which led to abnormal MT arrays. Our results suggest that GF induces abnormalities in spindle symmetry/polarity, while TBZ causes chromosome missegregation, polyploidy, and lack of cytokinesis.

  4. Bioremediation of Pharmaceuticals, Pesticides, and Petrochemicals with Gomeya/Cow Dung

    PubMed Central

    Randhawa, Gurpreet Kaur; Kullar, Jagdev Singh

    2011-01-01

    Use and misuse of pharmaceuticals, pesticides, and petrochemicals by man is causing havoc with nature, as they persist as such or as their toxic metabolites. These pollutants bioaccumulate in environment, and they ultimately reach man through various means. They are hazardous because of potential toxicity, mutagenicity, carcinogenicity, and genotoxicity. To rejuvenate nature, remediation methods currently available are usually expensive and might convert one toxic pollutant to another. Bioremediation methods use naturally occurring microorganisms to detoxify man-made pollutants so that they change pollutants to innocuous products that make soil fertile in the process. Taking cue from Ayurveda, Gomeya/cow dung is used as an excellent bioremediation method. Thus, utilizing freely available cow dung as slurry or after composting in rural areas, is a cheap and effective measure to bioremediate the harmful pollutants. Yet, more research in this direction is warranted to bioremediate nonbiodegradable, potentially toxic pollutants. PMID:22084712

  5. Genotoxicity of nanomaterials: refining strategies and tests for hazard identification.

    PubMed

    Pfuhler, Stefan; Elespuru, Rosalie; Aardema, Marilyn J; Doak, Shareen H; Maria Donner, E; Honma, Masamitsu; Kirsch-Volders, Micheline; Landsiedel, Robert; Manjanatha, Mugimane; Singer, Tim; Kim, James H

    2013-05-01

    A workshop addressing strategies for the genotoxicity assessment of nanomaterials (NMs) was held on October 23, 2010 in Fort Worth Texas, USA. The workshop was organized by the Environmental Mutagen Society and the International Life Sciences Institute (ILSI) Health and Environmental Sciences Institute. The workshop was attended by more than 80 participants from academia, regulatory agencies, and industry from North America, Europe and Japan. A plenary session featured summaries of the current status and issues related to the testing of NMs for genotoxic properties, as well as an update on international activities and regulatory approaches. This was followed by breakout sessions and a plenary session devoted to independent discussions of in vitro assays, in vivo assays, and the need for new assays or new approaches to develop a testing strategy for NMs. Each of the standard assays was critiqued as a resource for evaluation of NMs, and it became apparent that none was appropriate without special considerations or modifications. The need for nanospecific positive controls was questioned, as was the utility of bacterial assays. The latter was thought to increase the importance of including mammalian cell gene mutation assays into the test battery. For in-vivo testing, to inform the selection of appropriate tests or protocols, it was suggested to run repeated dose studies first to learn about disposition, potential accumulation, and possible tissue damage. It was acknowledged that mechanisms may be at play that a standard genotoxicity battery may not be able to capture.

  6. Safety pharmacology and genotoxicity evaluation of AVI-4658.

    PubMed

    Sazani, Peter; Weller, Doreen L; Shrewsbury, Stephen B

    2010-01-01

    Duchenne muscular dystrophy (DMD) is caused by dystrophin gene mutations. Restoration of dystrophin by exon skipping was demonstrated with the phosphorodiamidate morpholino oligomers (PMO) class of splice-switching oligomers, in both mouse and dog disease models. The authors report the results of Good Laboratory Practice-compliant safety pharmacology and genotoxicity evaluations of AVI-4658, a PMO under clinical evaluation for DMD. In cynomolgus monkeys, no test article-related effects were seen on cardiovascular, respiratory, global neurological, renal, or liver parameters at the maximum feasible dose (320 mg/kg). Genotoxicity battery showed that AVI-4658 has no genotoxic potential at up to 5000 microg/mL in an in vitro mammalian chromosome aberration test and a bacterial reverse mutation assay. In the mouse bone marrow erythrocyte micronucleus test, a single intravenous injection up to 2000 mg/kg was generally well tolerated and resulted in no mutagenic potential. These results allowed initiation of systemic clinical trials in DMD patients in the United Kingdom.

  7. Genotoxicity assessment of amaranth and allura red using Saccharomyces cerevisiae.

    PubMed

    Jabeen, Hafiza Sumara; ur Rahman, Sajjad; Mahmood, Shahid; Anwer, Sadaf

    2013-01-01

    Amaranth (E123) and Allura red (E129), very important food azo dyes used in food, drug, paper, cosmetic and textile industries, were assessed for their genotoxic potential through comet assay in yeast cells. Comet assay was standardized by with different concentration of H(2)O(2). Concentrations of Amaranth and Allura red were maintained in sorbitol buffer starting from 9.76 to 5,000 μg/mL and 1 × 10(4) cells were incubated at two different incubation temperatures 28 and 37°C. Amaranth (E123) and Allura red (E129) were found to exhibit their genotoxic effect directly in Saccharomyces cerevisiae. No significant genotoxic activity was observed for Amaranth and Allura red at 28°C but at 37°C direct relation of Amaranth concentration with comet tail was significant and no positive relation was seen with time exposure factor. At 37°C the minimum concentration of Amaranth and Allura red at which significant DNA damage observed through comet assay was 1,250 μg/mL in 2nd h post exposure time. The results indicated that food colors should be carefully used in baking products as heavy concentration of food colors could affect the fermentation process of baking.

  8. Genotoxic effects of profenofos on the marine fish, Therapon jarbua.

    PubMed

    Janaki Devi, V; Nagarani, N; Yokesh Babu, M; Vijayalakshimi, N; Kumaraguru, A K

    2012-02-01

    Profenofos (EC(50)) is a persistent and toxic organophosphorus insecticide. Animals get exposed to profenofos via food and water. The present study was designed to explore the genotoxic effect of profenofos in the marine fish. The ubiquitously occurring marine fish, Therapon jarbua, was exposed to profenofos and its effect on DNA was measured using comet (single-cell gel electrophoresis) assay. DNA damage were scored using mean percentage of tail length and compared with the comet classes' viz., 0, 1, 2, 3, and 4. In the first three doses, the (21.5, 43.0 and 86.0 µg L(-1)) comets were observed, of which the mean tail length differed significantly (p < 0.01) from those of unexposed, but not from each other. The mean tail length values were significantly (p < 0.05) higher in gill than in matured erythrocytes. The result indicates that DNA strand breaks in T. jarbua were due to the genotoxic potential of profenofos. From the study, we suggest that T. jarbua may be used as an indicator organism to assess the genotoxic risks of profenofos contamination in marine environments using Comet assay as an identification tool. We infer that organophosphorus insecticides may be dangerous to the marine lives. PMID:21859359

  9. Genotoxicity and toxicity assessment in urban hydrographic basins.

    PubMed

    Cardozo, Tatiane Rocha; Rosa, Danielle Pereira; Feiden, Ilda Rosa; Rocha, Jocelita Aparecida Vaz; de Oliveira, Nânci Cristina D'Avila; da Silva Pereira, Tatiana; Pastoriza, Thienne Flores; da Motta Marques, David; de Lemos, Clarice Torres; Terra, Nara Regina; Vargas, Vera Maria Ferrão

    2006-01-31

    The genotoxicity and cytotoxicity of water in small urban basins was evaluated by the Salmonella/microsome assay and micronucleus test in V79 cells. The results showed that the cytotoxic effect was the most significant response in areas with medium to heavy urban occupation for both assays evaluated. Water samples from these areas include different concentrations of chloroform, bromodichloromethane, toluene, ethylbenzene, m,p-xylene and 1,4-dichlorobenzene. As to genotoxic damage, the presence of mainly direct-acting frameshift mutagens was detected in areas with less urban concentration and showed genotoxic activity in V79 cells in more heavily urbanized areas. Water organic extracts, evaluated using a microsuspension procedure, showed frameshift mutagenic activity in the presence of hepatic metabolization that increased as the population density grow. Chronic toxicity studies of sediment samples with the microcrustacean Daphnia magna showed that, while survival was not highly affected, reproductive inhibition was found in 92% of the observations. A retrospective diagnosis of water quality using traditional physicochemical parameters that defined the differential contribution of urban wastes at the three sites was associated with the biological assays. It became clear that the biological assays were of significant benefit in the diagnosis of risks of contamination of hydrographic basins by pollutants from urban non-point sources. PMID:16413222

  10. Genotoxicity of Superparamagnetic Iron Oxide Nanoparticles in Granulosa Cells.

    PubMed

    Pöttler, Marina; Staicu, Andreas; Zaloga, Jan; Unterweger, Harald; Weigel, Bianca; Schreiber, Eveline; Hofmann, Simone; Wiest, Irmi; Jeschke, Udo; Alexiou, Christoph; Janko, Christina

    2015-01-01

    Nanoparticles that are aimed at targeting cancer cells, but sparing healthy tissue provide an attractive platform of implementation for hyperthermia or as carriers of chemotherapeutics. According to the literature, diverse effects of nanoparticles relating to mammalian reproductive tissue are described. To address the impact of nanoparticles on cyto- and genotoxicity concerning the reproductive system, we examined the effect of superparamagnetic iron oxide nanoparticles (SPIONs) on granulosa cells, which are very important for ovarian function and female fertility. Human granulosa cells (HLG-5) were treated with SPIONs, either coated with lauric acid (SEONLA) only, or additionally with a protein corona of bovine serum albumin (BSA; SEON(LA-BSA)), or with dextran (SEON(DEX)). Both micronuclei testing and the detection of γH2A.X revealed no genotoxic effects of SEON(LA-BSA), SEON(DEX) or SEON(LA). Thus, it was demonstrated that different coatings of SPIONs improve biocompatibility, especially in terms of genotoxicity towards cells of the reproductive system. PMID:26540051

  11. Monitoring Genotoxicity Potential in the Mumbuca Stream, Minas Gerais, Brazil.

    PubMed

    de Campos Júnior, Edimar Olegário; Pereira, Boscolli Barbosa; Morelli, Sandra

    2015-01-01

    Rivers are sites for water catchment to supply metropolitan areas but also serve as receptors for discharge of urban sewage, wastewater, and agri-industrial effluents. Bioindicators or sentinel organisms are widely used as markers of pollution in various environments. The objective of this study was to evaluate the genotoxic potential and consequent quality of the water from the Mumbuca stream, which supplies the city of Monte Carmelo, located in the Minas Triangle region, Minas Gerais, Brazil. This was achieved using two variable response bioindicators (Rhamdia quelen and Geophagus brasiliensis), the micronucleus (MN) test, and determining the presence of metals by flame atomic absorption spectrometry. Results showed that site 3 water (region of residential flow and intense industrial pottery activity) presented a greater possibility for induction of genotoxic activity, as evidenced by the increase in the MN frequency in Rhamdia quelen and Geophagus brasiliensis in comparison with the reference-site water. The water of the Mumbuca stream was influenced by genotoxic agents, especially lead and chromium, assessed by the rise in MN rate. Data suggested that discharge of industrial effluents in a specific stretch of the stream interfered with biota functions. PMID:26503827

  12. Molecular and cytogenetic assessment of Dipterygium glaucum genotoxicity.

    PubMed

    Altwaty, Nada H; El-Sayed, Osama E; Aly, Nariman A H; Baeshen, Mohamed N; Baeshen, Nabih A

    2016-01-01

    The aim of the present study is to assess the genotoxicity of Dipterygium glaucum grows widely in Saudi Arabia desert to produce safety herbal products. This work is considered the first and pioneer report so far due to the lack and poor evaluated reports of the plant species for their mutagensity, genotoxicity and cytogenetics effects. Cytogenetic effects of D. glaucum on mitotic in roots of Vicia faba showed reduction in mitotic activity using three extracts; water, ethanol and ethyl acetate. Chromosomal abnormalities were recorded that included stickiness of chromosomes, chromatin bridge, fragments, lagging chromosome and micronuclei. Protein bands and RAPD analyses of V. faba treated with three D. glaucum extracts revealed some newly induced proteins and DNA fragments and other disappeared. Chemical constitution of the plant species should be identified with their biological activities against human and animal cells like HeLa cancer cell line. We are recommending using additional genotoxicity tests and other toxicity tests on animal culture with different concentrations and also utilizing several drought and heat tolerant genes of the plant species in gene cloning to develop and improve other economical crop plants instead of using the species as oral herbal remedy. PMID:27142548

  13. Assessment of genotoxic activity of petroleum hydrocarbon-bioremediated soil.

    PubMed

    Płaza, Grazyna; Nałecz-Jawecki, Grzegorz; Ulfig, Krzysztof; Brigmon, Robin L

    2005-11-01

    The relationship between toxicity and soil contamination must be understood to develop reliable indicators of environmental restoration for bioremediation. Two bacterial rapid bioassays, SOS chromotest and the umu test with and without metabolic activation (S-9 mixture), were used to evaluate the genotoxicity of petroleum hydrocarbon-contaminated soil following bioremediation treatment. The soil was taken from an engineered biopile at the Czechowice-Dziedzice Polish oil refinery (CZOR). The bioremediation process in the biopile lasted 4 years, and the toxicity measurements were done after this treatment. Carcinogens detected in the soil, polyaromatic hydrocarbons (PAHs), were reduced to low concentrations (2mg/kg dry wt) by the bioremediation process. Genotoxicity was not observed for soils tested with and without metabolic activation by a liver homogenate (S-9 mixture). However, the umu test was more sensitive than the SOS chromotest in the analysis of petroleum hydrocarbon-bioremediated soil. Analytical results of soil used in the bioassays confirmed that the bioremediation process reduced 81% of the petroleum hydrocarbons including PAHs. We conclude that the combined test systems employed in this study are useful tools for the genotoxic examination of remediated petroleum hydrocarbon-contaminated soil.

  14. Monitoring Genotoxicity Potential in the Mumbuca Stream, Minas Gerais, Brazil.

    PubMed

    de Campos Júnior, Edimar Olegário; Pereira, Boscolli Barbosa; Morelli, Sandra

    2015-01-01

    Rivers are sites for water catchment to supply metropolitan areas but also serve as receptors for discharge of urban sewage, wastewater, and agri-industrial effluents. Bioindicators or sentinel organisms are widely used as markers of pollution in various environments. The objective of this study was to evaluate the genotoxic potential and consequent quality of the water from the Mumbuca stream, which supplies the city of Monte Carmelo, located in the Minas Triangle region, Minas Gerais, Brazil. This was achieved using two variable response bioindicators (Rhamdia quelen and Geophagus brasiliensis), the micronucleus (MN) test, and determining the presence of metals by flame atomic absorption spectrometry. Results showed that site 3 water (region of residential flow and intense industrial pottery activity) presented a greater possibility for induction of genotoxic activity, as evidenced by the increase in the MN frequency in Rhamdia quelen and Geophagus brasiliensis in comparison with the reference-site water. The water of the Mumbuca stream was influenced by genotoxic agents, especially lead and chromium, assessed by the rise in MN rate. Data suggested that discharge of industrial effluents in a specific stretch of the stream interfered with biota functions.

  15. Molecular and cytogenetic assessment of Dipterygium glaucum genotoxicity.

    PubMed

    Altwaty, Nada H; El-Sayed, Osama E; Aly, Nariman A H; Baeshen, Mohamed N; Baeshen, Nabih A

    2016-01-01

    The aim of the present study is to assess the genotoxicity of Dipterygium glaucum grows widely in Saudi Arabia desert to produce safety herbal products. This work is considered the first and pioneer report so far due to the lack and poor evaluated reports of the plant species for their mutagensity, genotoxicity and cytogenetics effects. Cytogenetic effects of D. glaucum on mitotic in roots of Vicia faba showed reduction in mitotic activity using three extracts; water, ethanol and ethyl acetate. Chromosomal abnormalities were recorded that included stickiness of chromosomes, chromatin bridge, fragments, lagging chromosome and micronuclei. Protein bands and RAPD analyses of V. faba treated with three D. glaucum extracts revealed some newly induced proteins and DNA fragments and other disappeared. Chemical constitution of the plant species should be identified with their biological activities against human and animal cells like HeLa cancer cell line. We are recommending using additional genotoxicity tests and other toxicity tests on animal culture with different concentrations and also utilizing several drought and heat tolerant genes of the plant species in gene cloning to develop and improve other economical crop plants instead of using the species as oral herbal remedy.

  16. ASSESSMENT OF GENOTOXIC ACTIVITY OF PETROLEUM HYDROCARBON-BIOREMEDIATED SOIL

    SciTech Connect

    BRIGMON, ROBIN

    2004-10-20

    The relationship between toxicity and soil contamination must be understood to develop reliable indicators of environmental restoration for bioremediation. Two bacterial rapid bioassays: SOS chromotest and umu-test with and without metabolic activation (S-9 mixture) were used to evaluate genotoxicity of petroleum hydrocarbon-contaminated soil following bioremediation treatment. The soil was taken from an engineered biopile at the Czor Polish oil refinery. The bioremediation process in the biopile lasted 4 years, and the toxicity measurements were done after this treatment. Carcinogens detected in the soil, polyaromatic hydrocarbons (PAHs), were reduced to low concentrations (2 mg/kg dry wt) by the bioremediation process. Genotoxicity was not observed for soils tested with and without metabolic activation by a liver homogenate (S-9 mixture). However, umu-test was more sensitive than SOS-chromotest in the analysis of petroleum hydrocarbon-bioremediated soil. Analytical results of soil used in the bioassays confirmed that the bioremediation process reduced 81 percent of the petroleum hydrocarbons including PAHs. We conclude that the combined test systems employed in this study are useful tools for the genotoxic examination of remediated petroleum hydrocarbon-contaminated soil.

  17. Genotoxic effects of sunlight-activated waste waters

    SciTech Connect

    Strniste, G.F.; Chen, D.J.; Okinaka, R.T.

    1981-01-01

    Natural sunlight induces a genotoxic response in cultured CHO cells pre-treated with shale oil retort process water. Near ultraviolet light (NUV) component of the solar spectrum is the apparent radiation responsible for photoactivation. Cultured human skin fibroblasts are acutely sensitive to the genotoxic effects of photoactivated process water. The mutagenic potential of photoactivated process water in human cells is the same as that witnessed for an equivalent killing dose of the potent skin carcinogen FUV. DNA repair processes are involved in modulating genotoxic effects of this photo-induced process. The exact magnitude of the potential health-related and environmental risks resulting from photoactivation of retort process waters and other oil shale by-products is unassessed at this time. Our demonstration that a significant rate of mutation occurs in cultured human cells exposed to high dilutions of process waters and fluences of NUV comparable to that encountered during nominal exposure to sunlight suggests that such assessment is a prerequisite to minimal risk development of our oil shale resources.

