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Sample records for pharmaceutical genotoxic impurities

  1. Identification, control strategies, and analytical approaches for the determination of potential genotoxic impurities in pharmaceuticals: a comprehensive review.

    PubMed

    Reddy, Ambavaram Vijaya Bhaskar; Jaafar, Jafariah; Umar, Khalid; Majid, Zaiton Abdul; Aris, Azmi Bin; Talib, Juhaizah; Madhavi, Gajulapalle

    2015-03-01

    Potential genotoxic impurities in pharmaceuticals at trace levels are of increasing concern to both pharmaceutical industries and regulatory agencies due to their possibility for human carcinogenesis. Molecular functional groups that render starting materials and synthetic intermediates as reactive building blocks for small molecules may also be responsible for their genotoxicity. Determination of these genotoxic impurities at trace levels requires highly sensitive and selective analytical methodologies, which poses tremendous challenges on analytical communities in pharmaceutical research and development. Experimental guidance for the analytical determination of some important classes of genotoxic impurities is still unavailable in the literature. Therefore, the present review explores the structural alerts of commonly encountered potential genotoxic impurities, draft guidance of various regulatory authorities in order to control the level of impurities in drug substances and to assess their toxicity. This review also describes the analytical considerations for the determination of potential genotoxic impurities at trace levels and finally few case studies are also discussed for the determination of some important classes of potential genotoxic impurities. It is the authors' intention to provide a complete strategy that helps analytical scientists for the analysis of such potential genotoxic impurities in pharmaceuticals.

  2. A rationale for determining, testing, and controlling specific impurities in pharmaceuticals that possess potential for genotoxicity.

    PubMed

    Müller, Lutz; Mauthe, Robert J; Riley, Christopher M; Andino, Marta M; Antonis, David De; Beels, Chris; DeGeorge, Joseph; De Knaep, Alfons G M; Ellison, Dean; Fagerland, Jane A; Frank, Rebecca; Fritschel, Betsy; Galloway, Sheila; Harpur, Ernie; Humfrey, Charles D N; Jacks, Alexander S; Jagota, Nirdosh; Mackinnon, John; Mohan, Ganapathy; Ness, Daniel K; O'Donovan, Michael R; Smith, Mark D; Vudathala, Gopi; Yotti, Larry

    2006-04-01

    The synthesis of pharmaceutical products frequently involves the use of reactive reagents and the formation of intermediates and by-products. Low levels of some of these may be present in the final drug substance and drug product as impurities. Such chemically reactive impurities may have at the same time the potential for unwanted toxicities including genotoxicity and carcinogenicity and hence can have an impact on product risk assessment. This paper outlines a procedure for testing, classification, qualification, toxicological risk assessment, and control of impurities possessing genotoxic potential in pharmaceutical products. Referencing accepted principles of cancer risk assessment, this document proposes a staged threshold of toxicological concern (TTC) approach for the intake of genotoxic impurities over various periods of exposure. This staged TTC is based on knowledge about tumorigenic potency of a wide range of genotoxic carcinogens and can be used for genotoxic compounds, for which cancer data are limited or not available. The delineated acceptable daily intake values of between approximately 1.5 microg/day for approximately lifetime intake and approximately 120 microg/day for < or = 1 month are virtually safe doses. Based on sound scientific reasoning, these virtually safe intake values do not pose an unacceptable risk to either human volunteers or patients at any stage of clinical development and marketing of a pharmaceutical product. The intake levels are estimated to give an excess cancer risk of 1 in 100,000 to 1 in a million over a lifetime, and are extremely conservative given the current lifetime cancer risk in the population of over 1 in 4 (http://seer.cancer.gov/statfacts/html.all.html). The proposals in this document apply to all clinical routes of administration and to compounds at all stages of clinical development. It is important to note that certain types of products, such as those for life-threatening indications for which there are no

  3. 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.

  4. Improved in silico prediction of carcinogenic potency (TD50) and the risk specific dose (RSD) adjusted Threshold of Toxicological Concern (TTC) for genotoxic chemicals and pharmaceutical impurities.

    PubMed

    Contrera, Joseph F

    2011-02-01

    The Threshold of Toxicological Concern (TTC) is a level of exposure to a genotoxic impurity that is considered to represent a negligible risk to humans. The TTC was derived from the results of rodent carcinogenicity TD50 values that are a measure of carcinogenic potency. The TTC currently sets a default limit of 1.5 μg/day in food contact substances and pharmaceuticals for all genotoxic impurities without carcinogenicity data. Bercu et al. (2010) used the QSAR predicted TD50 to calculate a risk specific dose (RSD) which is a carcinogenic potency adjusted TTC for genotoxic impurities. This promising approach is currently limited by the software used, a combination of MC4PC (www.multicase.com) and a Lilly Inc. in-house software (VISDOM) that is not available to the public. In this report the TD50 and RSD were predicted using a commercially available software, SciQSAR (formally MDL-QSAR, www.scimatics.com) employing the same TD50 training data set and external validation test set that was used by Bercu et al. (2010). The results demonstrate the general applicability of QSAR predicted TD50 values to determine the RSDs for genotoxic impurities and the improved performance of SciQSAR for predicting TD50 values.

  5. Control and analysis of alkyl and benzyl halides and other related reactive organohalides as potential genotoxic impurities in active pharmaceutical ingredients (APIs).

    PubMed

    Elder, D P; Lipczynski, A M; Teasdale, A

    2008-11-04

    This paper continues the review of the relevant scientific literature associated with the control and analysis of potential genotoxic impurities (PGIs) in active pharmaceutical ingredients (APIs). The initial review [D.P. Elder, A. Teasdale, A.M. Lipczynski, J. Pharm. Biomed. Anal. 46 (2008) 1-8.] focused on the specific class of sulfonate esters but in this instance reference is made to the analysis of alkyl and benzyl halides and other related reactive organohalide alkylating agents. Such reactive materials are commonly employed in pharmaceutical research and development as raw materials, reagents and intermediates in the chemical synthesis of new drug substances. Consequently a great deal of attention and effort is extended by the innovative and ethical pharmaceutical industry to ensure that appropriate and practicable control strategies are established during drug development to ensure residues of such agents, as potential impurities in new drug substances, are either eliminated or minimized to such an extent so as to not present a significant safety risk to volunteers and patients in clinical trials and beyond. The reliable trace analysis of such reactive organohalides is central to such control strategies and invariably involves a state-of-the-art combination of high-resolution separation science techniques coupled to sensitive and selective modes of detection. This article reports on the most recent developments in the regulatory environment, overall strategies for the control of alkylating agents and the latest developments in analysis culminating in a literature review of analytical approaches. The literature is sub-categorized by separation technique (gas chromatography (GC), high-performance liquid chromatography (HPLC), thin layer chromatography (TLC) and capillary zone electrophoresis (CZE)) and further tabulated by API type and impurity with brief method details and references. As part of this exercise, a selection of relevant pharmacopoeial

  6. 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.

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

    PubMed

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

    2008-08-01

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

  8. 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.

  9. 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

  10. 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

  11. In silico and in vitro genotoxicity evaluation of descarboxyl levofloxacin, an impurity in levofloxacin.

    PubMed

    Zhu, Qingfen; Li, Tao; Wei, Xia; Li, Jun; Wang, Weijian

    2014-07-01

    It is important to establish the safety of impurities in drug substances or drug products. The assessment of genotoxicity of impurities and the determination of acceptable limits for genotoxic impurities was addressed in some recent guidances as a difficult issue. Descarboxyl levofloxacin is an impurity isolated from levofloxacin, which may impose a risk without associated benefit. However, there is insufficient toxic information about descarboxyl levofloxacin. This study investigated the genotoxicity of this impurity by in silico and in vitro methods. We used Derek, a commercial structure-activity relationship software package, as an in silico tool. The results showed that there was a structural alert (quinoline) in this impurity. Then, the in vitro genotoxicity of descarboxyl levofloxacin was investigated by a modified Ames test and by a chromosomal aberration test, using Chinese hamster lung (CHL) cells. Both assays were conducted in the presence or absence of S-9 mix. The results showed that the test impurity was not mutagenic in the Ames test (31.25-500 μg/plate). Whereas there was a statistically significant increase in the number of metaphase CHL cells with structural aberrations at the concentration of 1 mg/mL with S-9 mix, the aberrations rate was 7.5%. It did not significantly increase the number of structural aberration in CHL cells in the presence (at 250 and 500 μg/mL) or absence of S-9 mix. Based on these assays, descarboxyl levofloxacin could be controlled as a nongenotoxic impurity.

  12. Sensitive derivatization methods for the determination of genotoxic impurities in drug substances using hyphenated techniques.

    PubMed

    Raman, Nanduri V V S S; Prasad, Adapa V S S; Reddy, Kura Ratnakar

    2014-02-01

    Six sensitive derivatization methods for the determination of genotoxic impurities in selected drug substances were developed using hyphenated techniques. Some of the raw materials, reagents and reaction intermediates of the selected drug substances were identified as genotoxic impurities through DEREK software for windows. The genotoxic impurities which are amenable for derivatization were selected as substrates. Derivatizing agents were selected based on the functional groups of the genotoxic impurities. The chemistry involved in the derivatization was explained with suitable mechanisms. An appropriate hyphenated technique viz. LC-MS and GC-MS was opted based on the sensitivity and aromaticity of the derivatized genotoxic impurities. All the methods were validated as per International Conference on Harmonization guidelines. Correlation coefficient values were found about 0.99. The obtained % R.S.D values from replicate injections in the range of 2.3-4.8 and % recoveries of the added impurities in the range of 83.7-101.7 ensured the precision and accuracy, respectively.

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

    PubMed

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

    2013-05-01

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

  14. Development of chromatographic methods for the determination of genotoxic impurities in cloperastine fendizoate.

    PubMed

    García, Antonia; Rupérez, Francisco J; Ceppa, Florencia; Pellati, Federica; Barbas, Coral

    2012-03-05

    The classification of an impurity of a drug substance as genotoxic means that the "threshold of toxicological concern" (TTC) value of 1.5 μg/day intake, considered to be associated with an acceptable risk, should be the admissible limit in the raw material and that leads to new analytical challenges. In this study, reliable chromatographic methods were developed and applied as limit tests for the control of three genotoxic impurities (GTIs) in cloperastine fendizoate, drug widely used as an antitussive active pharmaceutical ingredient (API). In particular, GC-MS was applied to the determination of one alkyl halide (2-chloroethanol, 2-CE), while HPLC-DAD was selected for the analysis of two sulfonate esters (methyl p-toluenesulfonate, MPTS, and 2-chloroethyl p-toluenesulfonate, CEPTS). Regarding GC-MS, strong anion-exchange (SAX)-SPE was applied to remove fendizoate from the sample solutions, due its low volatility and its high amount in the raw material. The GC-MS analysis was performed on a Factor Four VF-23 ms capillary column (30 m × 0.25 mm I.D., film thickness 0.25 μm, Varian). Single ion-monitoring (SIM) detection mode was set at m/z 80. In the case of HPLC-DAD, a suitable optimization of the chromatographic conditions was carried out in order to obtain a good separation of the impurity peaks from the drug substance peaks. The optimized method utilizes a SymmetryShield RP(8) column (250 mm × 4.6 mm, 5 μm, Waters) kept at 50°C, with phosphate buffer (pH 3.0; 10 mM)-methanol (containing 10% ACN) (45:55, v/v) as the mobile phase, at the flow-rate of 1.7 mL/min and UV detection at 227 nm. The required sensitivity level was achieved by injecting 80 μL of sample solution, purified from fendizoate by SAX-SPE, followed by a 1:1 (v/v) dilution of the SPE eluate with water. For both GC-MS and HPLC-DAD, the method validation was performed in relation to specificity and limit of detection (LOD), as required by ICH guidelines in relation to limit assays. The

  15. Impurities in Drug Products and Active Pharmaceutical Ingredients.

    PubMed

    Kątny, M; Frankowski, M

    2016-09-29

    Analytical methods should be selective and fast. In modern times, scientists strive to meet the criteria of green chemistry, so they choose analytical procedures that are as short as possible and use the least toxic solvents. It is quite obvious that the products intended for human consumption should be characterized as completely as possible. The safety of a drug is dependent mainly on the impurities that it contains. High pressure liquid chromatography and ultra-high pressure liquid chromatography have been proposed as the main techniques for forced degradation and impurity profiling. The aim of this article was to characterize the relevant classification of drug impurities and to review the methods of impurities determination for atorvastatin (ATV) and duloxetine (DLX) (both in active pharmaceutical ingredients and in different dosage forms). These drugs have an impact on two systems of the human body: cardiac and nervous. Simple characteristics of ATV and DLX, their properties and specificity of action on the human body, are also included in this review. The analyzed pharmaceuticals-ATV (brand name Lipiron) and DLX (brand name Cymbalta)-were selected for this study based on annual rankings prepared by Information Medical Statistics.