  18. Borax counteracts genotoxicity of aluminum in rat liver.

    PubMed

    Turkez, Hasan; Geyikoğlu, Fatime; Tatar, Abdulgani

    2013-10-01

    This study was carried out to evaluate the protective role of borax (BX) on genotoxicity induced by aluminum (Al) in rat liver, using liver micronucleus assay as an indicator of genotoxicity. Sprague-Dawley rats were randomly separated into six groups and each group had four animals. Aluminum chloride (AlCl₃; 5 mg/kg b.w.) and BX (3.25 and 13 mg/kg b.w.) were injected intraperitoneally to rats. Besides, animals were also treated with Al for 4 consecutive days followed by BX for 10 days. Rats were anesthetized after Al and BX injections and the hepatocytes were isolated for counting the number of micronucleated hepatocytes (MNHEPs). AlCl₃ was found to significantly (p < 0.05) increase the number of MNHEPs. Rats treated with BX, however, showed no increase in MNHEPs. Moreover, simultaneous treatments with BX significantly modulated the genotoxic effects of AlCl₃ in rats. It can be concluded that BX has beneficial influences and has the ability to antagonize Al toxicity. PMID:22491726

  19. Borax counteracts genotoxicity of aluminum in rat liver.

    PubMed

    Turkez, Hasan; Geyikoğlu, Fatime; Tatar, Abdulgani

    2013-10-01

    This study was carried out to evaluate the protective role of borax (BX) on genotoxicity induced by aluminum (Al) in rat liver, using liver micronucleus assay as an indicator of genotoxicity. Sprague-Dawley rats were randomly separated into six groups and each group had four animals. Aluminum chloride (AlCl₃; 5 mg/kg b.w.) and BX (3.25 and 13 mg/kg b.w.) were injected intraperitoneally to rats. Besides, animals were also treated with Al for 4 consecutive days followed by BX for 10 days. Rats were anesthetized after Al and BX injections and the hepatocytes were isolated for counting the number of micronucleated hepatocytes (MNHEPs). AlCl₃ was found to significantly (p < 0.05) increase the number of MNHEPs. Rats treated with BX, however, showed no increase in MNHEPs. Moreover, simultaneous treatments with BX significantly modulated the genotoxic effects of AlCl₃ in rats. It can be concluded that BX has beneficial influences and has the ability to antagonize Al toxicity.

  20. Evaluation of river water genotoxicity using the piscine micronucleus test.

    PubMed

    Ergene, Serap; Cavaş, Tolga; Celik, Ayla; Köleli, Nurcan; Aymak, Cemil

    2007-07-01

    The Berdan River, which empties into the Mediterranean Sea on the east coast of Turkey, receives discharges of industrial and municipal waste. In the present study, the in vivo piscine micronucleus (MN) test was used to evaluate the genotoxicity of water samples collected from different locations along the Berdan River. Nile tilapia (Oreochromis niloticus) were exposed in the laboratory for 2, 4, and 6 days, and micronuclei were evaluated in peripheral blood erythrocytes, gill cells, and caudal fin epithelial cells. A single dose of 5 mg/L cyclophosphamide was used as a positive control. In addition to micronuclei, nuclear abnormalities (NAs), such as binucleated cells and blebbed, notched, and lobed nuclei, were assessed in the erythrocytes, and chemical analyses were carried out to determine the amount of heavy metals in the water samples. MN and NA frequencies were significantly elevated (up to 2- to 3-fold) in fish exposed to river water samples taken downstream of potential discharges, and the elevated responses in gill and fin cells were related to the concentration of heavy metals in the water. MN frequencies (expressed as micronucleated cells/1,000 cells), in both treated and untreated fish, were greatest in gill cells (range: 0.80-3.70), and generally lower in erythrocytes (range: 0.50-2.80), and fin cells (range: 0.45-1.70). The results of this study indicate that the Berdan River is contaminated with genotoxic pollutants and that the genotoxicity is related to the discharge of wastes into the river water.

  1. Genotoxic assessment on river water using different biological systems.

    PubMed

    Nunes, Emilene Arusievicz; de Lemos, Clarice Torres; Gavronski, Léia; Moreira, Tiago Nunes; Oliveira, Nânci C D; da Silva, Juliana

    2011-06-01

    This paper reports genotoxicity and toxicity data in water samples collected in Sinos River, an important water course in the hydrographic region of Guaíba Lake, Rio Grande do Sul State, south of Brazil. This river is exposed to intense anthropic influence by numerous shoes, leather, petrochemical, and metallurgy industries. Water samples were collected at two moments (winter 2006 and spring 2006) at five sites of Sinos River and evaluated using in vitro V79 Chinese hamster lung fibroblasts (cytotoxicity, comet assay and micronucleus test) and Allium cepa test (toxicity and micronucleus test). Comet and micronucleus tests revealed that water samples collected exerted cytotoxic, toxic, genotoxic and mutagenic effects. The results showed the toxic action of organic and inorganic agents found in the water samples in all sites of Sinos River, for both data collections. The main causes behind pollution were the domestic and industrial toxic discharges. The V79 and A. cepa tests were proved efficient to detect toxicity and genotoxicity caused by complex mixtures. This study also showed the need for constant monitoring in sites with strong environmental degradation caused by industrial discharges and urban sewages. PMID:21435689

  2. Genotoxicity risk assessment of diversely substituted quinolines using the SOS chromotest.

    PubMed

    Duran, Leidy Tatiana Díaz; Rincón, Nathalia Olivar; Galvis, Carlos Eduardo Puerto; Kouznetsov, Vladimir V; Lorenzo, Jorge Luis Fuentes

    2015-03-01

    Quinolines are aromatic nitrogen compounds with wide therapeutic potential to treat parasitic and microbial diseases. In this study, the genotoxicity of quinoline, 4-methylquinoline, 4-nitroquinoline-1-oxide (4-NQO), and diversely functionalized quinoline derivatives and the influence of the substituents (functional groups and/or atoms) on their genotoxicity were tested using the SOS chromotest. Quinoline derivatives that induce genotoxicity by the formation of an enamine epoxide structure did not induce the SOS response in Escherichia coli PQ37 cells, with the exception of 4-methylquinoline that was weakly genotoxic. The chemical nature of the substitution (C-5 to C-8: hydroxyl, nitro, methyl, isopropyl, chlorine, fluorine, and iodine atoms; C-2: phenyl and 3,4-methylenedioxyphenyl rings) of quinoline skeleton did not significantly modify compound genotoxicities; however, C-2 substitution with α-, β-, or γ-pyridinyl groups removed 4-methylquinoline genotoxicity. On the other hand, 4-NQO derivatives whose genotoxic mechanism involves reduction of the C-4 nitro group were strong inducers of the SOS response. Methyl and nitrophenyl substituents at C-2 of 4-NQO core affected the genotoxic potency of this molecule. The relevance of these results is discussed in relation to the potential use of the substituted quinolines. The work showed the sensitivity of SOS chromotest for studying structure-genotoxicity relationships and bioassay-guided quinoline synthesis.

  3. Volatile hydrocarbons in pharmaceutical solutions

    SciTech Connect

    Kroneld, R. )

    1991-07-01

    Volatile pollutants such as hydrocarbons have, during many years, been analysed in small concentrations in air, water, food, pharmaceutical solutions, and human blood and tissues. It has also been shown that such substances have unexpected consequences for cell cultures and scientific experiments. These substances also accumulate in patients receiving haemodialysis and these patients are exposed to quite high concentrations. The knowledge of the toxicity of such compounds has led to the development of maximum limit concentrations with the aim to decrease the exposure of humans. This paper discusses the problems of human exposure in general and especially through pharmaceutical solutions, and the possibilities of eliminating such compounds with the aim of decreasing the exposure as a hygienic challenge.

  4. Biosafe Nanoscale Pharmaceutical Adjuvant Materials

    PubMed Central

    Jin, Shubin; Li, Shengliang; Wang, Chongxi; Liu, Juan; Yang, Xiaolong; Wang, Paul C.; Zhang, Xin; Liang, Xing-Jie

    2014-01-01

    Thanks to developments in the field of nanotechnology over the past decades, more and more biosafe nanoscale materials have become available for use as pharmaceutical adjuvants in medical research. Nanomaterials possess unique properties which could be employed to develop drug carriers with longer circulation time, higher loading capacity, better stability in physiological conditions, controlled drug release, and targeted drug delivery. In this review article, we will review recent progress in the application of representative organic, inorganic and hybrid biosafe nanoscale materials in pharmaceutical research, especially focusing on nanomaterial-based novel drug delivery systems. In addition, we briefly discuss the advantages and notable functions that make these nanomaterials suitable for the design of new medicines; the biosafety of each material discussed in this article is also highlighted to provide a comprehensive understanding of their adjuvant attributes. PMID:25429253

  5. Application of LC-MS(n) in conjunction with mechanism-based stress studies in the elucidation of drug impurity structure: rapid identification of a process impurity in betamethasone 17-valerate drug substance.

    PubMed

    Li, Min; Lin, Mingxiang; Rustum, Abu

    2008-12-15

    Through a case study, the use of LC-MS(n) technique in conjunction with a mechanism-based stress study is shown to be a very effective way in the rapid elucidation of unknown drug impurities. In this case, the drug substance sample was first analyzed using LC-MS(n) through which the unknown species was found to be a valeryl-containing, isomeric impurity of the active pharmaceutical ingredient (API), betamethasone 17-valerate, based on its molecular ion and major fragments. Since a substantial knowledge regarding a large number of isomeric impurities of betamethasone has been accumulated in the literature as well as in our laboratory, a hydrolytic stress study (forced degradation) of the isolated unknown species was then designed and carried out accordingly in order to remove the valeryl group from the unknown species. During the stress study, a betamethasone isomer was generated as expected. However, a new unknown species isomeric to betamethasone 17-valerate was also formed unexpectedly. By comparing the UV spectra and more importantly MS(n) fragmentation patterns of the two newly formed species with those of betamethasone, dexamethasone, betamethasone 17-valerate, and betamethasone 21-valerate, these two unknown species generated in the stress study were identified as dexamethasone and dexamethasone 21-valerate, respectively. Based on the plausible reaction mechanism of the forced degradation, the original impurity present in betamethasone 17-valerate drug substance was then identified as dexamethasone 17-valerate; the structure assignment was later confirmed by various 1D and 2D NMR experiments. The efficient conversion from dexamethasone 17-valerate to dexamethasone 21-valerate was also observed during a 2D NMR acquisition of the isolated dexamethasone 17-valerate sample.

  6. Economic analysis and pharmaceutical policy.

    PubMed

    Rovira, J

    1995-10-01

    Economic evaluation, a comparative analysis of alternative actions in terms of costs and consequences, allows rational decisions to be made concerning the deployment of resources (people, time, equipment, facilities and knowledge). Pharmaceutical policy reflects the various objectives of the many social groups, some of which are conflicting. While new methodologies for evaluation of health care programmes still need to gain wider acceptance, resource limitations for both care providers and decision makers make economic analysis an increasingly important tool.

  7. Pharmaceutical cocrystals: walking the talk.

    PubMed

    Bolla, Geetha; Nangia, Ashwini

    2016-06-28

    Pharmaceutical cocrystals belong to a sub-class of cocrystals wherein one of the components is a drug molecule (or an active pharmaceutical ingredient, API) and the second is a benign food or drug grade additive (generally regarded as safe, GRAS). The two components are hydrogen-bonded in a fixed stoichiometric ratio in the crystal lattice. In the past decade, pharmaceutical cocrystals have demonstrated significant promise in their ability to modify the physicochemical and pharmacokinetic properties of drug substances, such as the solubility and dissolution rate, bioavailability, particle morphology and size, tableting and compaction, melting point, physical form, biochemical and hydration stability, and permeability. In this feature review, we highlight some prominent examples of drug cocrystals which exhibit variable hardness/softness and elasticity/plasticity depending on coformer selection, improvement of solubility and permeability in the same cocrystal, increase of the melting point for solid formulation, enhanced color performance, photostability and hydration stability, and a longer half-life. Cocrystals of flavanoids and polyphenols can make improved pharmaceuticals and also extend to the larger class of nutraceuticals. The application of crystal engineering to assemble ternary cocrystals expands this field to drug-drug cocrystals which may be useful in multi-drug resistance, mitigating side effects of drugs, or attenuating/enhancing drug action synergistically by rational selection. The advent of new techniques for structural characterization beyond the standard X-ray diffraction will provide a better understanding of drug phases which are at the borderline of crystalline-amorphous nature and even newer opportunities in the future. PMID:27278109

  8. [E-commerce of pharmaceuticals].

    PubMed

    Shani, Segev

    2003-05-01

    The emergence of the Internet as a new communications and information technology caused major social and cultural changes. The dramatic increase in accessibility and availability of information empowered the consumer by closing the information gap between the consumer and different suppliers. The objective of this article is to review many new internet-supported applications related to the pharmaceutical market. E-commerce is divided into two major components: Business to Consumer (B to C), and Business to Business (B to B). The main applications in B to C are dissemination of medical and drug information, and the sale of drugs through the Internet. Medical information on the Internet is vast and very helpful for patients, however, its reliability is not guaranteed. Online pharmacies increase the accessibility and availability of drugs. Nevertheless, several obstacles such as security of the data provided (both financial and clinical) prevent the widespread use of online pharmacies. Another risk is the health authorities' inability to regulate Internet sites effectively. Therefore, unregulated sale of prescription drugs, fake or substandard, often occurs on the Internet. B to B relates to physicians, clinics, hospitals, HMO's and pharmaceutical companies. There is a vast number of applications ranging from clinical research, marketing and sales promotion, to drug distribution and logistics. In conclusion, the Internet is dynamic and has contributed to the development of numerous new applications in the field of pharmaceuticals. Regulatory authorities should be active in developing new policies that will deal with those new Internet-based applications. PMID:12803063

  9. [E-commerce of pharmaceuticals].

    PubMed

    Shani, Segev

    2003-05-01

    The emergence of the Internet as a new communications and information technology caused major social and cultural changes. The dramatic increase in accessibility and availability of information empowered the consumer by closing the information gap between the consumer and different suppliers. The objective of this article is to review many new internet-supported applications related to the pharmaceutical market. E-commerce is divided into two major components: Business to Consumer (B to C), and Business to Business (B to B). The main applications in B to C are dissemination of medical and drug information, and the sale of drugs through the Internet. Medical information on the Internet is vast and very helpful for patients, however, its reliability is not guaranteed. Online pharmacies increase the accessibility and availability of drugs. Nevertheless, several obstacles such as security of the data provided (both financial and clinical) prevent the widespread use of online pharmacies. Another risk is the health authorities' inability to regulate Internet sites effectively. Therefore, unregulated sale of prescription drugs, fake or substandard, often occurs on the Internet. B to B relates to physicians, clinics, hospitals, HMO's and pharmaceutical companies. There is a vast number of applications ranging from clinical research, marketing and sales promotion, to drug distribution and logistics. In conclusion, the Internet is dynamic and has contributed to the development of numerous new applications in the field of pharmaceuticals. Regulatory authorities should be active in developing new policies that will deal with those new Internet-based applications.

  10. Understanding pharmaceutical quality by design.

    PubMed

    Yu, Lawrence X; Amidon, Gregory; Khan, Mansoor A; Hoag, Stephen W; Polli, James; Raju, G K; Woodcock, Janet

    2014-07-01

    This review further clarifies the concept of pharmaceutical quality by design (QbD) and describes its objectives. QbD elements include the following: (1) a quality target product profile (QTPP) that identifies the critical quality attributes (CQAs) of the drug product; (2) product design and understanding including identification of critical material attributes (CMAs); (3) process design and understanding including identification of critical process parameters (CPPs), linking CMAs and CPPs to CQAs; (4) a control strategy that includes specifications for the drug substance(s), excipient(s), and drug product as well as controls for each step of the manufacturing process; and (5) process capability and continual improvement. QbD tools and studies include prior knowledge, risk assessment, mechanistic models, design of experiments (DoE) and data analysis, and process analytical technology (PAT). As the pharmaceutical industry moves toward the implementation of pharmaceutical QbD, a common terminology, understanding of concepts and expectations are necessary. This understanding will facilitate better communication between those involved in risk-based drug development and drug application review.

  11. Pharmaceutical study of Lauha Bhasma.

    PubMed

    Singh, Neetu; Reddy, K R C

    2010-07-01

    In the present research paper, the work done on pharmaceutical study of Lauha Bhasma conducted in the Department of Rasa Shastra under the postgraduate research programme is being presented. The pharmaceutical processing of Lauha Bhasma was performed by following samanya shodhana, vishesha shodhana and marana of Lauha. Under the process of marana, three specific pharmaceutical techniques were followed, viz. bhanupaka, sthalipaka and putapaka. During the putapaka process, an electric muffle furnace (EMF) was used. The temperature of puta was studied in two batches, viz. in Batch I, a temperature of 800°C was maintained whereas in Batch II, a temperature of 600°C was maintained. The purpose behind selecting two temperatures was to validate the process of marana of Lauha and to determine an ideal temperature for the preparation of Lauha Bhasma in EMF. It is found that after 20 puta at a temperature of 600°C, the Lauha Bhasma was prepared properly. The entire characteristic of Lauha Bhasma, like "pakwa jambu phala varna," varitar, etc. was attained at 600°. At a temperature of 800°C, the process could not be carried out smoothly. The pellets turned very hard and brassy yellow in color. The desired color was attained only after decreasing the temperature in further puta. PMID:22131745

  12. Examining pharmaceuticals using terahertz spectroscopy

    NASA Astrophysics Data System (ADS)

    Sulovská, Kateřina; Křesálek, Vojtěch

    2015-10-01

    Pharmaceutical trafficking is common issue in countries where they are under stricter dispensing regime with monitoring of users. Most commonly smuggled pharmaceuticals include trade names Paralen Plus, Modafen, Clarinase repetabs, Aspirin complex, etc. These are transported mainly from Eastern Europe (e.g. Poland, Ukraine, Russia) to countries like Czech Republic, which is said to have one of the highest number of methamphetamine producers in Europe. The aim of this paper is to describe the possibility of terahertz spectroscopy utilization as an examining tool to distinguish between pharmaceuticals containing pseudoephedrine compounds and those without it. Selected medicaments for experimental part contain as an active ingredient pseudoephedrine hydrochloride or pseudoephedrine sulphate. Results show a possibility to find a pseudoephedrine compound spectra in samples according to previously computed and experimentally found ones, and point out that spectra of same brand names pills may vary according to their expiration date, batch, and amount of absorbed water vapours from ambience. Mislead spectrum also occurs during experimental work in a sample without chosen active ingredient, which shows persistent minor inconveniences of terahertz spectroscopy. All measurement were done on the TPS Spectra 3000 instrument.

  13. Stability of Pharmaceuticals in Space

    NASA Technical Reports Server (NTRS)

    Nguyen, Y-Uyen

    2009-01-01

    Stability testing is a tool used to access shelf life and effects of storage conditions for pharmaceutical formulations. Early research from the International Space Station (ISS) revealed that some medications may have degraded while in space. This potential loss of medication efficacy would be very dangerous to Crew health. The aim of this research project, Stability of Pharmacotherapeutic Compounds, is to study how the stability of pharmaceutical compounds is affected by environmental conditions in space. Four identical pharmaceutical payload kits containing medications in different dosage forms (liquid for injection, tablet, capsule, ointment and suppository) were transported to the ISS aboard a Space Shuttle. One of the four kits was stored on that Shuttle and the other three were stored on the ISS for return to Earth at various time intervals aboard a pre-designated Shuttle flight. The Pharmacotherapeutics laboratory used stability test as defined by the United States Pharmacopeia (USP), to access the degree of degradation to the Payload kit medications that may have occurred during space flight. Once these medications returned, the results of stability test performed on them were compared to those from the matching ground controls stored on Earth. Analyses of the results obtained from physical and chemical stability assessments on these payload medications will provide researchers additional tools to promote safe and efficacious medications for space exploration.

  14. Impurity Effects on Momentum Transport and Residual Stress

    NASA Astrophysics Data System (ADS)

    Ko, Sehoon; Jhang, Hogun; Singh, R.

    2015-11-01

    Impurities are inevitable during tokamak plasma operation because of strong interaction of plasma and plasma facing component and helium ash as a byproduct of fusion process. They cause problems such as radiation power loss and fusion fuel dilution. On the other hands, they are used to diagnosis plasma parameters (CES, XICS etc) and to suppress edge-localized mode by wall-coating. In this research, we study the impact of impurities on turbulence driven intrinsic rotation (via residual stress) in the context of the quasi-linear theory. A two-fluid formulation for main and impurity ions is employed to study ion temperature gradient modes in sheared slab geometry modified by the presence of impurities. An effective form of the parallel Reynolds stress is derived in the center of mass frame of a coupled main ion-impurity system. Analyses show that the contents and the radial profile of impurities have a strong influence on the residual stress. In particular, an impurity profile aligned with that of main ions is shown to cause a considerable reduction of the residual stress, which may lead to the reduction of turbulence driven intrinsic rotation.