  16. A systematic assessment of genotoxicity on pivaloylacylation-7ADCA-a wide existing antibiotic impurity.

    PubMed

    Luo, Qingying; Li, Yang; Zhang, Zunzhen

    2014-01-01

    The safety of antibiotics has been becoming an important worldwide concern. As an inevitable and widespread existing impurity of β-lactam antibiotics, pivaloylacylation-7ADCA may has potential impact on drug safety. However, due to the restriction on traditional drug production technique, purified pivaloylacylation-7ADCA cannot be acquired and thus the toxicity of pivaloylacylation-7ADCA remains completely unknown. In this study, we firstly assessed the genotoxicity of newly purified pivaloylacylation-7ADCA. A series of well-designed experiments, including bacterial reverse mutation assay (Ames assay), mouse lymphoma assay (TK gene mutation test), chromosomal aberration assay, in vivo mouse micronucleus test and single cell gel electrophoresis assay (comet assay), were performed in genotoxicity assessment of pivaloylacylation-7ADCA at three different genetic endpoints, i.e. gene mutation, chromosome aberration or breakage, and DNA strand breaks. No genotoxicity were observed at all tested genetic endpoints, suggesting that pivaloylacylation-7ADCA has no mutagenic effect. To our knowledge, this is the first systematic assessment on the toxicity of newly synthesized pivaloylacylation-7ADCA, which should be an important part of the drug safety evaluation of β-lactam antibiotics. Moreover, our study is expected to serve as a reference for the genotoxicity assessment of other antibiotic impurities, by using purified impurity as test sample and by combining a group of well-designed genotoxic assays with different species, major genetic endpoints and in vivo/vitro tests.

  17. Analysis of pharmaceutical impurities in the methamphetamine crystals seized for drug trafficking in Korea.

    PubMed

    Choe, Sanggil; Heo, Sewoong; Choi, Hyeyoung; Kim, Eunmi; Chung, Heesun; Lee, Jaesin

    2013-04-10

    Some methamphetamine (MA) crystals contain pharmaceutical impurities. They often come from the co-ingredients of cold drugs used for extracting ephedrine or pseudoephedrine. Though these impurities are not so commonly encountered, they reflect the trends in precursor chemicals and manufacturing sources. As a result of monitoring impurities in the MA crystals seized in Korea during 2006-2011, 10 species of pharmaceutical impurities were identified by gas chromatography-flame ionization detection and gas chromatography-mass spectrometry. They may be co-ingredients of the legal drugs used as a source of ephedrine or pseudoephedrine. In contrast, some of them are presumed to be adulterants added during or after clandestine synthesis. It is interesting that some of these have been identified in the MA crystals seized in other countries in the same year. Species of pharmaceutical impurities in the MA crystals increased particularly in 2010, indicating a change in precursor chemicals and/or manufacturing sources.

  18. 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.

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

    PubMed

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

    2010-01-01

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

  20. Determination of impurities and counterions of pharmaceuticals by capillary electromigration methods.

    PubMed

    Stěpánová, Sille; Kašička, Václav

    2014-08-01

    The review presents a survey of recent applications of high-performance capillary electromigration methods-capillary zone electrophoresis, nonaqueous capillary electrophoresis, capillary isotachophoresis, micellar electrokinetic chromatography, microemulsion electrokinetic chromatography and capillary electrochromatography-for the determination of impurities of pharmaceuticals, including chiral impurities, for the period 2007-2013. In addition, due to the missing evaluation of the determination of counterions of pharmaceuticals by capillary electromigration methods in the last 20 years, the publications dealing with this topic since 1995 are included in this review. General aspects of both these types of applications of capillary electromigration methods in pharmaceutical analysis are discussed, and detailed experimental conditions used for determination of various chemical impurities and counterions of many particular drugs are described.

  1. 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.

  2. Guidelines and pharmacopoeial standards for pharmaceutical impurities: overview and critical assessment.

    PubMed

    Snodin, David J; McCrossen, Sean D

    2012-07-01

    ICH/regional guidances and agency scrutiny provide the regulatory framework for safety assessment and control of impurities in small-molecule drug substances and drug products. We provide a critical assessment of the principal impurity guidances and, in particular, focus on deficiencies in the derivation of the threshold of toxicological concern (TTC) as applied to genotoxic impurities and the many toxicological anomalies generated by following the current guidelines on impurities. In terms of pharmacopoeial standards, we aim to highlight the fact that strictly controlling numerous impurities, especially those that are minor structural variants of the active substance, is likely to produce minimal improvements in drug safety. It is believed that, wherever possible, there is a need to simplify and rebalance the current impurity paradigm, moving away from standards derived largely from batch analytical data towards structure-based qualification thresholds and risk assessments using readily available safety data. Such changes should also lead to a minimization of in vivo testing for toxicological qualification purposes. Recent improvements in analytical techniques and performance have enabled the detection of ever smaller amounts of impurities with increased confidence. The temptation to translate this information directly to the regulatory sphere without any kind of safety evaluation should be resisted.

  3. AOX contamination status and genotoxicity of AOX-bearing pharmaceutical wastewater.

    PubMed

    Xie, Yawei; Chen, Lujun; Liu, Rui

    2017-02-01

    Adsorbable organic halogens (AOX) are a general indicator for the total amount of compounds containing organically bonded halogens. AOX concentrations and components were investigated along the wastewater treatment process in four large-scale pharmaceutical factories of China, and genotoxicity based on the SOS/umu test was also evaluated. The results showed that AOX concentrations in wastewater of four factories ranged from 4.6 to 619.4mg/L, which were high but greatly different owing to differences in the raw materials and products. The wastewater treatment process removed 50.0%-89.9% of AOX, leaving 1.3-302.5mg/L AOX in the effluents. Genotoxicity levels ranged between 2.1 and 68.0μg 4-NQO/L in the raw wastewater and decreased to 1.2-41.2μg 4-NQO/L in the effluents of the wastewater treatment plants (WWTPs). One of the main products of factory I, ciprofloxacin, was identified as the predominant contributor to its genotoxicity. However, for the other three factories, no significant relationship was observed between genotoxicity and detected AOX compounds.

  4. General stress, detoxification pathways, neurotoxicity and genotoxicity evaluated in Ruditapes philippinarum exposed to human pharmaceuticals.

    PubMed

    Aguirre-Martínez, Gabriela V; DelValls, T Angel; Martín-Díaz, M Laura

    2016-02-01

    A battery of biomarkers was evaluated on Ruditapes philippinarum exposed during 14 days to caffeine, ibuprofen, carbamazepine and novobiocin (0.1, 1, 5, 10, 15, and 50µgL(-1)). The battery included general stress (lysosomal membrane stability - LMS) analysed in the hemolymph, and biochemical biomarkers analysed in digestive gland tissues including: biomarkers of phase I (etoxyresorufin O-deethylase - EROD, dibenzylfluorescein dealkylase - DBF), phase II (gluthathione-S-transferase - GST), oxidative stress (gluthathione reductase - GR, gluthathione peroxidase - GPX, lipid peroxidation - LPO), neurotoxicity (acetylcholinesterase activity - AChE), and genotoxicity (DNA damage). Pharmaceuticals tested induced the sublethal responses (even at the environmental range 0.1µgL(-1)). At this low concentration; caffeine, ibuprofen and carbamazepine decreased the LMS significantly compared with controls (p<0.05). The four compounds induced significantly the detoxification metabolism and oxidative stress (p<0.05). Neurotoxicity was noticed in clams exposed to caffeine and carbamazepine (p<0.05). Ibuprofen, carbamazepine and novobiocin produced genotoxic effects (p<0.05). Results from this research validate the use of biomarkers when assessing the effects of pharmaceuticals within a marine environmental risk assessment framework, using as a laboratory bioassay model the species R. philippinarum.

  5. 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

  6. 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.

  7. 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.

  8. Evaluation of mobile phase gradient supercritical fluid chromatography for impurity profiling of pharmaceutical compounds.

    PubMed

    Alexander, A J; Hooker, T F; Tomasella, F P

    2012-11-01

    The use of gradient supercritical fluid chromatography (SFC) for the impurity profiling of pharmaceutical products is not widely practiced. Historically, the limited advancement in SFC instrumentation and the lag in column development have resulted in marginal sensitivity, selectivity and reproducibility when compared with high performance liquid chromatography (HPLC). Using a recently developed commercial module, which allows an ordinary HPLC to be converted to a SFC system, a significant improvement in sensitivity (up to ~12-fold) has been obtained over previous studies. This has allowed for the first time a "real-world" head-to-head comparison of SFC to HPLC for impurity profiling of pharmaceutical products in a regulated environment. Retention time reproducibility and low level impurity detection were found to be comparable to reversed phase liquid chromatography (RPLC), that is, single digit %relative standard deviations (RSDs) were obtained for impurities present at less than 0.1 area%. Furthermore, these results were obtained with drug loading levels (≤2 mg/mL) that are not only comparable to those employed with HPLC, but are dictated by the limited solubility of many drug candidates. The elution of impurities was generally found to be orthogonal to that obtained with RPLC, but it was still challenging to find SFC conditions that would separate all of the components in the mixtures studied. In terms of enhancing selectivity, small amounts of mobile phase additives (0.1-1%) and temperature optimization were found to have a greater impact in SFC method development versus RPLC. However, unlike gradient RPLC, the relative changes in baseline noise and slope were found to be a complex function of the experimental conditions, with the largest differences in noise levels being generally observed for the widest and steepest gradients. It is likely that this gradient related noise is more apparent now because other sources of noise in SFC have been reduced

  9. A multispecies study to assess the toxic and genotoxic effect of pharmaceuticals: furosemide and its photoproduct.

    PubMed

    Isidori, Marina; Nardelli, Angela; Parrella, Alfredo; Pascarella, Luigia; Previtera, Lucio

    2006-05-01

    Pharmaceutical products for humans and animals, as well as their related metabolites end up in the aquatic environment after use. Recent investigations show that concentrations of pharmaceuticals are detectable in the order of ng/l-mug/l in municipal wastewater, groundwater and also drinking water. Little is known about the effects, and the hazard of long-term exposure to low concentrations of pharmaceuticals for non-target aquatic organisms. This study was designed to assess the ecotoxicity of furosemide, a potent diuretic agent, and its photoproduct in the aquatic environment. Bioassays were performed on bacteria, algae, rotifers and microcrustaceans to assess acute and chronic toxicity, while the SOS Chromotest and the Ames test were utilized to detect the genotoxic potential of the investigated compounds. A first approach to risk characterization was to calculate the environmental impact of furosemide by measured environmental concentration and predicted no effect concentration ratio (MEC/PNEC). To do so we used occurrence data reported in the literature and our toxicity results. The results showed that acute toxicity was in the order of mg/l for the crustaceans and absent for bacteria and rotifers. Chronic exposure to these compounds caused inhibition of growth population on the consumers, while the algae did not seem to be affected. A mutagenic potential was found for the photoproduct compared to the parental compound suggesting that byproducts ought to be considered in the environmental assessment of drugs. The risk calculated for furosemide suggested its harmlessness on the aquatic compartment.

  10. In silico prediction of genotoxicity.

    PubMed

    Wichard, Jörg D

    2016-12-12

    The in silico prediction of genotoxicity has made considerable progress during the last years. The main driver for the pharmaceutical industry is the ICH M7 guideline about the assessment of DNA reactive impurities. An important component of this guideline is the use of in silico models as an alternative approach to experimental testing. The in silico prediction of genotoxicity provides an established and accepted method that defines the first step in the assessment of DNA reactive impurities. This was made possible by the growing amount of reliable Ames screening data, the attempts to understand the activity pathways and the subsequent development of computer-based prediction systems. This paper gives an overview of how the in silico prediction of genotoxicity is performed under the ICH M7 guideline.

  11. 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

    2014-01-07

    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.

  12. A validated stability-indicating UPLC method for desloratadine and its impurities in pharmaceutical dosage forms.

    PubMed

    Rao, Dantu Durga; Satyanarayana, N V; Malleswara Reddy, A; Sait, Shakil S; Chakole, Dinesh; Mukkanti, K

    2010-02-05

    A novel stability-indicating gradient reverse phase ultra-performance liquid chromatographic (RP-UPLC) method was developed for the determination of purity of desloratadine in presence of its impurities and forced degradation products. The method was developed using Waters Aquity BEH C18 column with mobile phase containing a gradient mixture of solvents A and B. The eluted compounds were monitored at 280nm. The run time was 8min within which desloratadine and its five impurities were well separated. Desloratadine was subjected to the stress conditions of oxidative, acid, base, hydrolytic, thermal and photolytic degradation. Desloratadine was found to degrade significantly in oxidative and thermal stress conditions and stable in acid, base, hydrolytic and photolytic degradation conditions. The degradation products were well resolved from main peak and its impurities, thus proved the stability-indicating power of the method. 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 desloratadine in pharmaceutical dosage forms.

  13. 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.

  14. 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.

  15. An overview of recent applications of inductively coupled plasma-mass spectrometry (ICP-MS) in determination of inorganic impurities in drugs and pharmaceuticals.

    PubMed

    Nageswara Rao, R; Talluri, M V N Kumar

    2007-01-04

    The recent applications of inductively coupled plasma-mass spectrometry (ICP-MS) in determination of trace level inorganic impurities in drugs and pharmaceuticals have been reviewed. ICP-MS coupled with LC, GC and CE was used for speciation of heavy metals in pharmaceutical products. The review covers the period from 1995 to 2005 during which the technique was applied not only for determination of metallic impurities but also the assay of various trace elements in pharmaceuticals.

  16. 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.

  17. 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.

  18. 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.

  19. Simultaneous determination of the counter ion and possible impurity from the synthetic route in the pharmaceutical substance prasugrel hydrochloride.

    PubMed

    Maruszak, Wioleta; Cybulski, Marcin

    2015-02-01

    A fast and selective capillary electrophoresis method was developed and validated for the simultaneous determination of the hydrochloride and acetic acid content in prasugrel hydrochloride. Because of the poor chromophore, the indirect detection was chosen. Among different compositions studied as the background electrolyte, the pyromellitic acid with diethylamine (DEA) and myristyltrimethylammonium bromide (TTAB) was chosen. During the validation the specificity, linearity, accuracy, precision, range, and stability of the sample solution were confirmed. The results indicate that the method is suitable for the determination of the counter ion and impurity from the synthetic route of the pharmaceutical drug substance in the same assay.

  20. Quantification and structural elucidation of potential impurities in agomelatine active pharmaceutical ingredient.

    PubMed

    Liu, Yaxuan; Chen, Lei; Ji, Yibing

    2013-01-01

    Seven impurities in agomelatine drug substance were determined by a newly developed RP-HPLC method. Structures of potential impurities were confirmed by NMR and IR analysis. Efficient chromatographic separation was achieved on Hypersil BDS C18 column (250 mm × 4.6 mm, 5 μm) in gradient mode by using a binary mixture of potassium dihydrogen phosphate (15 mM, pH adjusted to 3.0) and acetonitrile at a flow rate of 1.0 ml/min. A photodiode array detector set at 230 nm was used for detection. Forced degradation studies showed that the proposed method was specific, and agomelatine was found to be susceptible to acidic and alkaline conditions. The method was validated according to ICH guidelines with respect to specificity, sensitivity, precision, linearity, accuracy, robustness and system suitability. Detection limit of impurities was in the range of 0.0008-0.0047%. Regression analysis showed correlation coefficient value greater than 0.999 for agomelatine and its seven impurities. Accuracy of the method was established based on the recovery obtained between 94.4% and 106.7% for all impurities. The validation results demonstrated that the developed method was suitable for the quantitative determination of potential impurities in agomelatine. A possible mechanism for the formation of impurities was proposed.

  1. 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.

  2. 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.

  3. 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

  4. 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.

  5. Doping in sport--2. Quantification of the impurity 19-norandrostenedione in pharmaceutical preparations of norethisterone.

    PubMed

    Walker, Christopher J; Cowan, David A; James, Vivian H T; Lau, Joanne C Y; Kicman, Andrew T

    2009-03-01

    The finding of measurable amounts of 19-norandrostenedione in norethisterone tablets prompted us to develop an assay to quantify this steroid. 19-Norandrostenedione is an anabolic steroid whose use in sport is prohibited by the World Anti-Doping Agency (WADA). The assay was developed using isotope dilution and liquid chromatography-tandem mass spectrometry (LC-MS/MS) for the quantification of 19-norandrostenedione in norethisterone formulations, with [3,4-(13)C(2)]-19-norandrostenedione as the internal standard. The results showed amounts up to 1.01+/-0.01microg (mean+/-S.E.M.) per tablet in those containing 5mg of norethisterone or norethisterone acetate (0.02%, w/w) and up to 0.5+/-0.01microg (mean+/-S.E.M.) per tablet (0.05%, w/w) in oral contraceptive tablets containing 0.35-1.5mg of norethisterone or norethisterone acetate. No tablet tested exceeded the British Pharmacopoeia limit of 0.1% for this impurity.

  6. Rapid and simultaneous determination of sulfonate ester genotoxic impurities in drug substance by liquid chromatography coupled to tandem mass spectrometry: comparison of different ionization modes.

    PubMed

    Guo, Tian; Shi, Yuanyuan; Zheng, Li; Feng, Feng; Zheng, Feng; Liu, Wenyuan

    2014-08-15

    Two ionization techniques for liquid chromatography-mass spectrometry (LC-MS) determination of sulfonate ester potentially genotoxic impurities (PGIs) were evaluated. Twelve PGIs including methyl, ethyl, propyl and isopropyl esters of methanesulfonate, benzenesulfonate and p-toluenesulfonate were studied in this research. Electrospray ionization (ESI) and atmospheric pressure chemical ionization (APCI) sources were compared in terms of performance and quality parameters for detection of the twelve PGIs. Their mass spectra obtained by APCI and ESI were very different in both fragment ions and relative abundances. In APCI negative ion mode the twelve sulfonate esters showed their stable precursor ions of [M-alkyl](-), which readily yielded product ions of [M-alkyl-CH3](-) (for aliphatic sulfonate esters) or [M-alkyl-SO2](-) (for aromatic sulfonate esters) with collision-induced dissociation (CID) applied; and working in selected reaction monitoring (SRM) mode has allowed limits of detection to be decreased. In the case of ESI ionization, these compounds showed their precursor ions [M+H](+), but their abundance was easily competed by formation of ions [M+NH4](+) and/or [M+Na](+), which led to poor analytical sensitivity and reproducibility. Although mobile phase additives could enhance the responses of adduct ions like [M+NH4](+) and [M+Na](+), no improvement was obtained when using SRM mode. Twelve sulfonate esters were systematically compared and APCI was shown to be a better ionization technique for rapid and sensitive determination of these PGIs. Performance of the developed approach for rapid determination of 12 PGIs was also evaluated. Quality parameters were established and good precision (relative standard deviations <8%) and very low limits (2-4ng/mL) of detection were obtained, mainly when using APCI in SRM mode.

  7. 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.

  8. Multiple heart-cutting two dimensional liquid chromatography mass spectrometry: Towards real time determination of related impurities of bio-pharmaceuticals in salt based separation methods.

    PubMed

    Petersson, Patrik; Haselmann, Kim; Buckenmaier, Stephan

    2016-10-14

    Many of the chromatographic methods used in industry to determine related impurities in bio pharmaceuticals employ salt containing mobile phases. "Salty" mobile phases often provide superior chromatographic performance but are not compatible with mass spectrometry (MS) detection. Peak tracking necessary for method development is therefore often based on peak areas and the chemist's experience/intuition. In addition, MS characterization of impurities usually is done by offline fraction collection, which apart from being time consuming often suffers from poor recovery or the degradation of impurities collected. The recent development of multiple heart-cutting (MHC) two-dimensional liquid chromatography (2D-LC) provides a way to address these problems. This study shows how MHC 2D-LC-MS can be used to obtain almost real time MS data for bovine insulin related impurities present at low level (<0.03%). High quality MS spectra were obtained even for a first dimension using a mobile phase containing high concentrations of sodium, sulphate and phosphate. Thereby MHC 2D-LC-MS offers a possibility to eliminate the guesswork currently associated with peak tracking during method development. Furthermore, in contrast to current characterization methods involving fraction collection, solvent reduction/exchange etc., MS determination is done directly, which markedly shortens the workflow (from days to hours) and reduces the risk for poor recovery and degradation.

  9. Development and Validation of a Precise, Single HPLC Method for the Determination of Tolperisone Impurities in API and Pharmaceutical Dosage Forms

    PubMed Central

    Raju, Thummala Veera Raghava; Seshadri, Raja Kumar; Arutla, Srinivas; Mohan, Tharlapu Satya Sankarsana Jagan; Rao, Ivaturi Mrutyunjaya; Nittala, Someswara Rao

    2013-01-01

    A novel, sensitive, stability-indicating HPLC method has been developed for the quantitative estimation of Tolperisone-related impurities in both bulk drugs and pharmaceutical dosage forms. Effective chromatographic separation was achieved on a C18 stationary phase with a simple mobile phase combination delivered in a simple gradient programme, and quantitation was by ultraviolet detection at 254 nm. The mobile phase consisted of a buffer and acetonitrile delivered at a flow rate 1.0 ml/min. The buffer consisted of 0.01 M potassium dihydrogen phosphate with the pH adjusted to 8.0 by using diethylamine. In the developed HPLC method, the resolution between Tolperisone and its four potential impurities was found to be greater than 2.0. Regression analysis showed an R value (correlation coefficient) of greater than 0.999 for the Tolperisone impurities. This method was capable of detecting all four impurities of Tolperisone at a level of 0.19 μg/mL with respect to the test concentration of 1000 μg/mL for a 10 µl injection volume. The tablets were subjected to the stress conditions of hydrolysis, oxidation, photolysis, and thermal degradation. Considerable degradation was found to occur in base hydrolysis, water hydrolysis, and oxidation. The stress samples were assayed against a qualified reference standard and the mass balance was found to be close to 100%. The established method was validated and found to be linear, accurate, precise, specific, robust, and rugged. PMID:23641333

  10. Development and Validation of a Precise, Single HPLC Method for the Determination of Tolperisone Impurities in API and Pharmaceutical Dosage Forms.

    PubMed

    Raju, Thummala Veera Raghava; Seshadri, Raja Kumar; Arutla, Srinivas; Mohan, Tharlapu Satya Sankarsana Jagan; Rao, Ivaturi Mrutyunjaya; Nittala, Someswara Rao

    2013-01-01

    A novel, sensitive, stability-indicating HPLC method has been developed for the quantitative estimation of Tolperisone-related impurities in both bulk drugs and pharmaceutical dosage forms. Effective chromatographic separation was achieved on a C18 stationary phase with a simple mobile phase combination delivered in a simple gradient programme, and quantitation was by ultraviolet detection at 254 nm. The mobile phase consisted of a buffer and acetonitrile delivered at a flow rate 1.0 ml/min. The buffer consisted of 0.01 M potassium dihydrogen phosphate with the pH adjusted to 8.0 by using diethylamine. In the developed HPLC method, the resolution between Tolperisone and its four potential impurities was found to be greater than 2.0. Regression analysis showed an R value (correlation coefficient) of greater than 0.999 for the Tolperisone impurities. This method was capable of detecting all four impurities of Tolperisone at a level of 0.19 μg/mL with respect to the test concentration of 1000 μg/mL for a 10 µl injection volume. The tablets were subjected to the stress conditions of hydrolysis, oxidation, photolysis, and thermal degradation. Considerable degradation was found to occur in base hydrolysis, water hydrolysis, and oxidation. The stress samples were assayed against a qualified reference standard and the mass balance was found to be close to 100%. The established method was validated and found to be linear, accurate, precise, specific, robust, and rugged.

  11. [The modern approaches to the determination of the content of elemental impurities in the pharmaceutical substances with the use of inductively-coupled plasma mass-spectrometry].

    PubMed

    Bol'shov, M A; Seregina, I F; Uspenskaya, E V; Titorovich, O V; Syroeshki, A V; Maksimova, T V; Pletneva, T V

    2015-01-01

    The elemental impurities contained in the composition of the pharmaceutical dose forms are known to be capable of interacting with their active substances and excipients and of catalyzing their degradation; thereby, they alter stability of the drug products and exert toxic effects on the human tissues. The present publication was designed to report the results of the purity tests for ascorbic acid, valine, and galactose substances by inductively-coupled plasma mass-spectrometry (IBP-MS). This method is recommended for use by the US and EU pharmacopoeias and for the replacement of the traditional test for heavy metals with the use of PbS ethanol suspension.

  12. A validated stability-indicating normal phase LC method for clopidogrel bisulfate and its impurities in bulk drug and pharmaceutical dosage form.

    PubMed

    Durga Rao, Dantu; Kalyanaraman, L; Sait, Shakil S; Venkata Rao, P

    2010-05-01

    A novel stability-indicating normal phase liquid chromatographic (NP-LC) method was developed for the determination of purity of clopidogrel drug substance and drug products in bulk samples and pharmaceutical dosage forms in the presence of its impurities and degradation products. This method is capable of separating all the related substances of clopidogrel along with the chiral impurities. This method can be also be used for the estimation of assay of clopidogrel in drug substance as well as in drug product. The method was developed using Chiralcel OJ-H (250mmx4.6mm, 5microm) column. n-Hexane, ethanol and diethyl amine in 95:5:0.05 (v/v/v) ratio was used as a mobile phase. The eluted compounds were monitored at 240nm. Clopidogrel bisulfate was subjected to the stress conditions of oxidative, acid, base, hydrolytic, thermal and photolytic degradation. The degradation products were well resolved from main peak and its impurities, proving the stability-indicating power of the method. The developed method was validated as per International Conference on Harmonization (ICH) guidelines with respect to specificity, limit of detection, limit of quantification, precision, linearity, accuracy, robustness and system suitability.

  13. Feasibility of wavelength dispersive X-ray fluorescence spectrometry for the determination of metal impurities in pharmaceutical products and dietary supplements in view of regulatory guidelines.