  15. Scattering of waves by impurities in precompressed granular chains.

    PubMed

    Martínez, Alejandro J; Yasuda, Hiromi; Kim, Eunho; Kevrekidis, P G; Porter, Mason A; Yang, Jinkyu

    2016-05-01

    We study scattering of waves by impurities in strongly precompressed granular chains. We explore the linear scattering of plane waves and identify a closed-form expression for the reflection and transmission coefficients for the scattering of the waves from both a single impurity and a double impurity. For single-impurity chains, we show that, within the transmission band of the host granular chain, high-frequency waves are strongly attenuated (such that the transmission coefficient vanishes as the wavenumber k→±π), whereas low-frequency waves are well-transmitted through the impurity. For double-impurity chains, we identify a resonance-enabling full transmission at a particular frequency-in a manner that is analogous to the Ramsauer-Townsend (RT) resonance from quantum physics. We also demonstrate that one can tune the frequency of the RT resonance to any value in the pass band of the host chain. We corroborate our theoretical predictions both numerically and experimentally, and we directly observe almost complete transmission for frequencies close to the RT resonance frequency. Finally, we show how this RT resonance can lead to the existence of reflectionless modes in granular chains (including disordered ones) with multiple double impurities. PMID:27300897

  16. Scattering of waves by impurities in precompressed granular chains

    NASA Astrophysics Data System (ADS)

    Martínez, Alejandro J.; Yasuda, Hiromi; Kim, Eunho; Kevrekidis, P. G.; Porter, Mason A.; Yang, Jinkyu

    2016-05-01

    We study scattering of waves by impurities in strongly precompressed granular chains. We explore the linear scattering of plane waves and identify a closed-form expression for the reflection and transmission coefficients for the scattering of the waves from both a single impurity and a double impurity. For single-impurity chains, we show that, within the transmission band of the host granular chain, high-frequency waves are strongly attenuated (such that the transmission coefficient vanishes as the wavenumber k →±π ), whereas low-frequency waves are well-transmitted through the impurity. For double-impurity chains, we identify a resonance—enabling full transmission at a particular frequency—in a manner that is analogous to the Ramsauer-Townsend (RT) resonance from quantum physics. We also demonstrate that one can tune the frequency of the RT resonance to any value in the pass band of the host chain. We corroborate our theoretical predictions both numerically and experimentally, and we directly observe almost complete transmission for frequencies close to the RT resonance frequency. Finally, we show how this RT resonance can lead to the existence of reflectionless modes in granular chains (including disordered ones) with multiple double impurities.

  17. Stability-Indicating UPLC Method for Tramadol HCl Impurities in the Tramadol Injection after Dilution by Infusion Fluids (5% Dextrose and 0.9% Sodium Chloride)

    PubMed Central

    Binnor, Anil K.; Mukkanti, Khagga; Suryanarayana, Mulukutla V.; Roy, Sunilendu B.

    2013-01-01

    A novel, rapid, and sensitive ultra-performance liquid chromatography (UPLC) method has been developed and validated as per ICH guidelines for the determination of tramadol HCl impurities in the tramadol HCl injection after reconstitution by infusion fluids (5% dextrose and 0.9% sodium chloride). The tramadol HCl injection is for the treatment of patients with moderate-to-severe pain. The stability of the reconstituted solution is critical before intravenous injection. The literature search resulted in few published articles on assays of tramadol in infusion fluids by conventional HPLC. No attempts have yet been made to determine the impurities in infusion fluids, as the concentration of tramadol after reconstitution is extremely low (0.4 mg/mL) and that of impurities is even lower. The proposed method is novel as it allows the quantitation of the impurities of tramadol HCl and is based on modern chromatographic techniques like UPLC. The method was developed using the Waters Acquity BEH C18 column with a mobile phase consisting of a gradient mixture of solvent A (trifluroacetic acid buffer) and solvent B (methanol: acetonitrile). The model stability study was designed by diluting the tramadol HCl injection in the 5% dextrose injection and 0.9% sodium chloride injection. Each mixture was kept under storage at room temperature (25 ± 2°C) for testing at initial, 2, 4, 8, 12, 18 & 24 hours. The validation study illustrates that the proposed method is suitable for the determination of tramadol and its impurities. The proposed method makes use of the LC-MS-compatible mobile phase. It can be useful for the determination of tramadol HCl and its impurities in plasma samples and other pharmaceutical dosage forms. PMID:24482769

  18. Impurity-limited resistance and phase interference of localized impurities under quasi-one dimensional nano-structures

    NASA Astrophysics Data System (ADS)

    Sano, Nobuyuki

    2015-12-01

    The impurity-limited resistance and the effect of the phase interference among localized multiple impurities in the quasi-one dimensional (quasi-1D) nanowire structures are systematically investigated under the framework of the scattering theory. We derive theoretical expressions of the impurity-limited resistance in the nanowire under the linear response regime from the Landauer formula and from the Boltzmann transport equation (BTE) with the relaxation time approximation. We show that the formula from the BTE exactly coincides with that from the Landauer approach with the weak-scattering limit when the energy spectrum of the in-coming electrons from the reservoirs is narrow and, thus, point out a possibility that the distinction of the impurity-limited resistances derived from the Landauer formula and that of the BTE could be made clear. The derived formulas are applied to the quasi-1D nanowires doped with multiple localized impurities with short-range scattering potential and the validity of various approximations on the resistance are discussed. It is shown that impurity scattering becomes so strong under the nanowire structures that the weak-scattering limit breaks down in most cases. Thus, both phase interference and phase randomization simultaneously play a crucial role in determining the impurity-limited resistance even under the fully coherent framework. When the impurity separation along the wire axis direction is small, the constructive phase interference dominates and the resistance is much greater than the average resistance. As the separation becomes larger, however, it approaches the series resistance of the single-impurity resistance due to the phase randomization. Furthermore, under the uniform configuration of impurities, the space-average resistance of multiple impurities at room temperature is very close to the series resistance of the single-impurity resistance, and thus, each impurity could be regarded as an independent scattering center. The

  19. Impurity-limited resistance and phase interference of localized impurities under quasi-one dimensional nano-structures

    SciTech Connect

    Sano, Nobuyuki

    2015-12-28

    The impurity-limited resistance and the effect of the phase interference among localized multiple impurities in the quasi-one dimensional (quasi-1D) nanowire structures are systematically investigated under the framework of the scattering theory. We derive theoretical expressions of the impurity-limited resistance in the nanowire under the linear response regime from the Landauer formula and from the Boltzmann transport equation (BTE) with the relaxation time approximation. We show that the formula from the BTE exactly coincides with that from the Landauer approach with the weak-scattering limit when the energy spectrum of the in-coming electrons from the reservoirs is narrow and, thus, point out a possibility that the distinction of the impurity-limited resistances derived from the Landauer formula and that of the BTE could be made clear. The derived formulas are applied to the quasi-1D nanowires doped with multiple localized impurities with short-range scattering potential and the validity of various approximations on the resistance are discussed. It is shown that impurity scattering becomes so strong under the nanowire structures that the weak-scattering limit breaks down in most cases. Thus, both phase interference and phase randomization simultaneously play a crucial role in determining the impurity-limited resistance even under the fully coherent framework. When the impurity separation along the wire axis direction is small, the constructive phase interference dominates and the resistance is much greater than the average resistance. As the separation becomes larger, however, it approaches the series resistance of the single-impurity resistance due to the phase randomization. Furthermore, under the uniform configuration of impurities, the space-average resistance of multiple impurities at room temperature is very close to the series resistance of the single-impurity resistance, and thus, each impurity could be regarded as an independent scattering center. The

  20. Kinetic model of impurity poisoning during growth of calcite

    SciTech Connect

    DeYoreo, J; Wasylenki, L; Dove, P; Wilson, D; Han, N

    2004-05-18

    The central role of the organic component in biologically controlled mineralization is widely recognized. These proteins are characterized by a high proportion of acidic amino acid residues, especially aspartate, Asp. At the same time, biomineralization takes place in the presence of a number of naturally-occurring, inorganic impurities, particularly Mg and Sr. In an attempt to decipher the controls on calcite growth imposed by both classes of modifiers, we have used in situ AFM to investigate the dependence of growth morphology and step kinetics on calcite in the presence of Sr{sup 2+}, as well as a wide suite of Aspartic acid-bearing polypeptides. In each case, we observe a distinct and step-specific modification. Most importantly, we find that the step speed exhibits a characteristic dependence on impurity concentration not predicted by existing crystal growth models. While all of the impurities clearly induce appearance of a 'dead zone,' neither the width of that dead zone nor the dependence of step speed on activity or impurity content can be explained by invoking the Gibbs-Thomson effect, which is the basis for the Cabrera-Vermilyea model of impurity poisoning. Common kink-blocking models also fail to explain the observed dependencies. Here we propose a kinetic model of inhibition based on a 'cooperative' effect of impurity adsorption at adjacent kink sites. The model is in qualitative agreement with the experimental results in that it predicts a non-linear dependence of dead zone width on impurity concentration, as well as a sharp drop in step speed above a certain impurity content. However, a detailed model of impurity adsorption kinetics that give quantitative agreement with the data has yet to be developed.

  1. Impurity effects on trapped electron mode in tokamak plasmas

    NASA Astrophysics Data System (ADS)

    Du, Huarong; Wang, Zheng-Xiong; Dong, J. Q.

    2016-07-01

    The effects of impurity ions on the trapped electron mode (TEM) in tokamak plasmas are numerically investigated with the gyrokinetic integral eigenmode equation. It is shown that in the case of large electron temperature gradient ( η e ), the impurity ions have stabilizing effects on the TEM, regardless of peaking directions of their density profiles for all normalized electron density gradient R / L n e . Here, R is the major radius and L n e is the electron density gradient scale length. In the case of intermediate and/or small η e , the light impurity ions with conventional inwardly (outwardly) peaked density profiles have stabilizing effects on the TEM for large (small) R / L n e , while the light impurity ions with steep inwardly (outwardly) peaked density profiles can destabilize the TEM for small (large) R / L n e . Besides, the TEM driven by density gradient is stabilized (destabilized) by the light carbon or oxygen ions with inwardly (outwardly) peaked density profiles. In particular, for flat and/or moderate R / L n e , two independent unstable modes, corresponding respectively to the TEM and impurity mode, are found to coexist in plasmas with impurity ions of outwardly peaked density profiles. The high Z tungsten impurity ions play a stronger stabilizing role in the TEM than the low Z impurity ions (such as carbon and oxygen) do. In addition, the effects of magnetic shear and collision on the TEM instability are analyzed. It is shown that the collisionality considered in this work weakens the trapped electron response, leading to a more stable TEM instability, and that the stabilizing effects of the negative magnetic shear on the TEM are more significant when the impurity ions with outwardly peaked density profile are taken into account.

  2. Acute toxic and genotoxic activities of widely used cytostatic drugs in higher plants: Possible impact on the environment.

    PubMed

    Mišík, Miroslav; Pichler, Clemens; Rainer, Bernhard; Filipic, Metka; Nersesyan, Armen; Knasmueller, Siegfried

    2014-11-01

    Cytostatic drugs are highly toxic pharmaceuticals and it was repeatedly postulated that they may cause adverse effects in ecosystems. The acute toxic and genotoxic properties of these drugs have not been adequately investigated in higher plants so far; therefore, we studied the most widely used drugs (5-flurouracil, 5FU; etoposide, Et; cisplatin, CisPt; carboplatin, CaPt; vincristine sulfate, VinS and cyclophosphamide monohydrate, CP) in micronucleus (MN) assays with meiotic pollen tetrad cells of Tradescantia and with root cells from Allium cepa. MNi are formed as a consequence of chromosome breaks and aneuploidy. We monitored also the acute toxic properties of the drugs, i.e. inhibition of cell division (mitotic indices and retardation of root growth) in the latter species. All compounds caused in both indicator plants genotoxic effects. The order of genotoxic potencies expressed as NOELs in µM was CisPt (0.1)≥ Et (0.5)>CP (1.0)>CaPt (10)>5FU (30)>VinS (100) in Tradescantia. A similar order was seen in Allium MN but Et was less active (5.0µM). Four compounds caused alterations of the mitotic indices under the present conditions namely CisPt (0.5), Et (10.0), 5FU (10.0) and VinS (100). Inhibition of root growth decreased in the order CisPt (0.5)>Et (1.0)≥VinS (1.0)>5FU (5.0)>CaPt (33.0)>CP (>1000). Comparisons of the NOELs with the predicted environmental concentrations (PEC) show that the latter values are at least 5 orders of magnitude lower and indicate that it is unlikely that their release in the environment may cause adverse effects in higher plants. However, it is notable that the levels of both platinum compounds and of 5FU in hospital effluents may reach levels which may induce damage of the genetic material.

  3. Laser Ablation Plume Expansion In The Presence Of Charged Impurities

    SciTech Connect

    Djebli, M.

    2008-09-23

    The expansion of plasma created by laser ablation is investigated using the fluid model. At the first stage of the expansion, electrons are considered in thermal equilibrium. The presence of highly charged impurities is considered through Poisson's equation. The set of nonlinear differential equations is solved using a moving boundary and taken into account the charge separation effect. The uniformly distributed impurities can accelerate or decelerate the ion motion depending on their charge and concentration. It is also found that the separation of the charge is valid for a specific time which depends on the impurities parameters.

  4. Alternating current response of carbon nanotubes with randomly distributed impurities

    SciTech Connect

    Hirai, Daisuke; Watanabe, Satoshi; Yamamoto, Takahiro

    2014-10-27

    The increasing need for nanodevices has necessitated a better understanding of the electronic transport behavior of nanomaterials. We therefore theoretically examine the AC transport properties of metallic carbon nanotubes with randomly distributed impurities. We find that the long-range impurity scattering increases the emittance, but does not affect the DC conductance. The estimated dwell time of electrons increases with the potential amplitudes. That is, multiple scattering by the impurities increases the kinetic inductance in proportion to the dwell time, which eventually increases the emittance. We believe that our findings can contribute significantly to nanodevice development.

  5. Fe impurities weaken the ferromagnetic behavior in Au nanoparticles.

    PubMed

    Crespo, P; García, M A; Fernández Pinel, E; Multigner, M; Alcántara, D; de la Fuente, J M; Penadés, S; Hernando, A

    2006-10-27

    In this Letter, we report on a crucial experiment showing that magnetic impurities reduce the ferromagnetic order temperature in thiol-capped Au glyconanoparticles (GNPs). The spontaneous magnetization of AuFe GNPs exhibits a fast decrease with temperature that contrasts with the almost constant value of the magnetization observed in Au NPs. Moreover, hysteresis disappears below 300 K. Both features indicate that Fe impurities reduce the high local anisotropy field responsible for the ferromagnetic behavior in Au GNPs. As a consequence, the amazing ferromagnetism in Au NPs should not be associated with the presence of magnetic impurities.

  6. Thermally Induced Re-Trapping of Impurity Pairs in Silicon

    NASA Astrophysics Data System (ADS)

    Tessema, Genene

    Trapping and de-trapping of the acceptor-donor impurity pairs in semiconductors have been studied in crystalline silicon. The existence of such pairs in semiconductors are reported to have influence on the optical and electrical properties of materials. The perturbed γ - γ angular correlation (PAC) method is employed here to study such thermally induced dynamics of impurity complexes in the host lattice. The various types of pairs which are identified via the measured quadrupole interaction frequencies (QIF) showed distinct population of the complexes at different annealing temperatures. Efforts made to re-trap formed complexes after their dissociation by high sample temperatures produce positive results for some impurities.

  7. Extraction process for removing metallic impurities from alkalide metals

    SciTech Connect

    Royer, Lamar T.

    1988-01-01

    A development is described for removing metallic impurities from alkali metals by employing an extraction process wherein the metallic impurities are extracted from a molten alkali metal into molten lithium metal due to the immiscibility of the alkali metals in lithium and the miscibility of the metallic contaminants or impurities in the lithium. The purified alkali metal may be readily separated from the contaminant-containing lithium metal by simple decanting due to the differences in densities and melting temperatures of the alkali metals as compared to lithium.

  8. Extraction process for removing metallic impurities from alkalide metals

    SciTech Connect

    Royer, L.T.

    1987-03-20

    A development is described for removing metallic impurities from alkali metals by employing an extraction process wherein the metallic impurities are extracted from a molten alkali metal into molten lithium metal due to the immiscibility of the alkali metals in lithium and the miscibility of the metallic contaminants or impurities in the lithium. The purified alkali metal may be readily separated from the contaminant-containing lithium metal by simple decanting due to the differences in densities and melting temperatures of the alkali metals as compared to lithium.

  9. The impact of impurities on long-term PEMFC performance

    SciTech Connect

    Garzon, Fernando H; Lopes, Thiago; Rockward, Tommy; Mukundan, Rangachary; Sansinena, Jose - Maria; Kienitz, Brian

    2009-06-23

    Electrochemical experimentation and modeling indicates that impurities degrade fuel cell performance by a variety of mechanisms. Electrokinetics may be inhibited by catalytic site poisoning from sulfur compounds and CO and by decreased local proton activity and mobility caused by the presence of foreign salt cations or ammonia. Cation impurity profiles vary with current density, valence and may change local conductivity and water concentrations in the ionomer. Nitrogen oxides and ammonia species may be electrochemically active under fuel cell operating conditions. The primary impurity removal mechanisms are electrooxidation and water fluxes through the fuel cell.

  10. Decoherence induced by magnetic impurities in a quantum hall system

    SciTech Connect

    Kagalovsky, V.; Chudnovskiy, A. L.

    2013-04-15

    Scattering by magnetic impurities is known to destroy coherence of electron motion in metals and semiconductors. We investigate the decoherence introduced in a single act of electron scattering by a magnetic impurity in a quantum Hall system. For this, we introduce a fictitious nonunitary scattering matrix for electrons that reproduces the exactly calculated scattering probabilities. The strength of decoherence is identified by the deviation of eigenvalues of the product from unity. Using the fictitious scattering matrix, we estimate the width of the metallic region at the quantum Hall effect inter-plateau transition and its dependence on the exchange coupling strength and the degree of polarization of magnetic impurities.

  11. Effect of ester impurities in PMR-polyimide resin

    NASA Technical Reports Server (NTRS)

    Lauver, R. W.

    1976-01-01

    Spectral and chomatographic studies were conducted which established the presence of tri- and tetraester impurities in aged monomer solutions employed in fabrication of PMR-polyimide resin composites. The equilibrium constant and apparent rate of the esterification were determined. It was demonstrated, using differential scanning calorimetry, that the ortho-ester moiety of these impurities does not completely react at typical cure conditions. It is concluded that voids formed in composites fabricated with aged monomer solution are due to gaseous decomposition products evolved by ester impurities and/or unreacted amine during elevated temperature post-cure treatment.

  12. Extrinsic spin Hall effect induced by iridium impurities in copper.

    PubMed

    Niimi, Y; Morota, M; Wei, D H; Deranlot, C; Basletic, M; Hamzic, A; Fert, A; Otani, Y

    2011-03-25

    We study the extrinsic spin Hall effect induced by Ir impurities in Cu by injecting a pure spin current into a CuIr wire from a lateral spin valve structure. While no spin Hall effect is observed without Ir impurity, the spin Hall resistivity of CuIr increases linearly with the impurity concentration. The spin Hall angle of CuIr, (2.1±0.6)% throughout the concentration range between 1% and 12%, is practically independent of temperature. These results represent a clear example of predominant skew scattering extrinsic contribution to the spin Hall effect in a nonmagnetic alloy.