    PubMed

    Figueiredo, Alexandra; Fernandes, Tânia; Costa, Isabel Margarida; Gonçalves, Luísa; Brito, José

    2016-04-15

    The aim of this study was to investigate the feasibility of Wavelength Dispersive X-ray Fluorescence (WDXRF) spectrometry for the measurement of As, Cd, Cr, Cu, Hg, Ir, Mn, Mo, Ni, Os, Pb, Pd, Pt, Rh, Ru and V impurities in pharmaceuticals and dietary supplements, in view of the requirements by EMA and USP for the measurement of elemental impurities in drug products and according to the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH guidelines). For that purpose, a 4 kW WDXRF spectrometer (S4 Pioneer, Bruker AXS) was used after system calibration. The linearity of the method was demonstrated by correlation coefficients in excess of 0.9 and by appropriate test of lack of fit, except for Cd, Hg, Pd, V and As, which were excluded from analysis. The calculated limits of detection and quantification were in the ranges 0.6-5.4 μg/g and 1.7-16.4 μg/g meeting defined acceptance criteria, except for Pb. The accuracy of the method, determined by the percent recovery (R) of known amounts of each element added to a selected drug, at 3 different concentration levels, was in the acceptance range 70-150% except for Os and Pt, in which case R was marginally outside that range. The repeatability of the method, assessed as the % residual standard deviation (%RSD) of 3 replicate measurements at 3 concentration levels, produced %RSD values lower than 20%, as required. These results show that the WDXRF method complies with the validation requirements defined by the European Pharmacopeia for Cu, Cr, Ir, Mn, Mo, Ni, Os, and Pt, and by the United States Pharmacopeia for Ir, Ni, Os and Pt. Therefore, it may be an alternative to the compendial analytical procedures recommended for such elements. The novelty of the present work is the application of WDXRF to final medicines and not only to active pharmaceutical ingredients and/or excipients.

  14. Flow injection combined with ICP-MS for accurate high throughput analysis of elemental impurities in pharmaceutical products according to USP <232>/<233>.

    PubMed

    Fischer, Lisa; Zipfel, Barbara; Koellensperger, Gunda; Kovac, Jessica; Bilz, Susanne; Kunkel, Andrea; Venzago, Cornel; Hann, Stephan

    2014-07-01

    New guidelines of the United States Pharmacopeia (USP), European Pharmacopeia (EP) and international organization (ICH, International Conference on Harmonization) regulating elemental impurity limits in pharmaceuticals seal the end of unspecific analysis of metal(oid)s as outlined in USP <231> and EP 2.4.8. Chapter USP <232> and EP 5.20 as well as drafts from ICH Q3D specify both daily doses and concentration limits of metallic impurities in pharmaceutical final products and in active pharmaceutical ingredients (API) and excipients. In chapters USP <233> and EP 2.4.20 method implementation, validation and quality control during the analytical process are described. By contrast with the--by now--applied methods, substance specific quantitative analysis features new basic requirements, further, significantly lower detection limits ask for the necessity of a general changeover of the methodology toward sensitive multi element analysis by ICP-AES and ICP-MS, respectively. A novel methodological approach based on flow injection analysis and ICP-SFMS/ICP-QMS for the quick and accurate analysis of Cd, Pb, As, Hg, Ir, Os, Pd, Pt, Rh, Ru, Cr, Mo, Ni, V, Cu, Mn, Fe and Zn in drug products by prior dilution, dissolution or microwave assisted closed vessel digestion according to the regulations is presented. In comparison to the acquisition of continuous signals, this method is advantageous with respect to the unprecedented high sample throughput due to a total analysis time of approximately 30s and the low sample consumption of below 50 μL, while meeting the strict USP demands on detection/quantification limits, precision and accuracy.

  15. 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

  16. 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

    2014-01-01

    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.

  17. Development of a quantitative approach using surface-enhanced Raman chemical imaging: first step for the determination of an impurity in a pharmaceutical model.

    PubMed

    De Bleye, C; Sacré, P-Y; Dumont, E; Netchacovitch, L; Chavez, P-F; Piel, G; Lebrun, P; Hubert, Ph; Ziemons, E

    2014-03-01

    This publication reports, for the first time, the development of a quantitative approach using surface-enhanced Raman chemical imaging (SER-CI). A pharmaceutical model presented as tablets based on paracetamol, which is the most sold drug around the world, was used to develop this approach. 4-Aminophenol is the main impurity of paracetamol and is actively researched in pharmaceutical formulations because of its toxicity. As its concentration is generally very low (<0.1%, w/w), conventional Raman chemical imaging cannot be used. In this context, a SER-CI method was developed to quantify 4-aminophenol assessing a limit of quantification below its limit of specification of 1000 ppm. Citrate-reduced silver nanoparticles were used as SERS substrate and these nanoparticles were functionalized using 1-butanethiol. Different ways to cover the tablets surface by butanethiol-functionalized silver nanoparticles were tested and a homogeneity study of the silver nanoparticles covering was realized. This homogeneity study was performed in order to choose the best way to cover the surface of tablets by silver colloid. Afterwards, the optimization of the SER-CI approach was necessary and different spectral intensity normalizations were tested. Finally, a quantitative approach using SER-CI was developed enabling to quantify 4-aminophenol from 0.025% to 0.2% in paracetamol tablets. This quantitative approach was tested on two different series of tablets using different batches of silver nanoparticles.

  18. Potentially mutagenic impurities: analysis of structural classes and carcinogenic potencies of chemical intermediates in pharmaceutical syntheses supports alternative methods to the default TTC for calculating safe levels of impurities.

    PubMed

    Galloway, Sheila M; Vijayaraj Reddy, M; McGettigan, Katherine; Gealy, Robert; Bercu, Joel

    2013-08-01

    Potentially mutagenic impurities in new pharmaceuticals are controlled to levels with negligible risk, the TTC (threshold of toxicological concern, 1.5 μg/day for a lifetime). The TTC was based on the more potent rodent carcinogens, excluding the highly potent "cohort of concern" (COC; for mutagenic carcinogens these are N-nitroso, Aflatoxin-like, and azoxy structures). We compared molecules with DEREK "structural alerts" for mutagenicity used in drug syntheses with the mutagenic carcinogens in the Gold Carcinogenicity Potency Database. Data from 108 diverse synthetic routes from 13 companies confirm that many "alerting" or mutagenic chemicals are in structural classes with lower carcinogenic potency than those used to derive the TTC. Acceptable daily intakes can be established that are higher than the default TTC for many structural classes (e.g., mono-functional alkyl halides and certain aromatic amines). Examples of ADIs for lifetime and shorter-term exposure are given for chemicals of various potencies. The percentage of chemicals with DEREK alerts that proved mutagenic in the Ames test ranged from 36% to 83%, depending on structural class, demonstrating that such SAR analysis to "flag" potential mutagens is conservative. We also note that aromatic azoxy compounds need not be classed as COC, which was based on alkyl azoxy chemicals.

  19. Development and validation of an HPLC method for determination of ziprasidone and its impurities in pharmaceutical dosage forms.

    PubMed

    Pavlovic, Marija; Malesevic, Marija; Nikolic, Katarina; Agbaba, Danica

    2011-01-01

    Ziprasidone is known as a novel "atypical" or "second-generation" antipsychotic drug. A sensitive and reproducible method was developed and validated for determination of ziprasidone and its major impurities, which are significantly different in polarity. The separation is performed on a Waters Spherisorb octadecylsilyl 1 column (5.0 microm particle size, 250 x 4.6 mm id) using a gradient with mobile phase A [buffer-acetonitrile (80+20, v/v)] and mobile phase B [buffer-acetonitrile (10+90, v/v)] at a working temperature of 25 degrees C. The buffer was 0.05 M KH2PO4 solution with an addition of 10 mL triethylamine/L solution, adjusted to pH 2.5 with orthophosphoric acid. The flow rate was 1.5 mL/min, and the eluate was monitored at 250 nm using a diode array detector. Optimization of the experimental conditions was performed using partial least squares regression, for which four factors were selected for optimization: buffer concentration, buffer pH, triethylamine concentration, and temperature. The proposed validated method is convenient and reliable for the assay and purity control in both raw materials and dosage forms.

  20. Rapid limit tests for metal impurities in pharmaceutical materials by X-ray fluorescence spectroscopy using wavelet transform filtering.

    PubMed

    Arzhantsev, Sergey; Li, Xiang; Kauffman, John F

    2011-02-01

    We introduce a new method for analysis of X-ray fluorescence (XRF) spectra based on continuous wavelet transform filters, and the method is applied to the determination of toxic metals in pharmaceutical materials using hand-held XRF spectrometers. The method uses the continuous wavelet transform to filter the signal and noise components of the spectrum. We present a limit test that compares the wavelet domain signal-to-noise ratios at the energies of the elements of interest to an empirically determined signal-to-noise decision threshold. The limit test is advantageous because it does not require the user to measure calibration samples prior to measurement, though system suitability tests are still recommended. The limit test was evaluated in a collaborative study that involved five different hand-held XRF spectrometers used by multiple analysts in six separate laboratories across the United States. In total, more than 1200 measurements were performed. The detection limits estimated for arsenic, lead, mercury, and chromium were 8, 14, 20, and 150 μg/g, respectively.

  1. 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

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

    2015-10-18

    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.

  2. 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. PMID:28117312

  3. Highly efficient, selective, sensitive and stability indicating RP-HPLC-UV method for the quantitative determination of potential impurities and characterization of four novel impurities in eslicarbazepine acetate active pharmaceutical ingredient by LC/ESI-IT/MS/MS.

    PubMed

    Thomas, Saji; Bharti, Amber; Maddhesia, Pawan Kumar; Shandilya, Sanjeev; Agarwal, Ashutosh; Dharamvir; Biswas, Sujay; Bhansal, Vikas; Gupta, Ashish Kumar; Tewari, Praveen Kumar; Mathela, Chandra S

    2012-03-05

    A novel, sensitive, selective and stability indicating LC-UV method was developed for the determination of potential impurities of eslicarbazepine acetate. High performance liquid chromatographic investigation of eslicarbazepine acetate laboratory sample revealed the presence of several impurities. Three impurities were characterized rapidly and four impurities were found to be unknown. The unknown impurities were identified by liquid chromatography coupled with electrospray ionization, ion trap mass spectrometry (LC/ESI-IT/MS/MS). Structural confirmation of these impurities was unambiguously carried out by synthesis followed by characterization using nuclear magnetic resonance spectroscopy (NMR), infrared spectroscopy (FT-IR) and mass spectrometry (MS). Based on the spectroscopic, spectrometric and elemental analysis data unknown impurities were characterized as 5-acetyl-5,11-dihydro-10H-dibenzo [b,f]azepin-10-one, N-acetyl-5H-dibenzo[b,f]azepine-5-carboxamide, 5-acetyl-10,11-dihydro-5H-dibenzo[b,f]azepin-10-yl acetate and 5-acetyl-5H-dibenzo[b,f]azepin-10-yl acetate. The newly developed LC-UV method was validated according to ICH guidelines considering eleven potential impurities and four new impurities to demonstrate specificity, precision, linearity, accuracy and stability indicating nature of the method. The newly developed method was found to be highly efficient, selective, sensitive and stability indicating. A plausible pathway for the formation of four new impurities is proposed.

  4. Identification, characterization and quantification of new impurities by LC-ESI/MS/MS and LC-UV methods in rivastigmine tartrate active pharmaceutical ingredient.

    PubMed

    Thomas, Saji; Shandilya, Sanjeev; Bharati, Amber; Paul, Saroj Kumar; Agarwal, Ashutosh; Mathela, Chandra S

    2012-01-05

    Six impurities were detected at trace level in rivastigmine tartrate drug substance by a newly developed high performance liquid chromatography method. Three impurities were characterized rapidly and three impurities were found to be unknown. The unknown impurities were enriched and identified with a combination of semi-preparative HPLC and LC/MS/MS techniques. Proposed structures were further confirmed by characterization using NMR, FT-IR, and EA techniques of impurity standards. Based on the spectroscopic, spectrometric and elemental analysis data unknown impurities were characterized as 3-[1-(dimethylamino)ethyl]phenyl N-ethyl-N-methyl carbamate N-oxide, ethyl-methyl-carbamic acid 4-(1-dimethylamino-ethyl)-phenyl ester and ethyl-methyl-carbamic acid 2-(1-dimethylamino-ethyl)-phenyl ester. A plausible mechanism for the formation of these impurities is also proposed. The method was validated according to ICH guidelines for fourteen impurities to demonstrate specificity, precision, linearity, accuracy and stability indicating nature of the method. Regression analysis showed correlation coefficient value greater than 0.999 for rivastigmine tartrate and its impurities. Accuracy of the method was established based on the recovery obtained between 93.41 and 113.33% for all impurities.

  5. A compatibility study of a secondary amine active pharmaceutical ingredient with starch: identification of a novel degradant formed between desloratadine and a starch impurity using LC-MS(n) and NMR spectroscopy.