  13. Extrinsic Spin Hall Effect Induced by Iridium Impurities in Copper

    NASA Astrophysics Data System (ADS)

    Niimi, Y.; Morota, M.; Wei, D. H.; Deranlot, C.; Basletic, M.; Hamzic, A.; Fert, A.; Otani, Y.

    2011-03-01

    We study the extrinsic spin Hall effect induced by Ir impurities in Cu by injecting a pure spin current into a CuIr wire from a lateral spin valve structure. While no spin Hall effect is observed without Ir impurity, the spin Hall resistivity of CuIr increases linearly with the impurity concentration. The spin Hall angle of CuIr, (2.1±0.6)% throughout the concentration range between 1% and 12%, is practically independent of temperature. These results represent a clear example of predominant skew scattering extrinsic contribution to the spin Hall effect in a nonmagnetic alloy.

  14. Modeling impurities and tilted plates in the ITER divertor

    SciTech Connect

    Rensink, M.E.; Rognlien, T.D.

    1996-07-29

    The UEDGE 2-D edge transport code is used to model the effect of impurities and tilted divertor plates for the ITER SOL/divertor region. The impurities are modeled as individual charge states using either the FMOMBAL 21-moment description or parallel force balance. Both helium and neon impurities are used together with a majority hydrogenic species. A fluid description of the neutrals is used that includes parallel inertia and neutral-neutral collisions. Effects of geometry are analyzed by using the nonorthogonal mesh capability of UEDGE to obtain solutions with the divertor plate tilted at various angles.

  15. Influence of grain boundary silica impurity on alumina toughness

    SciTech Connect

    Moya, J.S.; Kriven, W.M.; Pask, J.A.

    1980-08-01

    In a series of previous reports the effect of silica impurity on aggregation state and on electropheretic, pressing, filtering and sintering behavior on alumina powders was presented. The results obtained showed that the silica surface impurity plays an important role in the ceramic processing of powders by (a) decreasing the pH values of the isoelectric point (i.e.p.), which affects the aggregation state of the powder, and (b) decreasing the compactability and the activation energy for the initial stage of sintering. In the phase of the studies emphasis was given to the effect of the presence of silica impurity on the toughness and fracture behavior of alumina samples.

  16. Large impurity effects in rubrene crystals: First-principles calculations

    SciTech Connect

    Tsetseris, L.; Pantelides, Sokrates T.

    2008-01-01

    Carrier mobilities of rubrene films are among the highest values reported for any organic semiconductor. Here, we probe with first-principles calculations the sensitivity of rubrene crystals on impurities. We find that isolated oxygen impurities create distinct peaks in the electronic density of states consistent with observations of defect levels in rubrene and that increased O content changes the position and shape of rubrene energy bands significantly. We also establish a dual role of hydrogen as individual H species and H impurity pairs create and annihilate deep carrier traps, respectively. The results are relevant to the performance and reliability of rubrene-based devices.

  17. In Silico Models for Ecotoxicity of Pharmaceuticals.

    PubMed

    Roy, Kunal; Kar, Supratik

    2016-01-01

    Pharmaceuticals and their active metabolites are one of the significantly emerging environmental toxicants. The major routes of entry of pharmaceuticals into the environment are industries, hospitals, or direct disposal of unwanted or expired drugs made by the patient. The most important and distinct features of pharmaceuticals are that they are deliberately designed to have an explicit mode of action and designed to exert an effect on humans and other living systems. This distinctive feature makes pharmaceuticals and their metabolites different from other chemicals, and this necessitates the evaluation of the direct effects of pharmaceuticals in various environmental compartments as well as to living systems. In this background, the alarming situation of ecotoxicity of diverse pharmaceuticals have forced government and nongovernment regulatory authorities to recommend the application of in silico methods to provide quick information about the risk assessment and fate properties of pharmaceuticals as well as their ecological and indirect human health effects. This chapter aims to offer information regarding occurrence of pharmaceuticals in the environment, their persistence, environmental fate, and toxicity as well as application of in silico methods to provide information about the basic risk management and fate prediction of pharmaceuticals in the environment. Brief ideas about toxicity endpoints, available ecotoxicity databases, and expert systems employed for rapid toxicity predictions of ecotoxicity of pharmaceuticals are also discussed.

  18. Gyrokinetic simulations of ion and impurity transport

    SciTech Connect

    Estrada-Mila, C.; Candy, J.; Waltz, R.E.

    2005-02-01

    A systematic study of turbulent particle and energy transport in both pure and multicomponent plasmas is presented. In this study, gyrokinetic results from the GYRO code [J. Candy and R. E. Waltz, J. Comput. Phys. 186, 545 (2003)] are supplemented with those from the GLF23 [R. E. Waltz, G. M. Staebler, W. Dorland et al., Phys. Plasmas 4, 2482 (1997)] transport model, as well as from quasilinear theory. Various results are obtained. The production of a particle pinch driven by temperature gradients (a thermal pinch) is demonstrated, and further shown to be weakened by finite electron collisionality. Helium transport and the effects of helium density gradient and concentration in a deuterium plasma are examined. Interestingly, it is found that the simple D-v (diffusion versus convective velocity) model of impurity flow is consistent with results obtained from nonlinear gyrokinetic simulations. Also studied is the transport in a 50-50 deuterium-tritium plasma, where a symmetry breaking is observed indicating the potential for fuel separation in a burning plasma. Quasilinear theory together with linear simulations shows that the symmetry breaking which enhances the tritium confinement arises largely from finite-Larmor-radius effects. To justify the numerical methods used in the paper, a variety of linear benchmarks and nonlinear grid refinement studies are detailed.

  19. Light impurity in an equilibrium gas.

    PubMed

    D'Alessio, L; Krapivsky, P L

    2011-01-01

    We investigate the evolution of a light impurity particle in a Lorentz gas where the background atoms are in thermal equilibrium. As in the standard Lorentz gas, we assume that the particle is negligibly light in comparison with the background atoms. The thermal motion of atoms causes the average particle speed to grow. In the case of the hard-sphere particle-atom interaction, the temporal growth is ballistic, while generally it is sublinear. For the particle-atom potential that diverges as r^{-λ} in the small separation limit, the average particle speed grows as t^{λ/[2(d-1)+λ]} in d dimensions. The particle displacement exhibits a universal growth, linear in time, and the average (thermal) speed of the atoms. Surprisingly, the asymptotic growth is independent of the gas density and the particle-atom interaction. The velocity and position distributions approach universal scaling forms which are non-Gaussian. We determine the velocity distribution in arbitrary dimension and for arbitrary interaction exponent λ. For the hard-sphere particle-atom interaction, we compute the position distribution and the joint velocity-position distribution. PMID:21405661

  20. Impurity trapped excitons under high hydrostatic pressure

    NASA Astrophysics Data System (ADS)

    Grinberg, Marek

    2013-09-01

    Paper summarizes the results on pressure effect on energies of the 4fn → 4fn and 4fn-15d1 → 4fn transitions as well as influence of pressure on anomalous luminescence in Lnα+ doped oxides and fluorides. A model of impurity trapped exciton (ITE) was developed. Two types of ITE were considered. The first where a hole is localized at the Lnα+ ion (creation of Ln(α+1)+) and an electron is attracted by Coulomb potential at Rydberg-like states and the second where an electron captured at the Lnα+ ion (creation of Ln(α-1)+) and a hole is attracted by Coulomb potential at Rydberg-like states. Paper presents detailed analysis of nonlinear changes of energy of anomalous luminescence of BaxSr1-xF2:Eu2+ (x > 0.3) and LiBaF3:Eu2+, and relate them to ITE-4f65d1 states mixing.

  1. Detection of genotoxic substances in bivalve molluscs from the Saguenay Fjord (Canada), using the SOS chromotest.

    PubMed

    White, P A; Blaise, C; Rasmussen, J B

    1997-08-14

    Few studies have employed bioassays to investigate the accumulation of genotoxins in aquatic biota that inhabit areas contaminated with industrial and municipal wastes. This study employed the SOS Chromotest, a short-term bacterial genotoxicity assay, to investigate the presence of genotoxins in bivalve molluscs from the Saguenay Fjord (Canada). Genotoxicity analyses were performed on dichloromethane extracts of Mya arenaria and Mytilus edulis collected downstream from several aluminum refineries and forestry products industries known to produce and release genotoxic substances. The results confirmed that bivalve molluscs inhabiting downstream regions are contaminated with both direct-acting and pro-genotoxic substances. In several cases, SOS response induction factors exceeded 3.0. The results failed to reveal a clear downstream trend of decreasing genotoxicity with increasing distance from the presumed industrial sources(s). A significant relationship (r2 = 0.61, p < 0.007) between a demographic variable (population near shoreline) and lipid-corrected genotoxic potency suggest that the accumulated direct-acting genotoxins may be of municipal origin. Significant relationships between tissue extract genotoxicity (r2 = 0.75, p < 0.003) and tissue PAH contamination (r2 = 0.77, p < 0.0001) and drainage basin area suggests that the bivalves are accumulating airborne contaminants deposited on the surface of the relevant drainage basins. In spite of contamination with genotoxic PAHs, the addition of rat liver microsomal enzymes reduced the genotoxic potency of all samples investigated (31-94% decrease). The results also revealed a significant relationship between tissue extract genotoxicity and PAH concentration (r2 = 0.72, p < 0.0005). Further analyses confirmed that a variable portion (7-97%) of the S9-activated tissue extract genotoxicity can be attributed to the detected PAHs. Although the sources, identity and effects of genotoxins accumulated by bivalves of the

  2. Linking genotoxic responses with cytotoxic and behavioural or physiological consequences: differential sensitivity of echinoderms (Asterias rubens) and marine molluscs (Mytilus edulis).

    PubMed

    Canty, Martin N; Hutchinson, Thomas H; Brown, Rebecca J; Jones, Malcolm B; Jha, Awadhesh N

    2009-08-13

    Integrated laboratory studies addressed multiple biomarker responses in the sea star (Asterias rubens) and the blue mussel (Mytilus edulis) exposed to a range of concentrations of direct and indirect acting genotoxins: methyl methane sulfonate (MMS) and cyclophosphamide (CP; an environmentally relevant anti-cancer pharmaceutical), respectively, in order to determine if the expressed genotoxicity has knock-on effects at the higher levels of biological organisation. The experimental design aimed to concurrently evaluate biomarkers of behavioural and physiological conditions (i.e. 'righting time' and 'clearance rate' for sea stars and mussels, respectively) in addition to cytotoxicity (neutral red retention assay), induction of micronuclei (Mn) and DNA strand breaks (as determined by the Comet assay). The protocol also included the determination of the maximum tolerated concentration (MTC), prior to genotoxic evaluation. The 3d MTC, as determined by the survival of the organisms, showed sea stars to be more sensitive than mussels to MMS (18 and 32 mg L(-1), respectively) and CP (56 and 180 mg L(-1), respectively). For both species and chemicals, cytotoxicity was not found to be significantly different compared to controls. Apart from the MMS exposure to sea stars (which showed 100% mortality at higher concentrations after 5d exposure), clear dose-response relationships were observed for both genotoxicity endpoints in each species. Following exposure to CP, good correlations were also found between the behavioural and physiological responses and genetic damage in each species (sea stars-MN vs. RT: R=0.73; Comet vs. RT: R=0.91; mussels-MN vs. CR: R=0.69; Comet vs. CR: R=0.72). This integrated approach, applying non-invasive assays to simultaneously determine the responses at different levels of biological organisation, indicates the potential value of behavioural and physiological measures in determining the toxicity of chemicals to marine organisms and highlights also

  3. Development of a Validated LC Method for Separation of Process-Related Impurities Including the R-Enantiomer of S-Pramipexole on Polysaccharide Chiral Stationary Phases.

    PubMed

    Ramisetti, Nageswara Rao; Kuntamukkala, Ramakrishna; Arnipalli, Manikanta Swamy

    2015-07-01

    Despite the availability of a few methods for individual separation of S-pramipexole from its process-related impurities, no common liquid chromatography (LC) method is reported so far in the literature. The present article describes the development of a single-run LC method for simultaneous determination of S-pramipexole and its enantiomeric and process-related impurities on a Chiralpak AD-H (150 x 4.6 mm, 5μm) column using n-hexane/ethanol/n-butylamine (75:25:0.1 v/v/v) as a mobile phase in an isocratic mode of elution at a flow rate of 1.2 ml/min at 30°C. The chromatographic eluents were monitored at a wavelength of 260 nm using a photodiode array detector. Excellent enantioseparation with good resolutions (Rs ≥ 2.88) and peak shapes (As ≤ 1.21) for all analytes was achieved. The proposed method was validated according to International Conference Harmonization (ICH) guidelines in terms of accuracy, precision, sensitivity, and linearity. Limits of quantification of impurities (0.25-0.55 μg/ml) indicate the highest sensitivity achievable by the proposed method. The method has an advantage of selectivity and suitability for routine determination of not only chiral impurity but also all possible related substances in active pharmaceutical ingredients of S-pramipexole.

  4. Electrophysical properties of gallium arsenide in combination with impurity-doped germanium and isovalent indium and antimony impurities

    SciTech Connect

    Krivov, M.A.; Malisova, E.V.; Nikiforova, M.P.; Starikov, A.N.; Khludkov, S.S.; Grigor'ev, Yu.A.; Egorova, O.L.; Osvenskii, V.B.

    1988-03-01

    The temperature dependence of the charge carrier concentration and mobility in n-type GaAs monocrystals doped jointly by Ge and isovalent In and Sb impurities is investigated. The observable charge carrier concentration and mobility changes in the GaAs:Ge:In and GaAs:Ge:Sb are compared with the corresponding characteristics in GaAs:Ge, and the change in properties along the ingots can be explained by the Ge impurity redistribution in the gallium and arsenic sublattices in the presence of an isovalent impurity.

  5. Genotoxic potential of montmorillonite clay mineral and alteration in the expression of genes involved in toxicity mechanisms in the human hepatoma cell line HepG2.

    PubMed

    Maisanaba, Sara; Hercog, Klara; Filipic, Metka; Jos, Ángeles; Zegura, Bojana

    2016-03-01

    Montmorillonite, also known as Cloisite(®)Na(+) (CNa(+)), is a natural clay with a wide range of well-documented and novel applications, such as pharmaceutical products or food packaging. Although considered a low toxic product, the expected increased exposure to CNa(+) arises concern on the potential consequences on human and environmental health especially as its genotoxicity has scarcely been investigated so far. Thus, we investigated, for the first time, the influence of non-cytotoxic concentrations of CNa(+) (15.65, 31.25 and 62.5 μg/mL) on genomic instability of human hepatoma cell line (HepG2) by determining the formation of micronuclei (MNi), nucleoplasmic bridges (NPBs) and nuclear buds (NBUDs) with the Cytokinesis block micronucleus cytome assay. Further on we studied the influence of CNa(+) on the expression of several genes involved in toxicity mechanisms using the real-time quantitative PCR. The results showed that CNa(+) increased the number of MNi, while the numbers of NBUDs and NPBs were not affected. In addition it deregulated genes in all the groups studied, mainly after longer time of exposure. These findings provide the evidence that CNa(+) is potentially genotoxic. Therefore further studies that will elucidate the molecular mechanisms involved in toxic activity of CNa(+) are needed for hazard identification and human safety assessment.

  6. Impurity behavior during sawtooth activity in tokamak plasmas

    SciTech Connect

    Nicolas, T.; Garbet, X.; Sabot, R.; Lütjens, H.; Luciani, J.-F.

    2014-01-15

    The transport of impurities by a sawtooth crash is simulated with the XTOR-2F code. Impurities are modeled as passive scalars, evolving in the compressible MHD flow inferred from the main MHD plasma. For a peaked impurity density profile, the non-linear kink flow of the sawtooth crash redistributes the profile efficiently and most of the particles in the peak inside the q = 1 surface are expelled. For an initially hollow impurity density profile, the crash leads to a significant penetration up to the magnetic axis. The results are compared with Kadomtsev's model. Despite essentially different mechanisms, the evolution of the particle content inside the q = 1 surface for Kadomtsev's model and for the non-linear case are virtually identical for the peaked profile, while the model slightly overestimates penetration for the hollow case.

  7. Runaway electron dynamics in tokamak plasmas with high impurity content

    SciTech Connect

    Martín-Solís, J. R.; Loarte, A.; Lehnen, M.

    2015-09-15

    The dynamics of high energy runaway electrons is analyzed for plasmas with high impurity content. It is shown that modified collision terms are required in order to account for the collisions of the relativistic runaway electrons with partially stripped impurity ions, including the effect of the collisions with free and bound electrons, as well as the scattering by the full nuclear and the electron-shielded ion charge. The effect of the impurities on the avalanche runaway growth rate is discussed. The results are applied, for illustration, to the interpretation of the runaway electron behavior during disruptions, where large amounts of impurities are expected, particularly during disruption mitigation by massive gas injection. The consequences for the electron synchrotron radiation losses and the resulting runaway electron dynamics are also analyzed.

  8. Effect of impurity doping in gapped bilayer graphene

    SciTech Connect

    Han, Qi; Yan, Baoming; Jia, Zhenzhao; Niu, Jingjing; Yu, Dapeng; Wu, Xiaosong

    2015-10-19

    Impurity doping plays a pivotal role in semiconductor electronics. We study the doping effect in a two-dimensional semiconductor, gapped bilayer graphene. By employing in situ deposition of calcium on the bilayer graphene, dopants are controllably introduced. Low temperature transport results show a variable range hopping conduction near the charge neutrality point persisting up to 50 K, providing evidence for the impurity levels inside the gap. Our experiment confirms a predicted peculiar effect in the gapped bilayer graphene, i.e., formation of in-gap states even if the bare impurity level lies in the conduction band. The result provides perspective on the effect of doping and impurity levels in semiconducting bilayer graphene.

  9. [Isolation and identification of impurities in the natural vitamin E].

    PubMed

    Xie, Yunfengl; Yang, Youyou; Liu, Jiaji; Wu, Wenhua; Yang, Yongtan

    2013-07-01

    Two impurities in the natural vitamin E extracted from oil deodorizer distillate were separated and characterized by high-performance liquid chromatography (HPLC), gas chromatography-mass spectrometry (GC-MS) and Fourier transform ion cyclotron resonance mass spectrometry (FTICR-MS). The impurities were purified and collected by normal-phase HPLC. The accurate masses were determined using FTICR-MS and fragmentation behavior was studied by GC-MS. The results showed that the impurities had identical MS spectra and similar electron impact (EI) fragmentation patterns. Based on the spectra, the structures of the two impurities were proposed as the enantiomers of sesamin. The presented method is rapid and effective, and can be applied for the food safety to the vitamin E manufacturing industry.

  10. Energy levels of isoelectronic impurities by large scale LDA calculations

    SciTech Connect

    Li, Jingbo; Wang, Lin-Wang

    2002-11-22

    Isoelectronic impurity states are localized states induced by stoichiometric single atom substitution in bulk semiconductor. Photoluminescence spectra indicate deep impurity levels of 0.5 to 0.9eV above the top of valence band for systems like: GaN:As, GaN:P, CdS:Te, ZnS:Te. Previous calculations based on small supercells seemingly confirmed these experimental results. However, the current ab initio calculations based on thousand atom supercells indicate that the impurity levels of the above systems are actually much shallower(0.04 to 0.23 eV), and these impurity levels should be compared with photoluminescence excitation spectra, not photoluminescence spectra.

  11. Neoclassical momentum transport in an impure rotating tokamak plasma

    SciTech Connect

    Newton, S.; Helander, P.

    2006-01-15

    It is widely believed that transport barriers in tokamak plasmas are caused by radial electric-field shear, which is governed by angular momentum transport. Turbulence is suppressed in the barrier, and ion thermal transport is comparable to the neoclassical prediction, but experimentally angular momentum transport has remained anomalous. With this motivation, the collisional transport matrix is calculated for a low collisionality plasma with collisional impurity ions. The bulk plasma toroidal rotation velocity is taken to be subsonic, but heavy impurities undergo poloidal redistribution due to the centrifugal force. The impurities give rise to off-diagonal terms in the transport matrix, which cause the plasma to rotate spontaneously. At conventional aspect ratio, poloidal impurity redistribution increases the angular momentum flux by a factor up to {epsilon}{sup -3/2} over previous predictions, making it comparable to the 'banana' regime heat flux. The flux is primarily driven by radial pressure and temperature gradients.

  12. Ionized impurity induced photocarrier generation in organic energy conversion systems

    NASA Astrophysics Data System (ADS)

    Popovic, Z. D.

    1982-07-01

    The present study has the objective to investigate the influence of the discrete nature of ionized impurities in a Schottky barrier on the field dependent carrier generation of an organic photovoltaic cell. Attention is given to the influence of the local ionized impurity field on the carrier generation, compared to the influence of the average field in the barrier. It is assumed that exciton dissociation into electron-hole pairs can be adequately described as a function of the local electric field. The proposal is made that thermal regeneration of ionized impurities can lead to continuous charge production based on the proposed mechanism. The study has been motivated by a significant discrepancy observed between the measured and calculated carrier generation efficiencies in x-metal-free phthalocyanine photovoltaic cells. The proposed mechanism of ionized impurity-assisted carrier generation offers an explanation for the observed enhancement in x-metal-free phthalocyanine photovoltaic cells.

  13. A DMRG approach to impurities and interactions in carbon nanotubes

    NASA Astrophysics Data System (ADS)

    Struck, Alexander; Reyes, Sebastian; Eggert, Sebastian

    2009-03-01

    Carbon nanotubes (CNTs) are well suited to study strong electronic correlations in quasi-one-dimensional systems experimentally and theoretically. Of particular interest is the interplay of interactions between the conducting electrons and impurities in the nanotube. Impurities include the boundaries of short tubes as well as structural imperfections such as the Stone-Wales lattice distortion. Interactions can lead to different phases of the electron liquid, depending on their range and strength, and can produce quasi-localized ground states of e.g. the Mott insulator type or a charge density wave. Here we discuss a systematic approach using the density-matrix renormalization group (DMRG) method to treat a recently derived lattice model for a single-wall armchair CNT with short-range interactions and a Stone-Wales impurity. We show interaction driven modifications to the expected density patterns that can lead to anomalous Friedel oscillations around the impurity.

  14. Identification of an isomer impurity in piperaquine drug substance.

    PubMed

    Lindegårdh, N; Giorgi, F; Galletti, B; Di Mattia, M; Quaglia, M; Carnevale, D; White, N J; Mazzanti, A; Day, N P J

    2006-12-01

    A significant contaminant of the antimalarial drug piperaquine (1,3-bis-[4-(7-chloroquinolyl-4)-piperazinyl-1]propane) has been identified using liquid chromatography-mass spectrometry (LC-MS) and 2D NMR spectroscopy (1H-1H COSY, 1H-13C HSQC, 1H-13C HMBC). The impurity was identified as the positional isomer 1-[(5-chloroquinolin-4)-piperazinyl]-3-[(7-chloroquinolin-4)-piperazinyl]propane. The impurity is formed because of contamination of batches of 4,7-dichloroquinoline (a precursor in the synthesis of piperaquine) with 4,5-dichloroquinoline. The amount of impurity (peak area impurity/peak area piperaquine using LC-UV at 347 nm) in old batches of piperaquine and in Artekin (the combination of dihydroartemisinin-piperaquine) ranged from 1.5 to 5%. PMID:17046006

  15. Runaway electron dynamics in tokamak plasmas with high impurity content

    NASA Astrophysics Data System (ADS)

    Martín-Solís, J. R.; Loarte, A.; Lehnen, M.

    2015-09-01

    The dynamics of high energy runaway electrons is analyzed for plasmas with high impurity content. It is shown that modified collision terms are required in order to account for the collisions of the relativistic runaway electrons with partially stripped impurity ions, including the effect of the collisions with free and bound electrons, as well as the scattering by the full nuclear and the electron-shielded ion charge. The effect of the impurities on the avalanche runaway growth rate is discussed. The results are applied, for illustration, to the interpretation of the runaway electron behavior during disruptions, where large amounts of impurities are expected, particularly during disruption mitigation by massive gas injection. The consequences for the electron synchrotron radiation losses and the resulting runaway electron dynamics are also analyzed.

  16. Parallel impurity dynamics in the TJ-II stellarator

    NASA Astrophysics Data System (ADS)

    Alonso, J. A.; Velasco, J. L.; Calvo, I.; Estrada, T.; Fontdecaba, J. M.; García-Regaña, J. M.; Geiger, J.; Landreman, M.; McCarthy, K. J.; Medina, F.; Van Milligen, B. Ph; Ochando, M. A.; Parra, F. I.; the TJ-II Team; the W7-X Team

    2016-07-01

    We review in a tutorial fashion some of the causes of impurity density variations along field lines and radial impurity transport in the moment approach framework. An explicit and compact form of the parallel inertia force valid for arbitrary toroidal geometry and magnetic coordinates is derived and shown to be non-negligible for typical TJ-II plasma conditions. In the second part of the article, we apply the fluid model including main ion-impurity friction and inertia to observations of asymmetric emissivity patterns in neutral beam heated plasmas of the TJ-II stellarator. The model is able to explain qualitatively several features of the radiation asymmetry, both in stationary and transient conditions, based on the calculated in-surface variations of the impurity density.

  17. Impurity-assisted tunneling magnetoresistance under a weak magnetic field.

    PubMed

    Txoperena, Oihana; Song, Yang; Qing, Lan; Gobbi, Marco; Hueso, Luis E; Dery, Hanan; Casanova, Fèlix

    2014-10-01

    Injection of spins into semiconductors is essential for the integration of the spin functionality into conventional electronics. Insulating layers are often inserted between ferromagnetic metals and semiconductors for obtaining an efficient spin injection, and it is therefore crucial to distinguish between signatures of electrical spin injection and impurity-driven effects in the tunnel barrier. Here we demonstrate an impurity-assisted tunneling magnetoresistance effect in nonmagnetic-insulator-nonmagnetic and ferromagnetic-insulator-nonmagnetic tunnel barriers. In both cases, the effect reflects on-off switching of the tunneling current through impurity channels by the external magnetic field. The reported effect is universal for any impurity-assisted tunneling process and provides an alternative interpretation to a widely used technique that employs the same ferromagnetic electrode to inject and detect spin accumulation. PMID:25325651

  18. Surface Kondo Impurities in the Slave-Boson Approach

    NASA Astrophysics Data System (ADS)

    Anda, Enrique; Vernek, Edson

    2005-03-01

    Transport properties of magnetic impurities on surfaces have captured a great deal of attention lately. Atom manipulation and topographic imaging techniques using scanning tunneling microscope have confirmed some theoretical predictions on Kondo physics and at the same time revealed other interesting behavior in these systems. For example, experiments have reported unexpectedly high Kondo temperatures for multi-impurity and molecular structures on metallic surfaces. Motivated by these experimental results we apply slave boson techniques for finite Coulomb interaction (finite U) to study the transport properties of magnetic impurities on a metallic surface in the Kondo regime. We report here on our studies of the role of fluctuations on the slave boson number for the case of one impurity on metallic surfaces. We compare our results to other theoretical approaches and to experimental results. Supported by CAPES-Brazil and NSF-IMC and NSF-NIRT.

  19. China: current trends in pharmaceutical drug discovery.

    PubMed

    Luo, Ying

    2008-04-01

    Pharmaceutical discovery and development is expensive and highly risky, even for multinational corporations. As a developing country with limited financial resources, China has been seeking the most cost-effective means to reach the same level of innovation and productivity as Western countries in the pharmaceutical industry sector. After more than 50 years of building up talent and experience, the time for China to become a powerhouse in pharmaceutical innovation is finally approaching. Returnee scientists to China are one of the reasons for the wave of new discovery and commercialization occurring within the country. The consolidation of local Chinese pharmaceutical companies and foreign investment is also providing an agreeable environment for the evolution of a new generation of biotechnology. The opportunity for pharmaceutical innovation is also being expedited by the entry of multinational companies into the Chinese pharmaceutical market, and by the outsourcing of research from these companies to China. PMID:18379963

  20. Introduction: Institutional corruption and the pharmaceutical policy.

    PubMed

    Rodwin, Marc A

    2013-01-01

    Today, the goals of pharmaceutical policy and medical practice are often undermined due to institutional corruption - that is, widespread or systemic practices, usually legal, that undermine an institution's objectives or integrity. In this symposium, 16 articles investigate the corruption of pharmaceutical policy, each taking a different look at the sources of corruption, how it occurs, and what is corrupted. We will see that the pharmaceutical industry's own purposes are often undermined. Furthermore, pharmaceutical industry funding of election campaigns and lobbying skews the legislative process that sets pharmaceutical policy. Moreover, certain practices have corrupted medical research, the production of medical knowledge, the practice of medicine, drug safety, the Food and Drug Administration's oversight of the pharmaceutical market, and the trustworthiness of patient advocacy organizations.

  1. Introduction: Institutional corruption and the pharmaceutical policy.

    PubMed

    Rodwin, Marc A

    2013-01-01

    Today, the goals of pharmaceutical policy and medical practice are often undermined due to institutional corruption - that is, widespread or systemic practices, usually legal, that undermine an institution's objectives or integrity. In this symposium, 16 articles investigate the corruption of pharmaceutical policy, each taking a different look at the sources of corruption, how it occurs, and what is corrupted. We will see that the pharmaceutical industry's own purposes are often undermined. Furthermore, pharmaceutical industry funding of election campaigns and lobbying skews the legislative process that sets pharmaceutical policy. Moreover, certain practices have corrupted medical research, the production of medical knowledge, the practice of medicine, drug safety, the Food and Drug Administration's oversight of the pharmaceutical market, and the trustworthiness of patient advocacy organizations. PMID:24088143

  2. A qualitative glimpse at pharmaceutical care practice.

    PubMed

    Varela Dupotey, Niurka María; Ramalho de Oliveira, Djenane

    2009-12-01

    This manuscript presents an argument for a broader use of qualitative methodologies to investigate the practice and the surroundings of pharmaceutical care. Albeit the use of qualitative research methods is growing in the health care field, it is still insufficient in the area of pharmaceutical care. Pharmaceutical care, as a patient-centered practice, calls for a more comprehensive and humanistic approach to research. It is our contention that the attempt to understand pharmaceutical care practice from the perspective of patients, pharmacists and other health care professionals, by means of using qualitative methods, would notably contribute to a better assessment of the value of pharmaceutical care programs in the health care system. Moreover, because a deeper understanding of the nuances of this practice can be achieved with the use of qualitative methods, this approach might also assist us in making the necessary changes to create more effective pharmaceutical care practices.

  3. How to reduce false positive results when undertaking in vitro genotoxicity testing and thus avoid unnecessary follow-up animal tests: Report of an ECVAM Workshop.

    PubMed

    Kirkland, David; Pfuhler, Stefan; Tweats, David; Aardema, Marilyn; Corvi, Raffaella; Darroudi, Firouz; Elhajouji, Azeddine; Glatt, Hansruedi; Hastwell, Paul; Hayashi, Makoto; Kasper, Peter; Kirchner, Stephan; Lynch, Anthony; Marzin, Daniel; Maurici, Daniela; Meunier, Jean-Roc; Müller, Lutz; Nohynek, Gerhard; Parry, James; Parry, Elizabeth; Thybaud, Veronique; Tice, Ray; van Benthem, Jan; Vanparys, Philippe; White, Paul

    2007-03-30

    Workshop participants agreed that genotoxicity tests in mammalian cells in vitro produce a remarkably high and unacceptable occurrence of irrelevant positive results (e.g. when compared with rodent carcinogenicity). As reported in several recent reviews, the rate of irrelevant positives (i.e. low specificity) for some studies using in vitro methods (when compared to this "gold standard") means that an increased number of test articles are subjected to additional in vivo genotoxicity testing, in many cases before, e.g. the efficacy (in the case of pharmaceuticals) of the compound has been evaluated. If in vitro tests were more predictive for in vivo genotoxicity and carcinogenicity (i.e. fewer false positives) then there would be a significant reduction in the number of animals used. Beyond animal (or human) carcinogenicity as the "gold standard", it is acknowledged that genotoxicity tests provide much information about cellular behaviour, cell division processes and cellular fate to a (geno)toxic insult. Since the disease impact of these effects is seldom known, and a verification of relevant toxicity is normally also the subject of (sub)chronic animal studies, the prediction of in vivo relevant results from in vitro genotoxicity tests is also important for aspects that may not have a direct impact on carcinogenesis as the ultimate endpoint of concern. In order to address the high rate of in vitro false positive results, a 2-day workshop was held at the European Centre for the Validation of Alternative Methods (ECVAM), Ispra, Italy in April 2006. More than 20 genotoxicity experts from academia, government and industry were invited to review data from the currently available cell systems, to discuss whether there exist cells and test systems that have a reduced tendency to false positive results, to review potential modifications to existing protocols and cell systems that might result in improved specificity, and to review the performance of some new test systems

  4. Effects of Zr impurity on microscopic behavior of Hf metal

    NASA Astrophysics Data System (ADS)

    Dey, S. K.; Dey, C. C.; Saha, S.

    2016-08-01

    Hf metal with ∼ 3 wt% Zr impurity has been reinvestigated by perturbed angular correlation (PAC) spectroscopy using a LaBr3(Ce)-BaF2 detector set up to understand the microscopic behavior of this metal with temperature. From present measurements, five quadrupole interaction frequencies have been found at room temperature where both pure hcp fraction (∼33%) with 12 nearest neighbor Hf surrounding the probe 181Hf atom and the probe-impurity fraction (∼33%) corresponding to 11 nearest neighbor Hf plus one dissimilar Zr atom are clearly distinguished. At room temperature, the results for quadrupole frequency and asymmetry parameter are found to be ωQ=51.6(4) Mrad/s, η=0.20(4) for the impurity fraction and ωQ=46.8(2) Mrad/s, η=0 for the pure fraction with values of frequency distribution width δ=0 for both components. At 77 K, only 1 NN Zr impurity (∼93%) and pure hcp (∼7%) components have been found with a value of δ ∼ 10% for the impurity fraction. A drastic change in microstructural configuration of Hf metal is observed at 473 K where the impurity fraction increases to ∼ 50% and the pure hcp fraction reduces to ∼ 15% with abrupt changes in quadrupole frequencies for both components. The pure fraction then increases with temperature and enhances to ∼50% at 973 K. In the temperature range 473-973 K, quadrupole frequencies for both components are found to decrease slowly with temperature. Using the Arrhenius relation, binding energy (B) for the probe-impurity pair and the entropy of formation are measured from temperature dependent fractions of probe-impurity and pure hcp in the temperature range 473-773 K. The three other minor components found at different temperatures are attributed to crystalline defects.

  5. Impurity control and corrosion resistance of magnesium-aluminum alloy

    SciTech Connect

    Liu, M.; Song, GuangLing

    2013-01-01

    The corrosion resistance of magnesium alloys is very sensitive to the contents of impurity elements such as iron. In this study, a series of diecast AXJ530 magnesium alloy samples were prepared with additions of Mn and Fe. Through a comprehensive phase diagram calculation and corrosion evaluation, the mechanisms for the tolerance limit of Fe in magnesium alloy are discussed. This adds a new dimension to control the alloying impurity in terms of alloying composition design and casting conditions.

  6. The influence of finite impurity size on heterogeneous nucleation

    NASA Technical Reports Server (NTRS)

    Weinberg, Michael C.

    1992-01-01

    The effects of the finite size of impurities upon the heterogeneous nucleation rate is examined. Simple arguments based upon probability theory are used to find the relative nucleation rate, p(j), on particles containing j nuclei. The expression for p(j) is used in turn to compute the overall nucleation rate and average number of nuclei on an impurity as a function of time.

  7. Exact Solution for Perk-Schultz Model with Boundary Impurities

    NASA Astrophysics Data System (ADS)

    Li, Guang-Liang; Yue, Rui-Hong; Shi, Kang-Jie; Hou, Bo-Yu

    2001-03-01

    The Perk-Schultz model with SUq(m|n) spin boundary impurities is constructed by dressing the c-number reflecting K-matrix with the local L-matrix which acts non-trivially on an impurity Hilbert space. The eigenvalue of the transfer matrix and the corresponding Bethe ansatz equations with different c-number reflecting K-matrices are obtained by using the nested Bethe ansatz method (m&\

  8. Local Impurity States in Antiferromagnetic Cr-ALLOYS

    NASA Astrophysics Data System (ADS)

    Galkin, V. Yu.

    The concept of local impurity states within the energy gap of a spin-density-wave (SDW) system is introduced. It is shown that resonant scattering of conduction electrons at these states may lead to greatly enhanced low-temperature resistivity. This impurity resonance scattering (IRS) model is employed to explain the variation of residual resistivity and temperature dependence of resistivity at low temperatures of Cr-Fe and Cr-Si systems on V and Mn doping and application of high pressure.

  9. Acetylated Lysozyme as Impurity in Lysozyme Crystals: Constant Distribution Coefficient

    NASA Technical Reports Server (NTRS)

    Thomas, B. R.; Chernov, A. A.

    2000-01-01

    Hen egg white lysozyme (HEWL) was acetylated to modify molecular charge keeping the molecular size and weight nearly constant. Two derivatives, A and B, more and less acetylated, respectively, were obtained, separated, purified and added to the solution from which crystals of tetragonal HEWL crystals were grown. Amounts of the A or B impurities added were 0.76, 0.38 and 0.1 milligram per millimeter while HEWL concentration were 20, 30 and 40 milligram per milliliter. The crystals grown in 18 experiments for each impurity were dissolved and quantities of A or B additives in these crystals were analyzed by cation exchange high performance liquid chromatography. All the data for each set of 18 samples with the different impurity and regular HEWL concentrations is well described by one distribution coefficient K = 2.15 plus or minus 0.13 for A and K = 3.42 plus or minus 0.25 for B. The observed independence of the distribution coefficient on both the impurity concentration and supersaturation is explained by the dilution model described in this paper. It shows that impurity adsorption and incorporation rate is proportional to the impurity concentration and that the growth rate is proportional to the crystallizing protein in solution. With the kinetic coefficient for crystallization, beta = 5.10(exp -7) centimeters per second, the frequency at which an impurity molecule near the growing interface irreversibly joins a molecular site on the crystal was found to be 3 1 per second, much higher than the average frequency for crystal molecules. For best quality protein crystals it is better to have low microheterogeneous protein impurity concentration and high supers aturation.

  10. GENOTOXICITY OF TEN CIGARETTE SMOKE CONDENSATES IN FOUR TEST SYSTEMS: COMPARISONS AMONG ASSAYS AND CONDENSATES

    EPA Science Inventory

    The particulate fraction of cigarette smoke, cigarette smoke condensate (CSC), is genotoxic in many short-term in vitro tests and carcinogenic in rodents. However, no study has evaluatedd a set of CSCs prepared from a diverse set of cigarettes in a variety of short-term genotoxic...