    PubMed

    Yu, Xin; Buevich, Alexei V; Li, Min; Wang, Xin; Rustum, Abu M

    2013-02-01

    Active pharmaceutical ingredients (APIs) containing primary and secondary amine moieties have been extensively studied for their potential incompatibility with monosaccharides and disaccharides containing a reducing end such as glucose, lactose, and maltose because of the undesirable interaction between the amine and aldehyde functionalities. Compatibility studies of these APIs with olysaccharides such as starch are much less common. During a recent compatibility study between starch and desloratadine, an API that contains a secondary amine functional group, we observed a novel degradant formed between desloratadine and a previously unidentified starch impurity in addition to an Amadori degradant formed between desloratadine and maltose, a known starch impurity. An approach that combines liquid chromatography-tandem mass spectrometry (LC-MS(n)) analysis, stress studies, and comprehensive nuclear magnetic resonance (NMR) analyses was used to identify this novel degradant. On the basis of the structure determined by NMR spectroscopy and the results from the stress studies, a degradation mechanism is proposed to account for the formation of this novel degradant through the reaction of desloratadine with an isomer of acetylformoin, an impurity of polysaccharide origin. Because starch is a very common excipient used in solid dosage formulations, the results of this compatibility study should facilitate pharmaceutical development involving secondary amine APIs and starch.

  6. 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.

  7. Identification and structural elucidation of two process impurities and stress degradants in darifenacin hydrobromide active pharmaceutical ingredient by LC-ESI/MS(n).

    PubMed

    Thomas, Saji; Paul, Saroj Kumar; Shandilya, Sanjeev; Agarwal, Ashutosh; Saxena, Nitesh; Awasthi, Arun Kumar; Matta, Hari babu; Vir, Dharam; Mathela, Chandra S

    2012-08-07

    The present study describes the identification and characterization of two process impurities and major stress degradants in darifenacin hydrobromide using high performance liquid chromatography (HPLC) analysis. Forced degradation studies confirmed that the drug substance was stable under acidic, alkaline, aqueous hydrolysis, thermal and photolytic conditions and susceptible only to oxidative degradation. Impurities were identified using liquid chromatography coupled with ion trap mass spectrometry (LC-MS/MS(n)). Proposed structures were unambiguously confirmed by synthesis followed by characterization using nuclear magnetic resonance spectroscopy (NMR), infrared spectroscopy (IR) and elemental analysis (EA). Based on the spectroscopic, spectrometric and elemental analysis data, the unknown impurities were characterized as 2-{1-[2-(2,3-dihydrobenzofuran-5-yl)-2-oxo-ethyl]-pyrrolidin-3-yl}-2,2-diphenylacetamide (Imp-A), 2-[1-(2-benzofuran-5-yl-ethyl)-pyrrolidin-3-yl]-2,2-diphenylacetamide (Imp-B), 2-{1-[2-(2,3-dihydrobenzofuran-5-yl)-ethyl]-1-oxy-pyrrolidin-3-yl}-2,2-diphenylacetamide (Imp-C) and 2-{1-[2-(7-bromo-2,3-dihydrobenzofuran-5-yl)-ethyl]-pyrrolidin-3-yl}-2,2-diphenylacetamide (Imp-D). Plausible mechanisms for the formation and control of these impurities have also been proposed. The method was validated as per regulatory guidelines to demonstrate specificity, sensitivity, linearity, precision, accuracy and the stability-indicating nature. Regression analysis showed a correlation coefficient value greater than 0.99 for darifenacin hydrobromide and its impurities. The accuracy of the method was established based on the recovery obtained between 86.6 and 106.7% for all impurities.

  8. Genotoxicity and carcinogenicity studies of antihistamines.

    PubMed

    Brambilla, Giovanni; Mattioli, Francesca; Robbiano, Luigi; Martelli, Antonietta

    2011-10-01

    This review provides a compendium of the results of genotoxicity and carcinogenicity assays performed on marketed antihistamines. Of the 70 drugs examined, 29 (41.4%) have at least one genotoxicity and/or carcinogenicity test result: 12 tested positive in at least one genotoxicity assay, six in at least one carcinogenicity assay, and four gave a positive response in both at least one genotoxicity assay and at least one carcinogenicity assay. Of 19 drugs with both genotoxicity and carcinogenicity data, eight were neither genotoxic nor carcinogenic, two were carcinogenic in at least one sex of mice or rats but tested negative in genotoxicity assays, five tested positive in at least one genotoxicity assay but were non-carcinogenic, and four gave a positive response in at least one genotoxicity assay and in at least one carcinogenicity assay. Only 12 (17.1%) of the 70 drugs examined have all data required by present guidelines for testing of pharmaceuticals, but it should be considered that a large fraction of them were developed and marketed prior the present regulatory climate.

  9. Spectral correlation of high-performance liquid chromatography-diode array detection data from two independent chromatographic runs peak tracking in pharmaceutical impurity profiling.

    PubMed

    Li, Wei; Hu, Chang-qin

    2008-05-09

    A novel qualitative analytical method for peak tracking in impurity profiling control by the correlation of spectra was established. Two-dimensional (2D) standard spectrochromatographic data produced by high-performance liquid chromatography with diode array detection (HPLC-DAD) were compared with sample data to develop two-dimensional chromatographic spectral correlative maps. Taking full advantage of separation efficiency of HPLC and spectral specificity of the analytes, the method was successfully used to recognize impurities in quinolone antibacterials, when in combination with relative retention times (RRTs). For the comparison of spectra was expanded to three-dimensional space, simultaneous identification of the chromatographic peaks can be obtained rapidly without preparation and injection of a reference solution, even when the mobile phase changed or the peaks of multi-component samples overlapped.

  10. Simultaneous determination of paracetamol, chlorzoxazone, and related impurities 4-aminophenol, 4'-chloroacetanilide, and p-chlorophenol in pharmaceutical preparations by high-performance liquid chromatography.

    PubMed

    Ali, Mohammed Shahid; Rafiuddin, Syed; Ghori, Mohsin; Kahtri, Aamer Roshanali

    2007-01-01

    This paper presents a simple, specific, and precise high-performance liquid chromatographic method for the simultaneous determination of paracetamol (PCM), chlorzoxazone (CXZ), and their related impurities in bulk raw materials and solid dosage forms. The mobile phase consisted of water-methanol-glacial acetic acid (60 + 40 + 2, v/v/v). A column containing octadecylsilane chemically bonded to porous silica particles (Spherisorb ODS 1, 25 cm x 4.6 mm, 5 microm) was used as stationary phase. Detection was performed using a variable wavelength ultraviolet-visible detector set at 272 nm for all compounds. Solutions were injected into the chromatograph under isocratic condition at a constant flow rate of 1.2 mL/min. The method was validated according to International Conference on Harmonization requirements and demonstrates good accuracy and precision and a wide linearity range. The method separates PCM, CXZ, and 3 major impurities [4-aminophenol (4AP), 4'-chloracetanilide (4CA), and p-chlorophenol (PCP)] with fair resolution in less than 15 min. The developed method is rapid and sensitive (limit of detection for 4AP, 4CA, and PCP established at 31.25, 39.06, and 65.16 ng/mL, respectively) and, therefore, suitable for quality control and stability studies of these compounds in dosage forms.

  11. Related impurities in peptide medicines.

    PubMed

    D'Hondt, Matthias; Bracke, Nathalie; Taevernier, Lien; Gevaert, Bert; Verbeke, Frederick; Wynendaele, Evelien; De Spiegeleer, Bart

    2014-12-01

    Peptides are an increasingly important group of pharmaceuticals, positioned between classic small organic molecules and larger bio-molecules such as proteins. Currently, the peptide drug market is growing twice as fast as other drug markets, illustrating the increasing clinical as well as economical impact of this medicine group. Most peptides today are manufactured by solid-phase peptide synthesis (SPPS). This review will provide a structured overview of the most commonly observed peptide-related impurities in peptide medicines, encompassing the active pharmaceutical ingredients (API or drug substance) as well as the finished drug products. Not only is control of these peptide-related impurities and degradants critical for the already approved and clinically used peptide-drugs, these impurities also possess the capability of greatly influencing initial functionality studies during early drug discovery phases, possibly resulting in erroneous conclusions. The first group of peptide-related impurities is SPPS-related: deletion and insertion of amino acids are related to inefficient Fmoc-deprotection and excess use of amino acid reagents, respectively. Fmoc-deprotection can cause racemization of amino acid residues and thus diastereomeric impurities. Inefficient deprotection of amino acid side chains results into peptide-protection adducts. Furthermore, unprotected side chains can react with a variety of reagents used in the synthesis. Oxidation of amino acid side chains and dimeric-to-oligomeric impurities were also observed. Unwanted peptide counter ions such as trifluoroacetate, originating from the SPPS itself or from additional purification treatments, may also be present in the final peptide product. Contamination of the desired peptide product by other unrelated peptides was also seen, pointing out the lack of appropriate GMP. The second impurity group results from typical peptide degradation mechanisms such as β-elimination, diketopiperazine, pyroglutamate

  12. 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.

  13. 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.

  14. Development and Validation of a Stability-Indicating RP-HPLC Method for the Determination of Process-Related Impurities and Degradation Products of Rabeprazole Sodium in Pharmaceutical Formulation.

    PubMed

    Kumar, Navneet; Sangeetha, Dhanaraj

    2013-01-01

    The objective of the current study was to develop and validate a reversed-phase high-performance liquid chromatographic method for the quantitative determination of process-related impurities and degradation products of rabeprazole sodium in pharmaceutical formulation. Chromatographic separation was achieved on the Waters Symmetry Shield RP18 (250 mm × 4.6 mm) 5 μm column with a mobile phase containing a gradient mixture of solvent A (mixture of 0.025 M KH2PO4 buffer and 0.1% triethylamine in water, pH 6.4 and acetonitrile in the ratio of 90:10 v/v, respectively) and solvent B (mixture of acetonitrile and water in the ratio of 90:10 v/v, respectively). The mobile phase was delivered at a flow rate of 1.0 mL/min and with UV detection at 280 nm. Rabeprazole sodium was subjected to the stress conditions of oxidative, acid, base, hydrolytic, thermal, and photolytic degradation. Rabeprazole sodium was found to degrade significantly under acid hydrolysis, base hydrolysis, oxidative, and thermal degradation conditions. The degradation products were well-resolved from the main peak and its impurities, thus proving the stability-indicating power of the method. The mass balance was found to be in the range of 97.3-101.3% in all of the stressed conditions, thus proving the stability-indicating power of the method. The developed method was validated as per ICH guidelines with respect to specificity, linearity, limit of detection, limit of quantification, accuracy, precision, and robustness.

  15. Genotoxicity and carcinogenicity studies of bronchodilators and antiasthma drugs.

    PubMed

    Brambilla, Giovanni; Mattioli, Francesca; Robbiano, Luigi; Martelli, Antonietta

    2013-05-01

    This survey is a compendium of genotoxicity and carcinogenicity information of bronchodilators and antiasthma drugs. Data from 46 marketed drugs were collected. Of these 46 drugs, 25 (54.3%) did not have retrievable genotoxicity or carcinogenicity data. The remaining 21 (45.7%) had at least one genotoxicity or carcinogenicity test result. Of these 21 drugs, 10 had at least one positive finding: three tested positive in at least one genotoxicity assay, eight in at least one carcinogenicity assay, and one of them gave positive results in both genotoxicity assay and carcinogenicity assay. Concerning the predictivity of genetic toxicology findings for the result(s) of long-term carcinogenesis assays, 15 drugs had both genotoxicity and carcinogenicity data: seven of them (46.6%) were neither genotoxic nor carcinogenic, 6 (40.0%) were carcinogenic in at least one sex of mice or rats but tested negative in genotoxicity assays, 1 (6.7%) tested positive in genotoxicity assay but was non-carcinogenic, and 1 (6.7%) gave positive responses in both genotoxicity and carcinogenicity assay. Only 11 (23.9%) of the 46 drugs considered had all data required by current guidelines for testing of pharmaceuticals, but a large fraction of them were developed and marketed prior to the present regulatory climate.

  16. Analytical Quality by Design in pharmaceutical quality assurance: Development of a capillary electrophoresis method for the analysis of zolmitriptan and its impurities.

    PubMed

    Orlandini, Serena; Pasquini, Benedetta; Caprini, Claudia; Del Bubba, Massimo; Pinzauti, Sergio; Furlanetto, Sandra

    2015-11-01

    A fast and selective CE method for the determination of zolmitriptan (ZOL) and its five potential impurities has been developed applying the analytical Quality by Design principles. Voltage, temperature, buffer concentration, and pH were investigated as critical process parameters that can influence the critical quality attributes, represented by critical resolution values between peak pairs, analysis time, and peak efficiency of ZOL-dimer. A symmetric screening matrix was employed for investigating the knowledge space, and a Box-Behnken design was used to evaluate the main, interaction, and quadratic effects of the critical process parameters on the critical quality attributes. Contour plots were drawn highlighting important interactions between buffer concentration and pH, and the gained information was merged into the sweet spot plots. Design space (DS) was established by the combined use of response surface methodology and Monte Carlo simulations, introducing a probability concept and thus allowing the quality of the analytical performances to be assured in a defined domain. The working conditions (with the interval defining the DS) were as follows: BGE, 138 mM (115-150 mM) phosphate buffer pH 2.74 (2.54-2.94); temperature, 25°C (24-25°C); voltage, 30 kV. A control strategy was planned based on method robustness and system suitability criteria. The main advantages of applying the Quality by Design concept consisted of a great increase of knowledge of the analytical system, obtained throughout multivariate techniques, and of the achievement of analytical assurance of quality, derived by probability-based definition of DS. The developed method was finally validated and applied to the analysis of ZOL tablets.

  17. 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.

  18. 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.

  19. 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.

  20. Theoretical Purge Factor Determination as a Control Strategy for Potential Mutagenic Impurities in the Synthesis of Drug Substances.

    PubMed

    Kragelj Lapanja, Nevenka; Toplak Časar, Renata; Jurca, Sabina; Doljak, Bojan

    Mutagenic impurities (MIs) are of serious concern for pharmaceutical industry, regulatory agencies and public health. The first guideline addressing the control of genotoxic impurities (GTIs) dates back to 2006. Since then there have been several updates and refinements, which eventually resulted in the guideline, published by the International Conference on Harmonisation (ICH) in June 2014. The ICH M7 guideline, compared to previous ones, offers greater flexibility in terms of control strategies for GTIs in drug substances. More specifically, it describes a control strategy that relies on process controls in lieu of analytical testing which is based on understanding the process chemistry and process parameters that impact the levels of GTIs. This principle is adopted in the theoretical purge factor determination tool proposed by Teasdale et al. Several case studies applying the proposed theoretical purge factor determination tool were published in recent years. The results confirm the tool's good predictability of the extent to which the impurity is removed by the process. Hopefully, this approach will soon be released as an in-silico tool, generally accepted by the regulatory agencies.

  1. 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

    2015-10-06

    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.

  2. 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

  3. Genotoxicity investigations on nanomaterials.

    PubMed

    Oesch, Franz; Landsiedel, Robert

    2012-07-01

    This review is based on the lecture presented at the April 2010 nanomaterials safety assessment Postsatellite to the 2009 EUROTOX Meeting and summarizes genotoxicity investigations on nanomaterials published in the open scientific literature (up to 2008). Special attention is paid to the relationship between particle size and positive versus negative outcome, as well as the dependence of the outcome on the test used. Salient conclusions and outstanding recommendations emerging from the information summarized in this review are as follows: recognize that nanomaterials are not all the same; therefore know and document what nanomaterial has been tested and in what form; take nanomaterials specific properties into account; in order to make your results comparable with those of others and on other nanomaterials: use or at least include in your studies standardized methods; use in vivo studies to put in vitro results into perspective; take uptake and distribution of the nanomaterial into account; and in order to become able to make extrapolations to risk for human: learn about the mechanism of nanomaterials genotoxic effects. Past experience with standard non-nanosubstances already had shown that mechanisms of genotoxic effects can be complex and their elucidation can be demanding, while there often is an immediate need to assess the genotoxic hazard. Thus, a practical and pragmatic approach to genotoxicity investigations of novel nanomaterials is the use of a battery of standard genotoxicity testing methods covering a wide range of mechanisms. Application of these standard methods to nanomaterials demands, however, adaptations, and the interpretation of results from the genotoxicity testing of nanomaterials needs additional considerations exceeding those used for standard size materials.

  4. Studies on genotoxicity and carcinogenicity of antibacterial, antiviral, antimalarial and antifungal drugs.

    PubMed

    Brambilla, Giovanni; Mattioli, Francesca; Robbiano, Luigi; Martelli, Antonietta

    2012-07-01

    This review provides a compendium of retrievable results of genotoxicity and animal carcinogenicity studies performed of antibacterial, antiviral, antimalarial and antifungal drugs of long-term or intermittent frequent use. Of the 48 drugs considered, 9 (18.75%) do not have retrievable data, whereas the other 39 (81.25%) have at least one genotoxicity or carcinogenicity tests result. Of these 39 drugs, 24 tested positive in at least one genotoxicity assay and 19 in at least one carcinogenicity assay; 14 of them gave a positive response in both at least one genotoxicity assay and at least one carcinogenicity assay. Concerning the predictivity of genetic toxicology findings for the results of long-term carcinogenesis assays, of 23 drugs with both genotoxicity and carcinogenicity data: 2 (8.7%) were neither genotoxic nor carcinogenic, 2 (8.7%) tested positive in at least one genotoxicity assay but were non-carcinogenic, 4 (17.4%) tested negative in genotoxicity assays but were carcinogenic, and 15 (65.2%) gave a positive response in at least one genotoxicity assay and in at least one carcinogenicity assay. Only 18 (37.5%) of the 48 drugs examined had all data required by present guidelines for testing of pharmaceuticals, but a fraction of them (49%) were developed and marketed prior to the present regulatory climate. In the absence of compelling indications, the prescription of the 19 drugs that are animal carcinogens should be avoided.

  5. 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.

  6. Considerations on photochemical genotoxicity: report of the International Workshop on Genotoxicity Test Procedures Working Group.

    PubMed

    Gocke, E; Müller, L; Guzzie, P J; Brendler-Schwaab, S; Bulera, S; Chignell, C F; Henderson, L M; Jacobs, A; Murli, H; Snyder, R D; Tanaka, N

    2000-01-01

    Recent toxicological observations have caused concern regarding the need to test, for example, pharmaceuticals and cosmetic products for photochemical genotoxicity. The objective of this report is to give assistance on how to adapt existing test methods to investigate the potential of light-absorbing compounds to induce genotoxic effects on photoactivation. In general, the Organization for Economic Co-Operation & Economic Development (OECD) draft guideline on in vitro phototoxicity testing served as a basis for consideration. Concomitant exposure of the cells to the test compound and solar simulated light was considered appropriate as the initial, basic test condition. Optimization of the exposure scheme, e.g., a change of the irradiation spectrum, might be indicated depending on the initial test results. Selection of test compound concentrations should be based on results obtained with the dark version of the respective test system but might have to be modified if phototoxic effects are observed. Selection of the irradiation dose has to be performed individually for each test system based on dose-effect studies. The irradiation should induce per se a small, reproducible toxic or genotoxic effect. The report includes a specification of necessary controls, discusses factors that might have an impact on the irradiation characteristics, and gives a rationale for the omission of an external metabolic activation system. It also addresses the question that physicochemical and pharmacokinetic properties might trigger the need to test a chemical for photochemical genotoxicity. Relevant experimental observations are presented to back up the recommendations. The working group did not reach a consensus as to whether a single, adequately perfomed in vitro test for clastogenicity would be sufficient to exclude a photogenotoxic liability or whether a test battery including a gene mutation assay would be needed for product safety testing regarding photochemical genotoxicity.

  7. 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.

  8. Strategy for genotoxicity testing--metabolic considerations.

    PubMed

    Ku, Warren W; Bigger, Anita; Brambilla, Giovanni; Glatt, Hansruedi; Gocke, Elmar; Guzzie, Peggy J; Hakura, Atsushi; Honma, Masamitsu; Martus, Hans-Joerg; Obach, R Scott; Roberts, Stanley

    2007-02-03

    The report from the 2002 International Workshop on Genotoxicity Tests (IWGT) Strategy Expert Group emphasized metabolic considerations as an important area to address in developing a common strategy for genotoxicity testing. A working group convened at the 2005 4th IWGT to discuss this area further and propose practical strategy recommendations. To propose a strategy, the working group reviewed: (1) the current status and deficiencies, including examples of carcinogens "missed" in genotoxicity testing, established shortcomings of the standard in vitro induced S9 activation system and drug metabolite case examples; (2) the current status of possible remedies, including alternative S9 sources, other external metabolism systems or genetically engineered test systems; (3) any existing positions or guidance. The working group established consensus principles to guide strategy development. Thus, a human metabolite of interest should be represented in genotoxicity and carcinogenicity testing, including evaluation of alternative genotoxicity in vitro metabolic activation or test systems, and the selection of a carcinogenicity test species showing appropriate biotransformation. Appropriate action triggers need to be defined based on the extent of human exposure, considering any structural knowledge of the metabolite, and when genotoxicity is observed upon in vitro testing in the presence of metabolic activation. These triggers also need to be considered in defining the timing of human pharmaceutical ADME assessments. The working group proposed two strategies to consider; a more proactive approach, which emphasizes early metabolism predictions to drive appropriate hazard assessment; and a retroactive approach to manage safety risks of a unique or "major" metabolite once identified and quantitated from human clinical ADME studies. In both strategies, the assessment of the genotoxic potential of a metabolite could include the use of an alternative or optimized in vitro

  9. Nanoparticle Toxicity Mechanisms: Genotoxicity

    NASA Astrophysics Data System (ADS)

    Botta, Alain; Benameur, Laı̈la

    Despite the relatively small amount of convincing experimental data, the potentially genotoxic nature of certain nanoparticles seems plausible, owing in particular to the presence of reactive oxygen species (ROS) such as the superoxide anion O2 • - , the hydroxyl radical • OH, and singlet oxygen 1O2, and reactive nitrogen species (RNS) such as nitrogen monoxide NO, the peroxynitrite anion ONOO - , the peroxynitrite radical ONOO • , and dinitrogen trioxide N2O3, a powerful nitration agent.

  10. Genotoxicity of monosodium glutamate.

    PubMed

    Ataseven, Nazmiye; Yüzbaşıoğlu, Deniz; Keskin, Ayten Çelebi; Ünal, Fatma

    2016-05-01

    Monosodium glutamate (MSG) is one of the most widely used flavor enhancers throughout the world. The aim of this study is to investigate the genotoxic potential of MSG by using chromosome aberrations (CAs), sister-chromatid exchanges (SCEs), cytokinesis-blocked micronucleus (CBMN), and random amplified polymorphic DNA-polimerase chain reaction (RAPD-PCR) in cultured human lymphocytes and alkaline comet assays in isolated human lymphocytes, which were incubated with six concentrations (250, 500, 1000, 2000, 4000 and 8000 μg/mL) of MSG. The result of this study indicated that MSG significantly and dose dependently increased the frequencies of CAs, SCE and MN in all treatments and times, compared with control. However, the replication (RI) and nuclear division indices (NDI) were not affected. In this paper, in vitro genotoxic effects of the MSG was also investigated on human peripheral lymphocytes by analysing the RAPD-PCR with arbitrary 10-mer primers. The changes occurring in RAPD profiles after MSG treatment include increase or decrease in band intensity and gain or loss of bands. In the comet assay, this additive caused DNA damage at all concentrations in isolated human lymphocytes after 1-h in vitro exposure. Our results demonstrate that MSG is genotoxic to the human peripheral blood lymphocytes in vitro.

  11. 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

  12. Health care industries: potential generators of genotoxic waste.

    PubMed

    Sharma, Pratibha; Kumar, Manish; Mathur, N; Singh, A; Bhatnagar, P; Sogani, M

    2013-08-01

    Health care waste includes all the waste generated by health care establishments, research facilities, and laboratories. This constitutes a variety of chemical substances, such as pharmaceuticals, radionuclides, solvents, and disinfectants. Recently, scientists and environmentalists have discovered that wastewater produced by hospitals possesses toxic properties due to various toxic chemicals and pharmaceuticals capable of causing environmental impacts and even lethal effects to organisms in aquatic ecosystems. Many of these compounds resist normal wastewater treatment and end up in surface waters. Besides aquatic organisms, humans can be exposed through drinking water produced from contaminated surface water. Indeed, some of the substances found in wastewaters are genotoxic and are suspected to be potential contributors to certain cancers. The aim of this study was to evaluate the genotoxic and cytotoxic potential of wastewaters from two hospitals and three clinical diagnostic centers located in Jaipur (Rajasthan State), India using the prokaryotic Salmonella mutagenicity assay (Ames assay) and the eukaryotic Saccharomyces cerevisiae respiration inhibition assay. In the Ames assay, untreated wastewaters from both of the health care sectors resulted in significantly increased numbers of revertant colonies up to 1,000-4,050 as measured by the Salmonella typhimurium TA98 and TA100 strains (with and without metabolic activation) after exposure to undiluted samples, which indicated the highly genotoxic nature of these wastewaters. Furthermore, both hospital and diagnostic samples were found to be highly cytotoxic. Effective concentrations at which 20 % (EC20) and 50 % (EC50) inhibition of the respiration rate of the cells occurred ranged between ~0.00 and 0.52 % and between 0.005 and 41.30 % (calculated with the help of the MS excel software XLSTAT 2012.1.01; Addinsoft), respectively, as determined by the S. cerevisiae assay. The results indicated that hospital

  13. Submonolayer epitaxy with impurities

    NASA Astrophysics Data System (ADS)

    Kotrla, Miroslav; Krug, Joachim; Smilauer, Pavel

    2000-03-01

    The effect of impurities on epitaxial growth in the submonolayer regime is studied using kinetic Monte Carlo simulations of a two-species solid-on-solid growth model. Both species are mobile, and attractive interactions among adatoms and between adatoms and impurities are incorporated. Impurities can be codeposited with the growing material or predeposited prior to growth. The activated exchange of impurities and adatoms is identified as the key kinetic process in the formation a growth morphology in which the impurities decorate the island edges. The dependence of the island density N on flux F and coverage θ is studied in detail. The impurities strongly increase the island density without appreciably changing the exponent \\chi in the power law relation N ~ F^\\chi, apart from a saturation of the flux dependence at large F and small θ. Within the present model, even completely decorated island edges do not provide efficient barriers to the attachment of adatoms, and therefore the mechanism for the increase of \\chi proposed by D. Kandel [Phys. Rev. Lett. 78, 499 (1997)] is not operative. A simple analytic theory taking into account only the dependence of the adatom diffusion constant on impurity coverage is shown to provide semi-quantitative agreement with many features observed in the simulations.