  11. Quercetin tests negative for genotoxicity in transcriptome analyses of liver and small intestine of mice.

    PubMed

    Hoek-van den Hil, Elise F; van Schothorst, Evert M; van der Stelt, Inge; Hollman, Peter C H; Keijer, Jaap; Rietjens, Ivonne M C M

    2015-07-01

    Given the positive results of quercetin in in vitro genotoxicity studies, the in vivo genotoxic properties of this important dietary flavonoid warrant testing, especially considering possible high intake via widely available food supplements. Here, this was done by transcriptome analyses of the most relevant tissues, liver and small intestine, of quercetin supplemented mice. Quercetin (0.33%) supplemented to a high-fat diet was administered to mice during 12 weeks. Serum alanine aminotransferase and aspartate aminotransferase levels revealed no indications for hepatotoxicity. Microarray pathway analysis of liver and small intestine showed no regulation of genotoxicity related pathways. Analysis of DNA damage related genes also did not point at genotoxicity. Furthermore, a published classifier set of transcripts for identifying genotoxic compounds did not indicate genotoxicity. Only two transcripts of the classifier set were regulated, but in the opposite direction compared with the genotoxic compounds 2-acetylaminofluorene (2-AAF) and aflatoxin B1 (AFB1). Based on the weight of evidence of three different types of analysis, we conclude that supplementation with quercetin at ~350 mg/kg bw/day for 12 weeks in mice showed no up-regulation of genotoxicity related pathways in liver and small intestine.

  12. New strategies for pharmaceutical design.

    PubMed

    Gillmor, S A; Cohen, F E

    1993-01-01

    Parallel synthesis and testing procedures are being investigated to shorten the drug design and discovery process. These procedures have focused on peptides and nucleotides, although these compounds are unlikely to be useful therapeutics because of their low bioavailability and sensitivity to enzymatic degradation. More recently, the use of other modular systems with distinct linking chemistries have been explored. Structural data combined with computational screens of compound databases provides an alternative method to identify novel nonpeptide pharmaceuticals. When structural information is not available, homology-based models have proved to be sufficient to identify nonpeptide inhibitors active at low micromolar concentrations against important enzymes in parasite life cycles. PMID:8167566

  13. Pharmaceutical Compounds Studied Using NEXAFS

    SciTech Connect

    Murray Booth, A.; Braun, Simon; Lonsbourough, Tom; Schroeder, Sven L. M.; Purton, John; Patel, Sunil

    2007-02-02

    Total Electron Yield (TEY) oxygen K-edge NEXAFS detects the presence of strongly adsorbed water molecules on poloxamer-coated pharmaceutical actives, which provides a useful spectroscopic indicator for bioavailability. The results are supported by complementary XPS measurements. Carbon K-edge spectra obtained in a high-pressure NEXAFS cell were used in situ to establish how a polymer coating spread on a drug surface by using humidity induced dispersion of the coating. Finally, we demonstrate how combined Carbon and Oxygen K-edge measurements can be used to characterize amorphous surface layers on micronised crystals of a drug compound.

  14. Millimeter-Wave Spectroscopy for Analytical Chemistry: Thermal Evolution of Low Volatility Impurities and Detection with a Fourier Transform Molecular Rotational Resonance Spectrometer (tev Ft-Mrr

    NASA Astrophysics Data System (ADS)

    Harris, Brent; Fields, Shelby S.; Neill, Justin L.; Pulliam, Robin; Muckle, Matt; Pate, Brooks

    2016-06-01

    Recent advances in Fourier transform millimeter-wave spectroscopy techniques have renewed the application reach of molecular rotational spectroscopy for analytical chemistry. We present a sampling method for sub ppm analysis of low volatility impurities by thermal evolution from solid powders using a millimeter-wave Fourier transform molecular rotational resonance (FT-MRR) spectrometer for detection. This application of FT-MRR is relevant to the manufacturing of safe oral pharmaceuticals. Low volatility impurities can be challenging to detect at 1 ppm levels with chromatographic techniques. One such example of a potentially mutagenic impurity is acetamide (v.p. 1 Torr at 40 C, m.p. 80 C). We measured the pure reference spectrum of acetamide by flowing the sublimated vapor pressure of acetamide crystals through the FT-MRR spectrometer. The spectrometer lower detection level (LDL) for a broadband (> 20 GHz, 10 min.) spectrum is 300 nTorr, 30 pmol, or 2 ng. For a 50 mg powder, perfect sample transfer efficiency can yield a w/w % detection limit of 35 ppb. We extended the sampling method for the acetamide reference measurement to an acetaminophen sample spiked with 5000 ppm acetamide in order to test the sample transfer efficiency when liberated from an pharmaceutical powder. A spectral reference matching algorithm detected the presence of several impurities including acetaldehyde, acetic acid, and acetonitrile that evolved at the melting point of acetaminophen, demonstrating the capability of FT-MRR for identification without a routine chemical standard. The method detection limit (MDL) without further development is less than 10 ppm w/w %. Resolved FT-MRR mixture spectra will be presented with a description of sampling methods.

  15. Evaluation of P-Listed Pharmaceutical Residues in Empty Pharmaceutical Containers

    EPA Science Inventory

    Under the Resource Conservation and Recovery Act (RCRA), some pharmaceuticals are considered acute hazardous wastes because their sole active pharmaceutical ingredients are P-listed commercial chemical products (40 CFR 261.33). Hospitals and other healthcare facilities have stru...

  16. Interactions of structural defects with metallic impurities in multicrystalline silicon

    SciTech Connect

    McHugo, S.A.; Hieslmair, H.; Weber, E.R.; Rosenblum, M.D.; Kalejs, J.P.

    1996-11-01

    Interactions between structural defects and metallic impurities were studied in multicrystalline silicon for solar cells applications. The objective was to gain insight into the relationship between solar cell processing, metallic impurity behavior and the resultant effect on material/device performance. With an intense synchrotron x-ray source, high sensitivity x-ray fluorescence measurements were utilized to determine impurity distributions with a spatial resolution of {approx} 1{micro}m. Diffusion length mapping and final solar cell characteristics gauged material/device performance. The materials were tested in both the as-grown state and after full solar cell processing. Iron and nickel metal impurities were located at structural defects in as-grown material, while after solar cell processing, both impurities were still observed in low performance regions. These results indicate that multicrystalline silicon solar cell performance is directly related to metal impurities which are not completely removed during typical processing treatments. A discussion of possible mechanisms for this incomplete removal is presented.

  17. The impact of neutral impurity concentration on charge drift mobility

    NASA Astrophysics Data System (ADS)

    Mei, Hao; Wang, Guojian; Mei, Dongming; Yang, Gang; Guan, Yutong

    High-purity germanium crystals are being grown using the Czochralski technique at the University of South Dakota. The carrier concentration, mobility and resistivity are measured by Hall Effect system. Many factors contribute to the overall mobility. We investigated the impact of neutral impurity concentration on charge drift mobility. Several samples with measured mobility lager than 35000 cm2/Vs from the grown crystals were used for this investigation. With the measured mobility and the ionized impurity concentration, we were able to calculate the neutral impurity concentration by the Matthiessen's rule. The correlations between the neutral impurity concentrations with the radius of the crystals were studied. We report that the concentration of neutral impurity constrains charge draft mobility for high-purity germanium crystals and the non-uniform distribution of neutral impurity could result in an anisotropy of draft time distribution in a given germanium detector. This work is supported by DOE Grant DE-FG02-10ER46709 and the state of South Dakota.

  18. Classical impurities and boundary Majorana zero modes in quantum chains

    NASA Astrophysics Data System (ADS)

    Müller, Markus; Nersesyan, Alexander A.

    2016-09-01

    We study the response of classical impurities in quantum Ising chains. The Z2 degeneracy they entail renders the existence of two decoupled Majorana modes at zero energy, an exact property of a finite system at arbitrary values of its bulk parameters. We trace the evolution of these modes across the transition from the disordered phase to the ordered one and analyze the concomitant qualitative changes of local magnetic properties of an isolated impurity. In the disordered phase, the two ground states differ only close to the impurity, and they are related by the action of an explicitly constructed quasi-local operator. In this phase the local transverse spin susceptibility follows a Curie law. The critical response of a boundary impurity is logarithmically divergent and maps to the two-channel Kondo problem, while it saturates for critical bulk impurities, as well as in the ordered phase. The results for the Ising chain translate to the related problem of a resonant level coupled to a 1d p-wave superconductor or a Peierls chain, whereby the magnetic order is mapped to topological order. We find that the topological phase always exhibits a continuous impurity response to local fields as a result of the level repulsion of local levels from the boundary Majorana zero mode. In contrast, the disordered phase generically features a discontinuous magnetization or charging response. This difference constitutes a general thermodynamic fingerprint of topological order in phases with a bulk gap.

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

    SciTech Connect

    Valencia, Antoni; Prous, Josep; Mora, Oscar; Sadrieh, Nakissa; Valerio, Luis G.

    2013-12-15

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

  20. Pharmaceutical Cocrystals and Their Physicochemical Properties

    PubMed Central

    2009-01-01

    Over the last 20 years, the number of publications outlining the advances in design strategies, growing techniques, and characterization of cocrystals has continued to increase significantly within the crystal engineering field. However, only within the last decade have cocrystals found their place in pharmaceuticals, primarily due to their ability to alter physicochemical properties without compromising the structural integrity of the active pharmaceutical ingredient (API) and thus, possibly, the bioactivity. This review article will highlight and discuss the advances made over the last 10 years pertaining to physical and chemical property improvements through pharmaceutical cocrystalline materials and, hopefully, draw closer the fields of crystal engineering and pharmaceutical sciences. PMID:19503732

  1. Toward a definition of pharmaceutical innovation.

    PubMed

    Morgan, Steven; Lopert, Ruth; Greyson, Devon

    2008-01-01

    ONGOING DEBATES IN THE PHARMACEUTICAL SECTOR ABOUT INTELLECTUAL PROPERTY, PRICING AND REIMBURSEMENT, AND PUBLIC RESEARCH INVESTMENTS HAVE A COMMON DENOMINATOR: the pursuit of innovation. However, there is little clarity about what constitutes a true pharmaceutical innovation, and as a result there is confusion about what kind of new products should be pursued, protected and encouraged through health policy and clinical practice. If the concept of pharmaceutical innovation can be clarified, then it may become easier for health policy-makers and practitioners to evaluate, adopt and procure products in ways that appropriately recognize, encourage and give priority to truly valuable pharmaceutical innovations.

  2. Specialty pharmaceuticals: developing a management plan.

    PubMed

    Willcutts, Dave

    2002-01-01

    This is the first in a series of articles that address the complex issues associated with specialty pharmaceuticals in the development of a successful specialty pharmaceutical program, a critical component of managing this high-cost and highly fragmented sector. This article focuses on how to define specialty pharmaceuticals. Other articles in this series will explore such topics as the mechanics of developing and managing a specialty pharmaceutical program, how and when to establish clinical protocols and authorizations, the importance of data management, and the benefits from automated processes.

  3. Entrepreneurial patent management in pharmaceutical startups.

    PubMed

    Holgersson, Marcus; Phan, Tai; Hedner, Thomas

    2016-07-01

    Startups fill an increasingly important role as innovators in the pharmaceutical industry, and patenting is typically central to their success. This article aims to explore patent management in pharmaceutical startups. The results show that startups need to deal with several challenges related to patenting and an 'entrepreneurial' approach to patent management is called for. Resource constraints, venture capital provision, exits and other conditions and events must be readily considered in the patent management process to build a successful pharmaceutical venture, something that could benefit the pharmaceutical industry as a whole. PMID:26948802

  4. Direct determination of cadmium and lead in pharmaceutical ingredients using anodic stripping voltammetry in aqueous and DMSO/water solutions.

    PubMed

    Rosolina, Samuel M; Chambers, James Q; Lee, Carlos W; Xue, Zi-Ling

    2015-09-17

    A new electrochemical method has been developed to detect and quantify the elemental impurities, cadmium(II) (Cd(2+)) and lead(II) (Pb(2+)), either simultaneously or individually in pharmaceutical matrices. The electro-analytical approach, involving the use of anodic stripping voltammetry (ASV) on an unmodified glassy carbon electrode, was performed in both aqueous and in a 95/5 dimethyl sulfoxide (DMSO)/water solutions, without acid digestion or dry ashing to remove organic matrices. Limits of detection (LODs) in the μg L(-1) [or parts per billion (ppb), mass/volume] range were obtained for both heavy metals - in the presence and absence of representative pharmaceutical components. To the best of our knowledge, the work demonstrates the first analysis of heavy metals in DMSO/water solutions through ASV. The strong reproducibility and stability of the sensing platform, as well as obviation of sample pretreatment show the promise of utilizing ASV as a sensitive, robust, and inexpensive alternative to inductively-coupled-plasma (ICP)-based approaches for the analysis of elemental impurities in, e.g., pharmaceutical-related matrices.

  5. Genotoxicity of Different Nanocarriers: Possible Modifications for the Delivery of Nucleic Acids

    PubMed Central

    Shah, Vatsal; Taratula, Oleh; Garbuzenko, Olga B.; Patil, Mahesh L.; Savla, Ronak; Zhang, Min; Minko, Tamara

    2014-01-01

    The prevention of cyto- and genotoxicity of nanocarriers is an important task in nanomedicine. In the present investigation, we, at the first time using similar experimental conditions, compared genotoxicity of nanocarriers with different composition, architecture, size, molecular weight and charge. Poly(ethylene glycol) polymers, neutral and cationic liposomes, micelles, poly(amindo amine) and poly(propyleneimine) dendrimers, quantum dots, mesoporous silica, and supermagnetic iron oxide (SPIO) nanoparticles were studied. All nanoparticles were used in non-cytotoxic concentrations. However, even in these concentrations, positively charged cationic liposomes, dendrimers, and SPIO nanoparticles induced genotoxicity leading to the significant formation of micronuclei in cells. Negatively charged and neutral nanocarriers were not genotoxic. A strong positive correlation was found between the number of formed micronuclei and the positive charge of nanocarriers. We proposed modifications of both types of dendrimers and SPIO nanoparticles that substantially decreased their genotoxicity and allowed for an efficient intracellular delivery of nucleic acids. PMID:22564170

  6. Evaluation of the in vivo genotoxicity of Allura Red AC (Food Red No. 40).

    PubMed

    Honma, Masamitsu

    2015-10-01

    Allura Red AC (Food Red No. 40) is a red azo dye that is used for food coloring in beverage and confectionary products. However, its genotoxic properties remain controversial. To clarify the in vivo genotoxicity, we treated mice with Allura Red AC and investigated the induction of DNA damage (liver, glandular stomach), clastogenicity/anuegenicity (bone marrow), and mutagenicity (liver, glandular stomach) using Comet assays, micronucleus tests, and transgenic gene mutation assays, respectively. All studies were conducted in accordance with the Organization for Economic Co-operation and Development (OECD) guideline. Although Allura Red AC was administered up to the maximum doses recommended by the OECD guideline, no genotoxic effect was observed in any of the genotoxic endpoints. These data clearly show no evidence of in vivo genotoxic potential of Allura Red AC administered up to the maximum doses in mice.

  7. Evaluation of the in vivo genotoxicity of Allura Red AC (Food Red No. 40).

    PubMed

    Honma, Masamitsu

    2015-10-01

    Allura Red AC (Food Red No. 40) is a red azo dye that is used for food coloring in beverage and confectionary products. However, its genotoxic properties remain controversial. To clarify the in vivo genotoxicity, we treated mice with Allura Red AC and investigated the induction of DNA damage (liver, glandular stomach), clastogenicity/anuegenicity (bone marrow), and mutagenicity (liver, glandular stomach) using Comet assays, micronucleus tests, and transgenic gene mutation assays, respectively. All studies were conducted in accordance with the Organization for Economic Co-operation and Development (OECD) guideline. Although Allura Red AC was administered up to the maximum doses recommended by the OECD guideline, no genotoxic effect was observed in any of the genotoxic endpoints. These data clearly show no evidence of in vivo genotoxic potential of Allura Red AC administered up to the maximum doses in mice. PMID:26364875

  8. Reduction of acute toxicity and genotoxicity of dye effluent using Fenton-coagulation process.

    PubMed

    Zhang, Jing; Chen, Shuo; Zhang, Ying; Quan, Xie; Zhao, Huimin; Zhang, Yaobin

    2014-06-15

    Dye wastewater exhibits significant ecotoxicity even though its physico-chemical parameters meet the discharge standards. In this work, the acute toxicity and genotoxicity of dye effluent were tested, and the Fenton-coagulation process was carried out to detoxify this dye effluent. The acute toxicity was evaluated according to the mortality rate of zebrafish, and genotoxicity was evaluated by micronucleus (MN) and comet assays. Removal of color and chemical oxygen demand (COD) was also investigated. The results indicated that the dye effluent showed strong acute toxicity and genotoxicity to zebrafish. After 4h of treatment by Fenton-coagulation process, the dye effluent exhibited no significant acute toxicity and genotoxicity to zebrafish. In addition, its COD was less than 50mg/L, which met the discharge standard. It demonstrates that Fenton-coagulation process can comprehensively reduce the acute toxicity and genotoxicity as well as the COD of the dye effluent.

  9. Effects of impurity size and heavy doping on energy-band-structure parameters of various impurity-Si systems

    NASA Astrophysics Data System (ADS)

    Van Cong, H.

    2016-04-01

    The effects of impurity size and heavy doping on energy-band-structure parameters of various donor (or acceptor)-Si systems were investigated. A satisfactory description was obtained for intrinsic properties such as: the effective dielectric constant, effective impurity ionization energy, effective intrinsic band gap, being doping-independent, and critical impurity density, Ncn(cp) GMM, which is derived from our simple generalized Mott model (GMM), as well as for extrinsic properties such as: the Fermi energy, reduced band gap, optical band gap, being doping-dependent, and critical impurity density, Ncn(cp) SSS, which is determined by our complicated spin-susceptibility-singularity (SSS) method. That gives: Ncn(cp) SSS ≡ Ncn(cp) GMM for all the studied donor (or acceptor)-Si systems.

  10. Genotoxicity of leachates from a landfill using three bioassays.

    PubMed

    Cabrera, G L; Rodriguez, D M

    1999-05-19

    In the city of Queretaro, around 500 tons of solid wastes are produced everyday and are deposited in a landfill. This is the result of social and economic activities of human beings or from their normal physiological functions. As a result of rain, leachates are produced, which, if not handled and treated correctly, may pollute the underground water. Among the bioassays developed for the detection of mutagenicity in environmental pollutants, plant systems have been proven to be sensitive, cheap, and effective. The purpose of this study was to determine the presence of genotoxic agents in the leachates of the landfill of the city using three bioassays: Tradescantia-micronucleus (Trad-MCN), Tradescantia stamen hair mutations (Trad-SHM) and Allium root anaphase aberrations (AL-RAA) and make a comparison of the results in the three assays. Leachates were sampled during both the dry and rainy seasons. Plant cuttings of Tradescantia or the roots of Allium were treated by submerging them in the leachates. Three replicates of each sample were analyzed in each of the three bioassays. As expected the samples of leachates collected during the dry season showed a higher genotoxicity than those collected during the rainy season. In conclusion, there are substances present in the leachates capable of inducing genotoxicity in the plant assays. On the other hand, the plant assays showed different degrees of sensitivity: the more sensitive was the Trad-MCN bioassay and the less sensitive the Trad-SHM assay. Therefore, when analyzing environmental pollutants it is recommended to use a battery of bioassays.

  11. Characteristic expression profiles induced by genotoxic carcinogens in rat liver.

    PubMed

    Ellinger-Ziegelbauer, Heidrun; Stuart, Barry; Wahle, Brad; Bomann, Werner; Ahr, Hans-Jurgen

    2004-01-01

    When applied in toxicological studies, the recently developed gene expression profiling techniques using microarrays, which brought forth the new field of toxicogenomics, facilitate the interpretation of a toxic compound's mechanism of action. In this study, we investigated whether genotoxic carcinogens at doses known to induce liver tumors in the 2-year rat bioassay deregulate a common set of genes in a short-term in vivo study and, if so, whether these deregulated genes represent defined biological pathways. Rats were dosed with the four genotoxic hepatocarcinogens dimethylnitrosamine (4 mg/kg/day), 2-nitrofluorene (44 mg/kg/day), aflatoxin B1 (0.24 mg/kg/day), and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK, 20 mg/kg/day). After treatment for up to 14 days, the expression profiles of the livers were analyzed on Affymetrix RG_U34A microarrays. Among the significantly upregulated genes were a set of target genes of the tumor suppressor protein p53, indicating a DNA damage response. Such a response was expected and, therefore, confirmed the validity of our approach. In addition, the gene expression changes suggest a specific detoxification response, the activation of proliferative and survival signaling pathways, and some cell structural changes. These responses were strong throughout the 14 day time course for 2-nitrofluorene and aflatoxin B1; in the case of dimethylnitrosamine and NNK, the effects were weakly detectable at day 1 and then increased with time. For dimethylnitrosamine and aflatoxin B1, which caused observable inflammation in vivo, we found a corresponding upregulation of inflammatory genes at the same time points. Thus, by the toxicogenomic analysis of short-term in vivo studies, we identified genes and pathways commonly deregulated by genotoxic carcinogens, which may be indicative for the early events in tumorigenesis and, thus, predictive of later tumor development. PMID:14600272

  12. Integration of metabolic activation with a predictive toxicogenomics signature to classify genotoxic versus non-genotoxic chemicals in human TK6 cells

    PubMed Central

    Buick, Julie K.; Moffat, Ivy; Williams, Andrew; Swartz, Carol D.; Recio, Leslie; Hyduke, Daniel R.; Li, Heng-Hong; Fornace, Albert J.; Aubrecht, Jiri; Yauk, Carole L.

    2015-01-01

    The use of integrated approaches in genetic toxicology, including the incorporation of gene expression data to determine the molecular pathways involved in the response, is becoming more common. In a companion paper, a genomic biomarker was developed in human TK6 cells to classify chemicals as genotoxic or non-genotoxic. Because TK6 cells are not metabolically competent, we set out to broaden the utility of the biomarker for use with chemicals requiring metabolic activation. Specifically, chemical exposures were conducted in the presence of rat liver S9. The ability of the biomarker to classify genotoxic (benzo[a]pyrene, BaP; aflatoxin B1, AFB1) and non-genotoxic (dexamethasone, DEX; phenobarbital, PB) agents correctly was evaluated. Cells were exposed to increasing chemical concentrations for 4h and collected 0h, 4h and 20h post-exposure. Relative survival, apoptosis, and micronucleus frequency were measured at 24h. Transcriptome profiles were measured with Agilent microarrays. Statistical modeling and bioinformatics tools were applied to classify each chemical using the genomic biomarker. BaP and AFB1 were correctly classified as genotoxic at the mid- and high concentrations at all three time points, whereas DEX was correctly classified as non-genotoxic at all concentrations and time points. The high concentration of PB was misclassified at 24h, suggesting that cytotoxicity at later time points may cause misclassification. The data suggest that the use of S9 does not impair the ability of the biomarker to classify genotoxicity in TK6 cells. Finally, we demonstrate that the biomarker is also able to accurately classify genotoxicity using a publicly available dataset derived from human HepaRG cells. PMID:25733247

  13. Block Lanczos density-matrix renormalization group method for general Anderson impurity models: Application to magnetic impurity problems in graphene

    NASA Astrophysics Data System (ADS)

    Shirakawa, Tomonori; Yunoki, Seiji

    2014-11-01

    We introduce a block Lanczos (BL) recursive technique to construct quasi-one-dimensional models, suitable for density-matrix renormalization group (DMRG) calculations, from single- as well as multiple-impurity Anderson models in any spatial dimensions. This new scheme, named BL-DMRG method, allows us to calculate not only local but also spatially dependent static and dynamical quantities of the ground state for general Anderson impurity models without losing elaborate geometrical information of the lattice. We show that the BL-DMRG method can be easily extended to treat a multiorbital Anderson impurity model where not only inter- and intraorbital Coulomb interactions but also Hund's coupling and pair hopping interactions are included. We also show that the symmetry adapted BL bases can be utilized, when it is appropriate, to reduce the computational cost. As a demonstration, we apply the BL-DMRG method to three different models for graphene with a structural defect and with a single hydrogen or fluorine absorbed, where a single Anderson impurity is coupled to conduction electrons in the honeycomb lattice. These models include (i) a single adatom on the honeycomb lattice, (ii) a substitutional impurity in the honeycomb lattice, and (iii) an effective model for a single carbon vacancy in graphene. Our analysis of the local dynamical magnetic susceptibility and the local density of states at the impurity site reveals that, for the particle-hole symmetric case at half-filling of electron density, the ground state of model (i) behaves as an isolated magnetic impurity with no Kondo screening, while the ground state of the other two models forms a spin-singlet state where the impurity moment is screened by the conduction electrons. We also calculate the real-space dependence of the spin-spin correlation functions between the impurity site and the conduction sites for these three models. Our results clearly show that, reflecting the presence or absence of unscreened

  14. Destruction of genotoxic wastes mixed with radioactive products.

    PubMed

    Simonnet, F; Orts, J C; Simonnet, G

    1989-12-01

    Before their disposal, genotoxic substances are destroyed by strong oxidizing agents. If there are molecules labelled with radionuclides in the medium which is oxidized, then this treatment may bring about the release of gaseous radioactive compounds. We have looked for evidence of such a release following the action of K permanganate and sodium hypochlorite on molecules labelled with 3H, 14C, 32P, and 125I. Among the compounds examined, only those labelled with 14C showed significant quantities of radioactive gas released, with values up to 60% of the total radioactivity. For the other products, less than 0.6% of the radioactivity appeared in a volatile form.

  15. Testing systems for biologic markers of genotoxic exposure and effect

    SciTech Connect

    Mendelsohn, M.L.

    1986-11-19

    Societal interest in genotoxicity stems from two concerns: the fear of carcinogenesis secondary to somatic mutation; and the fear of birth defects and decreasing genetic fitness secondary to heritable mutation. There is a pressing need to identify agents that can cause these effects, to understand the underlying dose-response relationships, to identify exposed populations, and to estimate both the magnitude of exposure and the risk of adverse health effects in such populations. Biologic markers refer either to evidence in surrogate organisms, or to the expressions of exposure and effect in human populations. 21 refs.

  16. Elemental Impurities in Nigerian Pediatric Syrups: Mercury in Violation of Standard Guidelines.

    PubMed

    Orisakwe, Orish Ebere; Roberts, Irosanga Itamuno; Bagbi, Baribefe Monday

    2016-01-01

    Studies on the human exposure to elemental impurities like antimony, tin, and mercury pharmaceutical products in the African environment are scarce and limited. In this study, we determined the concentrations of these elemental impurities in 28 different brands of commonly used pediatric syrups, purchased randomly from patent medicine retail outlets in Port Harcourt, Rivers State, Nigeria. The aim of this study was to compare the antimony, tin, and mercury levels in these pediatric syrups with the recommended limits of United States Pharmacopeia. Twenty-eight different pediatric syrups were randomly sampled and purchased using the market basket protocol from pharmacy shops in Port Harcourt, Rivers State, Nigeria in December 2010. Syrups were ashed before digestion using concentrated aqua regia, HCl: HNO3 (3:1), and antimony, tin, and mercury were analyzed using Unicam Atomic Absorption Spectrophotometer (AAS) Model 929. The ranges of heavy metal content in these pediatric syrups were 0.54-1.27, 0.86-2.56, and 0.97-5.13 μg/g for antimony, tin, and mercury, respectively. About 75% of the syrups exceeded the United States Pharmacopeia mercury limit of 1.5 μg/g. The estimated or calculated amounts of antimony, tin, and mercury in the 3 most likely administered syrups were 17.15, 64.20, and 34.60 μg of antimony, tin, and mercury, respectively. The daily intake or estimated amount from the ingestion of syrups excluding background exposure (μg metal·kg body weight·d) for a 15-kg child were 1.17, 2.31, and 4.28 for antimony, tin, and mercury, respectively. Mercury content in pediatric syrups may constitute a significant source of heavy metal exposure to children and may be of public health importance in Nigeria. PMID:23676346

  17. Evaluation of anti-herpetic and antioxidant activities, and cytotoxic and genotoxic effects of synthetic alkyl-esters of gallic acid.

    PubMed

    Savi, Luciane A; Leal, Paulo C; Vieira, Tiago O; Rosso, Rober; Nunes, Ricardo J; Yunes, Rosendo A; Creczynski-Pasa, Tânia B; Barardi, Célia R M; Simões, Cláudia M O

    2005-01-01

    The n-alkyl esters of gallic acid (CAS 13857-8) have a diverse range of uses as antioxidants in food, cosmetics and pharmaceutical industries. Pharmaceutical studies performed with these compounds have found that they have many therapeutic potentialities including anti-cancer, antiviral and antimicrobial properties. However, more interest has been devoted to their antioxidant activity due to the ability to scavenge and reduce reactive oxygen species (ROS) formation. In this study, gallic acid and 14 different alkyl gallates were tested. The cytotoxicity and anti-herpetic (HSV-1, KOS and 29-R strains) activity were studied by using the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide) colorimetric assay and the cell viability by using the Trypan blue dye exclusion method. The genotoxicity was studied by the Comet assay and the antioxidant activity by using the DPPH (1,1-diphenyl-2-picrylhydrazyl) radical scavenging and microsomal lipid peroxidation-inhibiting activities. The results showed that all the tested compounds have anti-herpetic activity at non cytotoxic concentrations with selectivity indices (SI = CC50/EC50) varying from 0.89 to 18.34, depending on the used HSV-1 strain. It was observed that all tested alkyl gallates showed some degree of genotoxicity, at the tested concentrations, except cetyl gallate, at 256.60 micromol/L (p <0.05, t-Student test), probably induced by ROS released by infected cells and/or by the alkyl gallates that were not antioxidants, at the tested concentrations, in which they demonstrated anti-herpetic activity. The hydroxyl groups can induce DNA damage due interactions with some metal ions, which are naturally present in the culture medium supplemented with fetal bovine serum, probably explaining the genotoxicity detected. However, the obtained results showed considerable antioxidant activity at smaller concentrations, when compared to quercetin which is considered as a reference drug due to its already described

  18. Evaluating the efficiency of advanced wastewater treatment: target analysis of organic contaminants and (geno-)toxicity assessment tell a different story.

    PubMed

    Magdeburg, Axel; Stalter, Daniel; Schlüsener, Michael; Ternes, Thomas; Oehlmann, Jörg

    2014-03-01

    At a pilot scale wastewater treatment plant ozonation and powdered activated carbon filtration were assessed for their efficacy to remove trace organic contaminants from secondary treated effluents. A chemical analysis of 16 organic compounds was accompanied by a comprehensive suite of in vitro and in vivo bioassays with the focus on genotoxicity to account for the potential formation of reactive oxidation products. In vitro experiments were performed with solid phase extracted water samples, in vivo experiments with native wastewater in a flow through test system on site at the treatment plant. The chemical evaluation revealed an efficient oxidation of about half of the selected compounds by more than 90% at an ozone dose of 0.7 g/g DOC. A lower oxidizing efficiency was observed for the iodinated X-ray contrast media (49-55%). Activated carbon treatment (20 mg/L) was less effective for the removal of most pharmaceuticals monitored. The umuC assay on genotoxicity delivered results with about 90% decrease of the effects by ozonation and slightly lower efficiency for PAC treatment. However, the Ames test on mutagenicity with the strain YG7108 revealed a consistent and ozone-dose dependent increase of mutagenicity after wastewater ozonation compared to secondary treatment. Sand filtration as post treatment step reduced the ozone induced mutagenicity only partly. Also the fish early life stage toxicity test revealed an increase in mortality after ozonation and a reduced effect after sand filtration. Only activated carbon treatment reduced the fish mortality compared to conventional treatment on control level. Likewise the in vivo genotoxicity detected with the comet assay using fish erythrocytes confirmed an increased (geno-)toxicity after ozonation, an effect decrease after sand-filtration and no toxic effects after activated carbon treatment. This study demonstrates the need for a cautious selection of methods for the evaluation of advanced (oxidative

  19. The use of microemulsion electrokinetic chromatography in pharmaceutical analysis.

    PubMed

    Miola, M F; Snowden, M J; Altria, K D

    1998-12-01

    The use of a single set of microemulsion electrokinetic chromatography (MEEKC) separation conditions has been assessed for its applicability in the analysis of a range of pharmaceutical compounds. Particular emphasis was placed on neutral or very hydrophobic compounds, which can be difficult to analyse by conventional capillary electrophoresis. The microemulsion employed for the majority of separations consisted of 0.81% w/w octane, 6.61% w/w 1-butanol, 3.31% w/w sodium dodecyl sulphate and 89.27% w/w 10 mM sodium tetraborate buffer. Good separations of methyl, ethyl, butyl and propyl hydroxybenzoates, and a range of ionic and neutral water soluble and insoluble compounds was achieved using a single set of separation conditions. A number of novel applications of MEEKC were developed included the simultaneous determination of the active components and preservatives in liquid formulation and determination of drug related impurities. Improved performance was obtained through use of internal standards and preparation of the samples dissolved in the microemulsion solution. Validation aspects such as linearity, repeatability, accuracy, injection precision and sensitivity were successfully assessed. PMID:9919981

  20. The Impact of Biotechnology on Pharmaceutics.

    ERIC Educational Resources Information Center

    Block, Lawrence H.

    1990-01-01

    The emergence of bioactive peptides and proteins as new drug species poses formidable problems for the pharmaceutical scientist. Implications for revision or change in undergraduate and graduate pharmaceutics curricula derive from the biopharmaceutical, pharmacokinetic, and physiochemical aspects of the new drug species, which differ from…

  1. Nanostructured materials in electroanalysis of pharmaceuticals.

    PubMed

    Rahi, A; Karimian, K; Heli, H

    2016-03-15

    Basic strategies and recent developments for the enhancement of the sensory performance of nanostructures in the electroanalysis of pharmaceuticals are reviewed. A discussion of the properties of nanostructures and their application as modified electrodes for drug assays is presented. The electrocatalytic effect of nanostructured materials and their application in determining low levels of drugs in pharmaceutical forms and biofluids are discussed.

  2. Biotech pharmaceuticals and biotherapy: an overview.

    PubMed

    Steinberg, F M; Raso, J

    1998-01-01

    Broadly, the history of pharmaceutical biotechnology includes Alexander Fleming"s discovery of penicillin in a common mold, in 1928, and the subsequent development-prompted by World War II injuries-of large-scale manufacturing methods to grow the organism in tanks of broth. Pharmaceutical biotechnology has since changed enormously. Two breakthroughs of the late 1970s became the basis of the modern biotech industry: the interspecies transplantation of genetic material, and the fusion of tumor cells and certain leukocytes. The cells resulting from such fusion-hybridomas-replicate endlessly and can be geared to produce specific antibodies in bulk. Modern pharmaceutical biotechnology encompasses gene cloning and recombinant DNA technology. Gene cloning comprises isolating a DNA-molecule segment that corresponds to a single gene and synthesizing ("copying") the segment. Recombinant DNA technology, or gene splicing, comprises altering genetic material outside an organism-for example, by inserting into a DNA molecule a segment from a very different DNA molecule-and making the altered material (recombinant DNA) function in living things. Recombinant DNA technology enables modifying microorganisms, animals, and plants so that they yield medically useful substances, particularly scarce human proteins (by giving animals human genes, for example). This review, however, focuses not on pharmaceutical biotechnology"s methods but on its products, notably recombinant pharmaceuticals. It describes various types of biotech pharmaceuticals, their safety and effectiveness relative to the safety and effectiveness of conventionally produced pharmaceuticals, and the regulation of biotech pharmaceuticals.

  3. Pharmaceutical experiment aboard STS-67 mission

    NASA Technical Reports Server (NTRS)

    1995-01-01

    Astronaut William G. Gregory, pilot, works with a pharmaceutical experiment on the middeck of the Earth-orbiting Space Shuttle Endeavour during the STS-67 mission. Commercial Materials Dispersion Apparatus Instruments Technology Associates Experiments (CMIX-03) includes not only pharmaceutical, but also biotechnology, cell biology, fluids, and crystal growth investigation

  4. Synthetic biology advances for pharmaceutical production

    PubMed Central

    Breitling, Rainer; Takano, Eriko

    2015-01-01

    Synthetic biology enables a new generation of microbial engineering for the biotechnological production of pharmaceuticals and other high-value chemicals. This review presents an overview of recent advances in the field, describing new computational and experimental tools for the discovery, optimization and production of bioactive molecules, and outlining progress towards the application of these tools to pharmaceutical production systems. PMID:25744872

  5. Antiproliferative and genotoxic effects of Mikania glomerata (Asteraceae).

    PubMed

    Dalla Nora, Gracieli; Pastori, Tamara; Laughinghouse, Haywood Dail; Do Canto-Dorow, Thais Scotti; Tedesco, Solange Bosio

    2010-12-01

    Mikania glomerata is a plant used in Brazilian traditional medicine, known as 'guaco'. It possesses anti-inflammatory properties and the aqueous extracts of its leaves are indicated for the treatment of diseases of the respiratory tract. This study aimed at evaluating the antiproliferative and genotoxic effect of Mikania glomerata leaf infusions on the cell cycle of onion. The material used was collected in the native environment from Rio Grande do Sul State, Brazil. Aqueous extracts through infusions were prepared in two concentrations: 4g/L (usual concentration) and 16g/L (4x more concentrated) of each of the populations. Two groups of four onion bulbs for each plant population were used plus a control group. The rootlets were fixed in ethanol-acetic acid (3:1), conserved in ethanol 70% and slides were prepared using the squashing technique colored with orcein 2%. The cells were observed and analyzed during cell cycle. Per group of bulbs, 2000 cells were analyzed, and the mean values of the cell number of each of the phases of the cell cycle were calculated, determining the mitotic index (MI). Statistic analyses of the data were carried out by the x2 ( p= 0.05) test. We conclude that M. glomerata presents both antiproliferative and genotoxic activity. PMID:21443139

  6. The role of oxidative stress in nickel and chromate genotoxicity.

    PubMed

    Costa, Max; Salnikow, Konstantin; Sutherland, Jessica E; Broday, Limor; Peng, Wu; Zhang, Qunwei; Kluz, Thomas

    2002-01-01

    Some general principles regarding oxidative stress and molecular responses to toxic metals are presented in this manuscript. The remainder of the manuscript, however, will focus on the role of oxidative stress in particulate nickel-induced genetic damage and mutations. The phagocytosis of particulate nickel compounds and the dissolution of the particles inside the cell and the resulting oxidative stress produced in the nucleus is a key component of the nickel carcinogenic mechanism. The crosslinking of amino acids to DNA by nickel that does not involve direct participation of nickel in a ternary complex but nickel-induced oxidative stress will be discussed as well. The selective ability of particulate nickel compounds to silence the expression of genes located near heterochromatin and the effect of vitamin E on the genotoxicity and mutations induced by particulate and soluble nickel compounds will also be discussed. Particulate nickel compounds have been shown to produce more oxidative stress than water-soluble nickel compounds. In addition to nickel, the role of oxidative stress in chromate-induced genotoxicity will also be discussed with particular attention directed to the effects of vitamin E on mutations and chromosomal aberrations inducedby chromate.