  14. Impurities in snowpacks.

    PubMed

    Sommerfeld, R A

    1989-04-01

    Snow can be involved in the acquisition, transport, storage and release of atmospheric impurities. Because it can store impurities for periods of time ranging from hours to millenia, it provides a medium for monitoring atmospheric impurities for a wide range of time scales.In most climates, snow is involved in the precipitation process. It can acquire atmospheric impurities either as aerosols or as gases. The aereosols can be included in the body of the snow crystals or adhered to their surfaces. Gases may be included in bubbles, particularly in the case of rime, or adsorbed on the ice surfaces. The amount of ice surface in a small storm is about 10(10) m(2).Snow on the ground can store the impurities acquired in the precipitation process and can acquire additional impurities as dry deposition. The low temperatures and the fact that ice is a solid reduces biological activity and rates of inorganic reactions. However, the assumption that there is no activity in the winter is not well found. Exchange is possible between different layers of the snow and between the snow and the atmosphere, resulting in relocation of gases and aerosols. These processes also insure that the impurities reside on the exterior surfaces of the ice particles that form the snowpack. Biological activity is possible near the ground-snow interface in most climates.The seasonal snowpack releases its impurities when it melts. Because below freezing processes relocate any internal impurities to the ice surfaces within the snowpack, the impurities are available to the first melt water. Pulses of both acidic and alkalinic impurities have been observed with the initial snow melt water. However, the monitoring of such pulses is difficult and the measurements are inconsistent.Impurities are incorporated for longer periods of time in perennial snowpacks and finally in ice fields. These can be glaciers, or, at the largest scale, continental ice sheets. Coring such ice is expensive but provides data on

  15. Application of Snyder-Dolan Classification Scheme to the Selection of “Orthogonal” Columns for Fast Screening for Illicit Drugs and Impurity Profiling of Pharmaceuticals - I. Isocratic Elution

    PubMed Central

    Fan, Wenzhe; Zhang, Yu; Carr, Peter W.; Rutan, Sarah C.; Dumarey, Melanie; Schellinger, Adam P.; Pritts, Wayne

    2011-01-01

    Fourteen judiciously selected reversed-phase columns were tested with 18 cationic drug solutes under the isocratic elution conditions advised in the Snyder-Dolan (S-D) hydrophobic subtraction method of column classification. The standard errors (S.E.) of the least squares regressions of log k′ vs. log k′REF were obtained for a given column against a reference column and used to compare and classify columns based on their selectivity. The results are consistent with those obtained with a study of the 16 test solutes recommended by Snyder and Dolan. To the extent that these drugs are representative these results show that the S-D classification scheme is also generally applicable to pharmaceuticals under isocratic conditions. That is, those columns judged to be similar based on the S-D 16 solutes were similar based on the 18 drugs; furthermore those columns judged to have significantly different selectivities based on the 16 S-D probes appeared to be quite different for the drugs as well. Given that the S-D method has been used to classify more than 400 different types of reversed phases the extension to cationic drugs is a significant finding. PMID:19698948

  16. Reactive impurities in excipients: profiling, identification and mitigation of drug-excipient incompatibility.

    PubMed

    Wu, Yongmei; Levons, Jaquan; Narang, Ajit S; Raghavan, Krishnaswamy; Rao, Venkatramana M

    2011-12-01

    Reactive impurities in pharmaceutical excipients could cause drug product instability, leading to decreased product performance, loss in potency, and/or formation of potentially toxic degradants. The levels of reactive impurities in excipients may vary between lots and vendors. Screening of excipients for these impurities and a thorough understanding of their potential interaction with drug candidates during early formulation development ensure robust drug product development. In this review paper, excipient impurities are categorized into six major classes, including reducing sugars, aldehydes, peroxides, metals, nitrate/nitrite, and organic acids. The sources of generation, the analytical method for detection, the stability of impurities upon storage and processing, and the potential reactions with drug candidates of these impurities are reviewed. Specific examples of drug-excipient impurity interaction from internal research and literature are provided. Mitigation strategies and corrective measures are also discussed.

  17. Bioremediation of industrial pharmaceutical drugs.

    PubMed

    Mansour, Hedi Ben; Mosrati, Ridha; Barillier, Daniel; Ghedira, Kamel; Chekir-Ghedira, Leila

    2012-07-01

    Recently, attention has been drawn toward the occurrence of pharmaceuticals in the environment. In recent years, many reports have been made on the occurrence of the large, differentiated group of pharmaceuticals in wastewater (PW), surface water, ground water, and in soil. The pharmaceutical sector is currently expanding in Tunisia, with more than 34 industries. The aim of this work was to evaluate the ability of Pseudomonas putida mt-2 to treat PW. P. putida was very efficient in reducing chemical oxygen demand (COD), total dissolved solids (TDS), and turbidity of solution (85.5, 89.1, and 81.5%, respectively). Genotoxicity of effluent, before and after biodegradation, was evaluated in vivo in mouse bone marrow by assessing the percentage of cells bearing different chromosome aberrations. Results indicated that PW showed a significant ability to induce DNA damage. In addition, PW induced a remarkable lipid peroxidation (LPO) effect, however, activities of both acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) were unchanged when treated with PW, compared to nontreated PW. This toxicity was imputed to the presence of pharmaceutical compounds in wastewater. However, chromosome aberration, as well as LPO of PW, were significantly reduced after bioremediation. Thus, the use of this strain for testing on the industrial scale seems possible and advantageous.

  18. Impurity gettering in semiconductors

    DOEpatents

    Sopori, Bhushan L.

    1995-01-01

    A process for impurity gettering in a semiconductor substrate or device such as a silicon substrate or device. 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.degree. C. to about 700.degree. 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.

  19. 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.

  20. 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.

  1. Genotoxic effects of metronidazole.

    PubMed

    Elizondo, G; Gonsebatt, M E; Salazar, A M; Lares, I; Santiago, P; Herrera, J; Hong, E; Ostrosky-Wegman, P

    1996-09-13

    Metronidazole (MTZ) is an effective agent used in the treatment of parasitic infections. Its genotoxic effects have been shown in a variety of prokaryotic systems; however, negative results have been reported in human in vivo studies. Due to its wide spread use, a study was performed to evaluate the chromosomal aberration frequencies in peripheral blood lymphocyte cultures from 10 individuals, before and after metronidazole treatment. A significant increase in the percentage of cells with chromatid and isochromatid breaks was observed after metronidazole treatment (1500 mg per day for 10 days). The percentages of cells with aberrations did not correlate with the levels of MTZ found in plasma. Individual variability was observed with respect to both the induction of aberrations and the concentration of MTZ in plasma. They could represent differences at the metabolic level, since metronidazole is known to be biotransformed by a polymorphic P450 cytochrome, and its metabolites have shown mutagenic activity.

  2. 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.

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

    PubMed

    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.

  4. Semi-preparative LC-SPE-cryoflow NMR for impurity identifications: use of mother liquor as a better source of impurities.

    PubMed

    Rinaldi, Frank; Fan, Junying; Pathirana, Charles; Palaniswamy, Venkatapurim

    2013-09-01

    Unambiguous structural elucidation of active pharmaceutical ingredients (API) impurities is a particularly challenging necessity of pharmaceutical development, particularly if the impurities are low level (0.1% level). In many cases, this requires acquiring high-quality NMR data on a pure sample of each impurity. High-quality, high signal-to-noise (S/N) one- and two-dimensional NMR data can be obtained using liquid chromatography-solid phase extraction-cryoflow NMR (LC-SPE-cryoflow NMR) with a combination of semi-preparative column for separation and mother liquor as a source of concentrated impurities. These NMR data, in conjunction with mass spectrometry data, allowed for quick and unambiguous structural elucidations of four impurities found at low level in the crystallized API but found at appreciable levels in the mother liquor that was used as the source for these impurities. These data show that semi-preparative columns can be used at lower than ideal flow rates to facilitate trapping of HPLC components for LC-SPE-cryoflow NMR analysis without compromising chromatographic resolution. Also, despite the complex chromatography encountered with the use of mother liquor as a source of impurities, acceptably pure analytes were obtained for acquiring NMR data for unambiguous structure elucidations.

  5. 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.

  6. 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.

  7. The micronucleus test-most widely used in vivo genotoxicity test.

    PubMed

    Hayashi, Makoto

    2016-01-01

    Genotoxicity is commonly evaluated during the chemical safety assessment together with other toxicological endpoints. The micronucleus test is always included in many genotoxic test guidelines for long time in many classes of chemicals, e.g., pharmaceutical chemicals, agricultural chemicals, food additives. Although the trend of the safety assessment of chemicals faces to animal welfare and in vitro systems are more welcome than the in vivo systems, the in vivo test systems are paid more attention in the field of genotoxicity because of its weight of evidence. In this review, I will summarize the following points: 1) historical consideration of the test development, 2) characteristics of the test including advantages and limitations, 3) new approaches considering to the animal welfare.

  8. 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...

  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. Locked nucleic acid (LNA): Based single-stranded oligonucleotides are not genotoxic.

    PubMed

    Guérard, Melanie; Andreas, Zeller; Erich, Koller; Christine, Marchand; Martina, Müller B; Christian, Weile; Franz, Schuler; Thomas, Singer; Yann, Tessier

    2017-04-01

    Over the last decade, single stranded oligonucleotides (ON) have gained increased attention as a new drug modality. Because the assessment of genotoxicity risk during early development of pharmaceuticals is essential, we evaluated the potential of locked nucleic acids (LNA)-ONs to induce DNA damage in L5178Y tk(+/-) cells both with the mouse lymphoma assay (MLA) and the micronucleus test (MNT). Further, the MLA was performed to assess gene and chromosome mutation over 3 and 24h (± metabolic activation). In addition, the MNT was performed to assess, in addition, a potential aneugenic liability. None of the experiments demonstrated a genotoxic effect for the five tested LNA-ONs. We further show data from four proprietary LNA-ONs tested in standard genotoxicity assays in vitro and partially in vivo, which were all negative. In addition, cellular and nuclear uptake of LNA-ONs in L5178Y tk(+/-) cells was demonstrated. Based on the results presented here as well as in the literature about other representatives of this class, we consider LNA-ONs as generally not DNA reactive and question whether genotoxicity testing of this class of ONs should be required. This is in line with recent recommendation made by the OSWG that extensively assessed the genotoxicity of oligonucleotides. Environ. Mol. Mutagen. 58:112-121, 2017. © 2017 Wiley Periodicals, Inc.

  11. Impurities in silicon solar cells

    NASA Technical Reports Server (NTRS)

    Hopkins, R. H.

    1985-01-01

    Metallic impurities, both singly and in combinations, affect the performance of silicon solar cells. Czochralski silicon web crystals were grown with controlled additions of secondary impurities. The primary electrical dopants were boron and phosphorus. The silicon test ingots were grown under controlled and carefully monitored conditions from high-purity charge and dopant material to minimize unintentional contamination. Following growth, each crystal was characterized by chemical, microstructural, electrical, and solar cell tests to provide a detailed and internally consistent description of the relationships between silicon impurity concentration and solar cell performance. Deep-level spectroscopy measurements were used to measure impurity concentrations at levels below the detectability of other techniques and to study thermally-induced changes in impurity activity. For the majority of contaminants, impurity-induced performance loss is due to a reduction of the base diffusion length. From these observations, a semi-empirical model which predicts cell performance as a function of metal impurity concentration was formulated. The model was then used successfully to predict the behavior of solar cells bearing as many as 11 different impurities.

  12. 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.

  13. Characterization of impurities of HIV NNRTI Doravirine by UHPLC-high resolution MS and tandem MS analysis.

    PubMed

    Zhang, Li-Kang; Yang, Ross; Sheng, Huaming; Helmy, Roy; Zheng, Jinjian; Cao, Yang; Gauthier, Donald R

    2016-10-01

    World Health Organization estimates that 34 million individuals globally are living with Human Immunodeficiency Virus (HIV). Doravirine is a non-nucleoside reverse transcriptase inhibitors (NNRTI) being evaluated by Merck for the treatment of HIV-1 infection. Drug regulation authorities require the purity of a pharmaceutical to be fully defined. This is important to ensure that the pharmacological and toxicological effects are truly those of the drug substances and not because of the impurities. Thus, understanding the drug impurity profiles is critical to the safety and potency assessment of the drug candidate for clinical trials. The impurity characterization can also provide useful information for critical assessment of pharmaceutical processes. Advances in mass spectrometry instrumentation and methods allow the identification of impurities in pharmaceuticals with a minimum of sample material and increased sensitivity. In this study, a rapid and sensitive method was developed for the structural determination of the major impurities of doravirine. The study utilizes ultra performance liquid chromatography-high-resolution-tandem mass spectrometry (UHPLC-HRMS/MS) techniques to perform structure elucidation of the unknown structures. This approach has significant impact on impurity structural elucidation, and a total of five trace-level impurities of doravirine were characterized using the developed method. Copyright © 2016 John Wiley & Sons, Ltd.