  7. Neurologic dysfunction and genotoxicity induced by low levels of chlorpyrifos.

    PubMed

    Muller, Mariel; Hess, Leonardo; Tardivo, Agostina; Lajmanovich, Rafael; Attademo, Andres; Poletta, Gisela; Simoniello, Maria Fernanda; Yodice, Agustina; Lavarello, Simona; Chialvo, Dante; Scremin, Oscar

    2014-12-01

    Chlorpyrifos (CPF) is an organophosphorus cholinesterase inhibitor widely used as an insecticide. Neuro and genotoxicity of this agent were evaluated following daily subcutaneous injections at 0.1, 1 and 10mg/kg or its vehicle to laboratory rats during one week, at the end of which somatosensory evoked potentials (SEP) and power spectrum of the electroencephalogram (EEGp) were recorded under urethane anesthesia. In another group of conscious animals, auditory startle reflex (ASR) was evaluated followed, after euthanasia, with measurements of plasma B-esterases, and genotoxicity with the alkaline comet assay (ACA) at the same CPF doses. The results indicated a CPF dose related inhibition of B-esterases. Enhanced inhibition of the ASR by a subthreshold pre-pulse was observed at all doses and ACA showed a significant higher DNA damage than vehicle controls in animals exposed to 10mg/kg CPF. A trend to higher frequencies of EEGp and an increase in amplitude of the first negative wave of the SEP were found at all doses. The first positive wave of the SEP decreased at the CPF dose of 10mg/kg. In summary, a shift to higher EEG frequencies and alterations of somatosensory and auditory input to the central nervous system were sensitive manifestations of CPF toxicity, associated with depression of B-esterases. The changes in electrical activity of the cerebral cortex and DNA damage observed at doses that do not elicit overt toxicity may be useful in the detection of CPF exposure before clinical signs appear.

  8. In vivo genotoxicity assessment of acrylamide and glycidyl methacrylate.

    PubMed

    Dobrovolsky, Vasily N; Pacheco-Martinez, M Monserrat; McDaniel, L Patrice; Pearce, Mason G; Ding, Wei

    2016-01-01

    Acrylamide (ACR) and glycidyl methacrylate (GMA) are structurally related compounds used for making polymers with various properties. Both chemicals can be present in food either as a byproduct of processing or a constituent of packaging. We performed a comprehensive evaluation of ACR and GMA genotoxicity in Fisher 344 rats using repeated gavage administrations. Clastogenicity was measured by scoring micronucleated (MN) erythrocytes from peripheral blood, DNA damage in liver, bone marrow and kidneys was measured using the Comet assay, and gene mutation was measured using the red blood cell (RBC) and reticulocyte Pig-a assay. A limited histopathology evaluation was performed in order to determine levels of cytotoxicity. Doses of up to 20 mg/kg/day of ACR and up to 250 mg/kg/day of GMA were used. ACR treatment resulted in DNA damage in the liver, but not in the bone marrow. While ACR was not a clastogen, it was a weak (equivocal) mutagen in the cells of bone marrow. GMA caused DNA damage in the cells of bone marrow, liver and kidney, and induced MN reticulocytes and Pig-a mutant RBCs in a dose-dependent manner. Collectively, our data suggest that both compounds are in vivo genotoxins, but the genotoxicity of ACR is tissue specific.

  9. Genotoxicity Assessment of Erythritol by Using Short-term Assay

    PubMed Central

    Chung, Young-Shin

    2013-01-01

    Erythritol is a sugar alcohol that is widely used as a natural sugar substitute. Thus, the safety of its usage is very important. In the present study, short-term genotoxicity assays were conducted to evaluate the potential genotoxic effects of erythritol. According to the OECD test guidelines, the maximum test dose was 5,000 μg/plate in bacterial reverse mutation tests, 5,000 μg/ml in cell-based assays, and 5,000 mg/kg for in vivo testing. An Ames test did not reveal any positive results. No clastogenicity was observed in a chromosomal aberration test with CHL cells or an in vitro micronucleus test with L5178Y tk+/− cells. Erythritol induced a marginal increase of DNA damage at two high doses by 24 hr of exposure in a comet assay using L5178Y tk+/− cells. Additionally, in vivo micronucleus tests clearly demonstrated that oral administration of erythritol did not induce micronuclei formation of the bone marrow cells of male ICR mice. Taken together, our results indicate that erythritol is not mutagenic to bacterial cells and does not cause chromosomal damage in mammalian cells either in vitro or in vivo. PMID:24578795

  10. Argentine folk medicine: genotoxic effects of Chenopodiaceae family.

    PubMed

    Gadano, A B; Gurni, A A; Carballo, M A

    2006-01-16

    Chenopodium ambrosioides L. and Chenopodium multifidum L. (Chenopodiaceae), common name: Paico, are medicinal plants. They are aromatic shrubs growing in South America. For centuries, they have been used due to its medicinal properties. However, there are few reports in literature about the genotoxic effects of these plants. There for, the aim of these work is the evaluation of genetic damage induced by decoction and infusion of this plants which were assayed in different concentrations (1, 10, 100, 1,000 microL extract/mL culture), by addition of the extract to human lymphocyte cell cultures, negative controls were included. The endpoints evaluated were chromosomal aberrations (CA), sister chromatid exchanges (SCE), cell proliferation kinetics (CPK) and mitotic index (MI). The repeated measure analysis of variance was used for statistic evaluation of the results. The results showed: (a) statistical increase in the percentage of cells with CA and in the frequency of SCE when cultures were exposed to both aromatic plants, (b) a decrease in MI of both Paicos assayed, although no modification in the CPK values was observed, (c) no effect was noticed in the analysis of Chenopodium album L., which was used as negative control of the essential oil. These results suggest a cyto and genotoxic effect of Chenopodium ambrosioides and Chenopodium multifidum aqueous extracts related to the essential oil of the plant (as Chenopodium album did not perform).

  11. Insecticidal, mutagenic and genotoxic evaluation of annonaceous acetogenins.

    PubMed

    Alvarez Colom, Olga; Salvatore, Analia; Willink, Eduardo; Ordóñez, Roxana; Isla, María I; Neske, Adriana; Bardón, Alicia

    2010-03-01

    Annonaceous acetogenins represent a class of bioactive compounds whose primary mode of action is the inhibition of NADH-ubiquinone oxidoreductase (Mitochondrial Complex I). Given the potential pesticidal use of these compounds, we evaluated the effects of seven acetogenins: squamocin (1), molvizarin (2), itrabin (3), almuñequin (4), cherimolin-1 (5), cherimolin-2 (6), and tucumanin (7) isolated from Annona cherimolia Mill. against Ceratitis capitata Wiedemann (Tephritidae). These acetogenins did not display insecticidal action at 250 microg of treatment per g of adult diet. However, the oviposition capacity of C. capitata females was significantly altered by some of the acetogenins at this concentration. The most potent compounds were itrabin, molvizarin and squamocin. Moreover, significant differences were detected in the preference of oviposition sites when itrabin and squamocin were spread on the surface of artificial fruits at doses of 30 microg/cm2. Additionally, we investigated the mutagenic effects displayed by itrabin, as well as the phytotoxic and genotoxic action of squamocin and itrabin. Both compounds displayed slight phytotoxic and genotoxic effects on roots of Allium cepa at 2.5 microg/mL though no mutagenic effects were detected at 0.25, 0.5 and 2.5 microg/mL on Salmonella typhimurium strains TA98 and TA100. PMID:20420314

  12. Genotoxic and antiapoptotic effect of nicotine on human gingival fibroblasts.

    PubMed

    Argentin, Gabriella; Cicchetti, Rosadele

    2004-05-01

    Growing evidence suggests that nicotine, the addictive component of cigarettes, can have a direct role in tumor development by enhancing cell proliferation and impairing apoptotic process in certain types of human cancer cell lines. Since the correlation between apoptosis and DNA damage is already well documented, we investigated the response of human gingival fibroblasts (HGFs) to nicotine exposure by examining its effect on DNA damage induction and apoptotic process in parallel. To assess the genotoxicity of this drug, the cytokinesis-block micronucleus (CBMN) test was performed. Treatment of HGFs with nicotine, at a concentration of 1 microM, caused a statistically significant increase of micronucleus (MN) frequency at the tested time intervals, while no change was detected in cell growth under the same conditions. Furthermore, we found that preincubation of HGFs with 1 microM nicotine strongly attenuated staurosporine (STP)-induced apoptosis. Finally, we found that cultures exposed to nicotine showed an increase of reactive oxygen species, as determined by increased levels of 2,7-dichlorofluorescein (DCF). When cells were prelabeled with N-acetyl-cysteine (NAC), a substrate for glutathione synthesis, and catalase (CAT), the oxygen free radical scavenger, a significant reduction in cytogenetic damage was observed. Thus, for the first time, we report a concomitant genotoxic and antiapoptotic effect of nicotine in HGFs. PMID:14718647

  13. Genotoxicity monitoring of freshwater environments using caged crayfish (Astacus leptodactylus).

    PubMed

    Klobučar, Göran I V; Malev, Olga; Šrut, Maja; Štambuk, Anamaria; Lorenzon, Simonetta; Cvetković, Želimira; Ferrero, Enrico A; Maguire, Ivana

    2012-03-01

    Genotoxicity of freshwater pollution was assessed by measuring DNA damage in haemocytes of caged freshwater crayfish Astacus leptodactylus by the means of Comet assay and micronucleus test, integrated with the measurements of physiological (total protein concentration) and immunological (total haemocyte count) haemolymph parameters as biomarkers of undergone stress. Crayfish were collected at the reference site (River Mrežnica) and exposed in cages for 1 week at three polluted sites along the Sava River (Zagreb, Sisak, Krapje). The long term pollution status of these locations was confirmed by chemical analyses of sediments. Statistically significant increase in DNA damage measured by the Comet assay was observed at all three polluted sites comparing to the crayfish from reference site. In addition, native crayfish from the mildly polluted site (Krapje) cage-exposed on another polluted site (Zagreb) showed lower DNA damage than crayfish from the reference site exposed at the same location indicating adaptation and acclimatisation of crayfish to lower levels of pollution. Micronuclei induction showed similar gradient of DNA damage as Comet assay, but did not reach the statistical significance. Observed increase in total haemocyte count and total protein content in crayfish from polluted environments in the Sava River also confirmed stress caused by exposure to pollution. The results of this study have proved the applicability of caging exposure of freshwater crayfish A. leptodactylus in environmental genotoxicity monitoring using Comet assay and micronucleus test.

  14. Antioxidant, genotoxic and antigenotoxic activities of daphne gnidium leaf extracts

    PubMed Central

    2012-01-01

    Background Plants play a significant role in maintaining human health and improving the quality of human life. They serve humans well as valuable components of food, as well as in cosmetics, dyes, and medicines. In fact, many plant extracts prepared from plants have been shown to exert biological activity in vitro and in vivo. The present study explored antioxidant and antigenotoxic effects of Daphne gnidium leaf extracts. Methods The genotoxic potential of petroleum ether, chloroform, ethyl acetate, methanol and total oligomer flavonoid (TOF) enriched extracts from leaves of Daphne gnidium, was assessed using Escherichia coli PQ37. Likewise, the antigenotoxicity of the same extracts was tested using the “SOS chromotest test”. Antioxidant activities were studied using non enzymatic and enzymatic method: NBT/Riboflavine and xantine oxidase. Results None of the different extracts produced a genotoxic effect, except TOF extract at the lowest tested dose. Our results showed that D. gnidium leaf extracts possess an antigenotoxic effect against the nitrofurantoin a mutagen of reference. Ethyl acetate and TOF extracts were the most effective in inhibiting xanthine oxidase activity. While, methanol extract was the most potent superoxide scavenger when tested with the NBT/Riboflavine assay. Conclusions The present study has demonstrated that D. gnidium leaf extract possess antioxidant and antigenotoxic effects. These activities could be ascribed to compounds like polyphenols and flavonoid. Further studies are required to isolate the active molecules. PMID:22974481

  15. Genotoxicity of Nicotiana tabacum leaves on Helix aspersa.

    PubMed

    da Silva, Fernanda R; Erdtmann, Bernardo; Dalpiaz, Tiago; Nunes, Emilene; Ferraz, Alexandre; Martins, Tales L C; Dias, Johny F; da Rosa, Darlan P; Porawskie, Marilene; Bona, Silvia; da Silva, Juliana

    2013-07-01

    Tobacco farmers are routinely exposed to complex mixtures of inorganic and organic chemicals present in tobacco leaves. In this study, we examined the genotoxicity of tobacco leaves in the snail Helix aspersa as a measure of the risk to human health. DNA damage was evaluated using the micronucleus test and the Comet assay and the concentration of cytochrome P450 enzymes was estimated. Two groups of snails were studied: one fed on tobacco leaves and one fed on lettuce (Lactuca sativa L) leaves (control group). All of the snails received leaves (tobacco and lettuce leaves were the only food provided) and water ad libitum. Hemolymph cells were collected after 0, 24, 48 and 72 h. The Comet assay and micronucleus test showed that exposure to tobacco leaves for different periods of time caused significant DNA damage. Inhibition of cytochrome P450 enzymes occurred only in the tobacco group. Chemical analysis indicated the presence of the alkaloid nicotine, coumarins, saponins, flavonoids and various metals. These results show that tobacco leaves are genotoxic in H. aspersa and inhibit cytochrome P450 activity, probably through the action of the complex chemical mixture present in the plant. PMID:23885210

  16. Evaluation of environmental genotoxicity by comet assay in Columba livia.

    PubMed

    González-Acevedo, Anahi; García-Salas, Juan A; Gosálvez, Jaime; Fernández, José Luis; Dávila-Rodríguez, Martha I; Cerda-Flores, Ricardo M; Méndez-López, Luis F; Cortés-Gutiérrez, Elva I

    2016-01-01

    The concentrations of recognized or suspected genotoxic and carcinogenic agents found in the air of large cities and, in particular, developing countries, have raised concerns about the potential for chronic health effects in the populations exposed to them. The biomonitoring of environmental genotoxicity requires the selection of representative organisms as "sentinels," as well as the development of suitable and sensitive assays, such as those aimed at assessing DNA damage. The aim of this study was to evaluate DNA damage levels in erythrocytes from Columba livia living in the metropolitan area of Monterrey, Mexico, compared with control animals via comet assay, and to confirm the results via Micronuclei test (MN) and DNA breakage detection-fluorescence in situ hybridization (DBD-FISH). Our results showed a significant increase in DNA migration in animals from the area assayed compared with that observed in control animals sampled in non-contaminated areas. These results were confirmed by MN test and DBD-FISH. In conclusion, these observations confirm that the examination of erythrocytes from Columba livia via alkaline comet assay provides a sensitive and reliable end point for the detection of environmental genotoxicants.

  17. Argentine folk medicine: genotoxic effects of Chenopodiaceae family.

    PubMed

    Gadano, A B; Gurni, A A; Carballo, M A

    2006-01-16

    Chenopodium ambrosioides L. and Chenopodium multifidum L. (Chenopodiaceae), common name: Paico, are medicinal plants. They are aromatic shrubs growing in South America. For centuries, they have been used due to its medicinal properties. However, there are few reports in literature about the genotoxic effects of these plants. There for, the aim of these work is the evaluation of genetic damage induced by decoction and infusion of this plants which were assayed in different concentrations (1, 10, 100, 1,000 microL extract/mL culture), by addition of the extract to human lymphocyte cell cultures, negative controls were included. The endpoints evaluated were chromosomal aberrations (CA), sister chromatid exchanges (SCE), cell proliferation kinetics (CPK) and mitotic index (MI). The repeated measure analysis of variance was used for statistic evaluation of the results. The results showed: (a) statistical increase in the percentage of cells with CA and in the frequency of SCE when cultures were exposed to both aromatic plants, (b) a decrease in MI of both Paicos assayed, although no modification in the CPK values was observed, (c) no effect was noticed in the analysis of Chenopodium album L., which was used as negative control of the essential oil. These results suggest a cyto and genotoxic effect of Chenopodium ambrosioides and Chenopodium multifidum aqueous extracts related to the essential oil of the plant (as Chenopodium album did not perform). PMID:16219440

  18. Broccoli seed extract: Genotoxicity and subchronic toxicity studies.

    PubMed

    Zhou, Yu; Yang, Hui; Li, Yongning; Lynch, B; Jia, Xudong

    2015-10-01

    Potential health benefits have been attributed to broccoli consumption. Hence, there is potential for use of broccoli seed extract (BSE) in food or for use as a dietary supplement. To assess the potential safety of a BSE product, three genotoxicity experiments, including an Ames, in vivo mouse micronucleus, and in vivo mouse sperm abnormality assay, were carried out. BSE was subject to an acute oral toxicity test and was evaluated in a 30-day feeding study in rats. BSE showed no mutagenic activity in the Ames assay and no evidence of genotoxic potential in the in vivo assays at doses up to 10 g/kg body weight (bw). The LD50 of BSE in rats was >10 g/kg bw/d. In the 30-day feeding study, in which BSE was administered in the diet to provide doses of 0, 0.3, 1.0, or 3.0 g/kg bw/d, no toxicological significant effects were noted on body weight, body weight gain, organ weights, or on the results of hematological, clinical chemistry and histopathological evaluations. The no-observed-adverse-effect level was considered to be 3.0 g/kg bw/d, the highest dose tested. Collectively, these results support the safe use of BSE as a food ingredient or product. PMID:26271574

  19. Neurobehavioral and genotoxic evaluation of (-)-linalool in mice.

    PubMed

    Coelho, Vanessa; Mazzardo-Martins, Leidiane; Martins, Daniel Fernandes; Santos, Adair Roberto Soares; da Silva Brum, Lucimar Filot; Picada, Jaqueline Nascimento; Pereira, Patrícia

    2013-10-01

    (-)-Linalool is a monoterpene compound commonly found as a major component of the essential oil of several aromatic species. It has been shown to exert several actions in the central nervous system (CNS) and is able to inhibit glutamate receptors. This study investigated the effect of (-)-linalool in depression and genotoxicity models. Mice were given (-)-linalool (10, 50, 100 or 200 mg/kg i.p.) and were evaluated using the tail suspension test (TST). Genotoxic and antigenotoxic effects in blood and brain were investigated using the alkaline comet assay. In the TST, the animals that received doses of 100 and 200 mg/kg presented a decrease in immobility times. No increase in DNA damage was observed in either tissue, and resistance to DNA oxidative damage induced by hydrogen peroxide did not increase. (-)-Linalool showed an antidepressant-like activity in the TST and was unable to cause damage/protection to DNA in brain tissue and peripheral blood. This investigation provides evidence of an important effect of (-)-linalool on the CNS; however, more studies are necessary to support its possible clinical uses.

  20. Genotoxicity and subchronic oral toxicity of L-ornithine monohydrochloride.

    PubMed

    Ishida, Shigeru; Sarada, Miko; Seki, Hiroshi; McGirr, Larry; Lau, Annette; Morishita, Koji

    2013-12-01

    L-Ornithine monohydrochloride was evaluated in two in vitro genotoxicity assays and a rat 90-day oral toxicity study. No evidence of genotoxicity was observed in the reverse bacterial mutation assay or the chromosome aberration test at doses of up to 5000 μg/plate or 1686 μg/mL, respectively, both in the presence and absence of metabolic activation. Rats were administered L-ornithine monohydrochloride at dietary concentrations of 0 (basal diet), 1.25%, 2.5%, or 5.0% for 90 days. No changes in body weight, food consumption, ophthalmoscopy, or hematology were observed. Transient increases in water intake and urinary volume, and a decrease in specific gravity were observed in males receiving 5.0% L-ornithine monohydrochloride; however, these were likely attributable to the central role of ornithine in the urea cycle and the consequent increase in urea production. A decrease in serum chloride concentration and an increase in urinary chloride excretion were observed; however, these were likely attributable to administration of the hydrochloride salt of ornithine and were not considered to be of any toxicological significance. No remarkable findings were noted at necropsy. Based on the results of the study, a no-observed-adverse effect level (NOAEL) of 3445 and 3986 mg/kg body weight/day was established for male and female rats. PMID:23994624