  14. Genotoxicity of organic extracts from atmospheric particles

    SciTech Connect

    Courtois, Y.A.; Min, S.; Lachenal, C.; Jacquot-Deschamps, J.M.; Callais, F.; Festy, B.

    1988-01-01

    Experiments to evaluate the genotoxic potentialities of urban air particles sampled in Paris (France) after organic solvent extraction have been carried out using four in vitro genotoxicity tests. The two bacterial tests (the Ames test and the SOS Chromotest) demonstrate the genotoxicity of the organic extracts of atmospheric particles; two additional tests (induction of 6-thioguanine mutants and sister chromatid exchanges), carried out on V79 Chinese hamster cells, also confirm these potentialities. These results show clearly that particulate organic extracts induce point mutations in both bacteria and mammalian cells, or the cellular response (SOS repair) to these mutations in bacteria; likewise, they are responsible for clastogenic effects in mammalian cells. Genotoxicity is due either to direct genotoxic chemicals or to active metabolic products of the action of microsomal enzymes. The optimalization of testing procedures is discussed in order to appreciate the contribution of genotoxicity tests to the study of atmospheric pollution.

  15. 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

  16. Evolution of genotoxicity test methods in Japan.

    PubMed

    Sofuni, Toshio

    2017-01-01

    The evolution of methods to assess genotoxicity of test compounds is thought to be one of the important subjects in The Japanese Environmental and Mutagen Society (JEMS). In 1970, the Ministry of Education of Japan (at that time) organized a research group (Organizer: Y. Tazima, National Institute of Genetics), and started a systematic research on the genotoxic effects induced by chemical substances. Considering the importance of this issue through the outcomes of the research group, JEMS was established in 1972, and President Tazima organized the 1st annual meeting in the August in Tokyo with the participation of experts in this field working in national institutes, universities and others in Japan. The discovery that food additives possessed genotoxic potential triggered various scientific activities in the field of genotoxicity. Another important point was the correlation between genotoxicity and carcinogenicity, in which the establishment of the reverse mutation assay played an important role. Other critical factors, such as side effects of drugs, occupational cancer, and environmental pollution due to genotoxic chemicals, emphasized the importance of genotoxicity tests for human safety. The tests performed to assess genotoxicity from 1960s to 1980s will be described to understand that many different genotoxic methodologies were discussed in these periods.

  17. 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.

  18. Recovery of surfaces from impurity poisoning during crystal growth

    NASA Astrophysics Data System (ADS)

    Land, Terry A.; Martin, Tracie L.; Potapenko, Sergey; Palmore, G. Tayhas; de Yoreo, James J.

    1999-06-01

    Growth and dissolution of crystal surfaces are central to processes as diverse as pharmaceutical manufacturing,, corrosion, single-crystal production and mineralization in geochemical and biological environments,. Impurities are either unavoidable features of these processes or intentionally introduced to modify the products. Those that act as inhibiting agents induce a so-called `dead zone', a regime of low supersaturation where growth ceases. Models based on the classic theory of Cabrera and Vermilyea explain behaviour near the dead zone in terms of the pinning of elementary step motion by impurities,. Despite general acceptance of this theory, a number of commonly investigated systems exhibit behaviour not predicted by such models. Moreover, no clear microscopic picture of impurity-step interactions currently exists. Here we use atomic force microscopy to investigate the potassium dihydrogen phosphate {100} surface as it emerges from the dead zone. We show that traditional models are not able to account for the behaviour of this system because they consider only elementary steps, whereas it is the propagation of macrosteps (bunches of monolayer steps) that leads to resurrection of growthout of the dead zone. We present a simple physical model of this process that includes macrosteps and relates characteristics of growth near the dead zone to the timescale for impurity adsorption.

  19. Urinary screening for potentially genotoxic exposures in a chemical industry.

    PubMed Central

    Ahlborg, G; Bergström, B; Hogstedt, C; Einistö, P; Sorsa, M

    1985-01-01

    Mutagenic activity, measured by the bacterial fluctuation assay and thioether concentration in urine from workers at a chemical plant producing pharmaceuticals and explosives, was determined before and after exposure. Of 12 groups only those exposed to trinitrotoluene (n = 14) showed a significant increase in mutagenic activity using Salmonella typhimurium TA 98 without any exogenous metabolic system. The same strain responded only weakly when the S-9 mix was used; with Escherichia coli WP2 uvrA no effect of exposure was observed. Urinary thioether concentration was higher among smokers than among non-smokers, but occupational exposure had no effect. Urinary mutagenicity testing may be a useful tool for screening potentially genotoxic exposures in complex chemical environments. PMID:3899158

  20. Viral Vectors: The Road to Reducing Genotoxicity.

    PubMed

    David, Rhiannon M; Doherty, Ann T

    2017-02-01

    Viral vector use in gene therapy has highlighted several safety concerns, including genotoxic events. Generally, vector-mediated genotoxicity results from upregulation of cellular proto-oncogenes via promoter insertion, promoter activation, or gene transcript truncation, with enhancer-mediated activation of nearby genes the primary mechanism reported in gene therapy trials. Vector-mediated genotoxicity can be influenced by virus type, integration target site, and target cell type; different vectors have distinct integration profiles which are cell-specific. Non-viral factors, including patient age, disease, and dose can also influence genotoxic potential, thus the choice of test models and clinical trial populations is important to ensure they are indicative of efficacy and safety. Efforts have been made to develop viral vectors with less risk of insertional mutagenesis, including self-inactivating (SIN) vectors, enhancer-blocking insulators, and microRNA targeting of vectors, although insertional mutagenesis is not completely abrogated. Here we provide an overview of the current understanding of viral vector-mediated genotoxicity risk from factors contributing to viral vector-mediated genotoxicity to efforts made to reduce genotoxicity, and testing strategies required to adequately assess the risk of insertional mutagenesis. It is clear that there is not a 'one size fits all' approach to vector modification for reducing genotoxicity, and addressing these challenges will be a key step in the development of therapies such as CRISPR-Cas9 and delivery of future gene-editing technologies.

  1. Validation of a human cell based high-throughput genotoxicity assay 'Anthem's Genotoxicity screen' using ECVAM recommended lists of genotoxic and non-genotoxic chemicals.

    PubMed

    Rajakrishna, Lakshmi; Krishnan Unni, Salini; Subbiah, Madhuri; Sadagopan, Sathish; Nair, Ayyappan R; Chandrappa, Ravindra; Sambasivam, Ganesh; Sukumaran, Sunil Kumar

    2014-02-01

    A novel high throughput-enabled human cell based screen, Anthem's Genotoxicity screen, was developed to achieve higher specificity for predicting in vivo genotoxins by an in vitro method. The assay employs engineered human colon carcinoma cell line; HCT116 cells that are stably engineered with three promoter-reporter cassettes such that an increased reporter activity reflects the activation of associated signaling events in a human cell. The current study focuses on the evaluation of sensitivity and specificity of Anthem's Genotoxicity screen using 62 compounds recommended by the European Centre for the Validation of Alternative Methods (ECVAM). The concordance of Anthem's Genotoxicity screen with in vivo tests was 95.5% with sensitivity of 95.2% and specificity of 95.7%. Thus Anthem's Genotoxicity screen, a high-throughput mechanism based genotox indicator test can be employed by a variety of industries for rapid screening and early detection of potential genotoxins.

  2. Effects of radiation and vitamin C treatment on metronidazole genotoxicity in mice.

    PubMed

    Das Roy, Lopamudra; Giri, Sarbani; Singh, Supriya; Giri, Anirudha

    2013-05-15

    The impact of exposure to low dose radiation (LDR) on human health is not clear. Besides, cross adaptation or sensitization with pharmaceutical agents may modify the risk of LDR. In the present study, we analyzed the interaction of radiation and metronidazole (MTZ) in inducing chromosome aberration (CA) and micronucleus (MN) in the bone marrow cells of Balb/C mice in vivo. Further, we evaluated the efficacy of vitamin C to reduce MTZ induced genotoxicity. We found that 10, 20 and 40mg/kg of MTZ induced dose dependent increase in the frequency of CA (r=0.9923, P<0.01) as well as MN (r=0.9823, P<0.05) in polychromatic erythrocytes. However, MTZ did not affect the ratio of polychromatic erythrocytes to normochromatic erythrocytes indicating lack of cytotoxicity. Supplementation with vitamin C prior to MTZ treatment significantly reduced the frequency of CA (P<0.001) as well as MN (P<0.001). Radiation (0.5Gy) exposure prior to MTZ treatment produced a less than additive (for CA) to additive (for MN) effects. However, radiation exposure following MTZ treatment produced additive (for CA) and synergistic (for MN) effects. Further, vitamin C pre-treatment also reduced the genotoxicity indices following the combined treatment of MTZ and radiation. Our findings suggest that MTZ may sensitize bone marrow cells to radiation exposure and enhances genotoxicity. We recommend more studies on the interaction of LDR and marketed pharmaceuticals to minimize possible harmful outcomes through appropriate precautionary measures.

  3. Genotoxicity assessment of peptide/protein-related biotherapeutics: points to consider before testing.

    PubMed

    Thybaud, Veronique; Kasper, Peter; Sobol, Zhanna; Elhajouji, Azeddine; Fellows, Mick; Guerard, Melanie; Lynch, Anthony M; Sutter, Andreas; Tanir, Jennifer Y

    2016-07-01

    The ICH S6(R1) recommendations on safety evaluation of biotherapeutics have led to uncertainty in determining what would constitute a cause for concern that would require genotoxicity testing. A Health and Environmental Sciences Institute's Genetic Toxicology Technical Committee Workgroup was formed to review the current practice of genotoxicity assessment of peptide/protein-related biotherapeutics. There are a number of properties of peptide/protein-related biotherapeutics that distinguish such products from traditional 'small molecule' drugs and need to be taken into consideration when assessing whether genotoxicity testing may be warranted and if so, how to do it appropriately. Case examples were provided by participating companies and decision trees were elaborated to determine whether and when genotoxicity evaluation is needed for peptides containing natural amino acids, non-natural amino acids and other chemical entities and for unconjugated and conjugated proteins. From a scientific point of view, there is no reason for testing peptides containing exclusively natural amino acids irrespective of the manufacturing process. If non-natural amino acids, organic linkers and other non-linker chemical components have already been tested for genotoxicity, there is no need to re-evaluate them when used in different peptide/protein-related biotherapeutics. Unless the peptides have been modified to be able to enter the cells, it is generally more appropriate to evaluate the peptides containing the non-natural amino acids and other non-linker chemical moieties in vivo where the cleavage products can be formed. For linkers, it is important to determine if exposure to reactive forms are likely to occur and from which origin. When the linkers are anticipated to be potential mutagenic impurities they should be evaluated according to ICH M7. If linkers are expected to be catabolic products, it is recommended to test the entire conjugate in vivo, as this would ensure that the

  4. [Genotoxicity research thought and method on traditional Chinese medicine].

    PubMed

    Han, Jia-yin; Yi, Yan; Liang, Ai-hua; Zhang, Yu-shi; Li, Chun-ying; Zhao, Yong; Wang, Lian-mei; Li, Gui-qin

    2015-07-01

    Genotoxicity research takes an important place in traditional Chinese medicine safety evaluation. Genotoxicity test on traditional Chinese medicine has been paid great attention since 1970s. Currently, the most developed genotoxicity test methods included: bacterial reverse mutation test and mouse lymphoma assay which are used to detect relevant genetic changes, micronucleus test and chromosomal analysis which are used to measure chromosomal aberration, and single cell electrophoresis assay which is used to test DNA damage. This article reviews research progress on genotoxicity of traditional Chinese medicine, evaluation methods of genotoxicity, the problems and solutions on genotoxicity evaluation of traditional Chinese medicine, and new technique used in genotoxicity test.

  5. 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.

  6. 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.

  7. Levothyroxine sodium revisited: A wholistic structural elucidation approach of new impurities via HPLC-HRMS/MS, on-line H/D exchange, NMR spectroscopy and chemical synthesis.

    PubMed

    Ruggenthaler, M; Grass, J; Schuh, W; Huber, C G; Reischl, R J

    2017-02-20

    The structural elucidation of unknown pharmaceutical impurities plays an important role in the quality control of newly developed and well-established active pharmaceutical ingredients (APIs). The United States Pharmacopeia (USP) monograph for the API Levothyroxine Sodium, a synthetic thyroid hormone, features two high pressure liquid chromatography (HPLC) methods using UV-VIS absorption detection to determine organic impurities in the drug substance. The impurity profile of the first USP method ("Procedure 1") has already been extensively studied, however for the second method ("Procedure 2"), which exhibits a significantly different impurity profile, no wholistic structural elucidation of impurities has been performed yet. Applying minor modifications to the chromatographic parameters of USP "Procedure 2" and using various comprehensive structural elucidation methods such as high resolution tandem mass spectrometry with on-line hydrogen-deuterium (H/D) exchange or two-dimensional nuclear magnetic resonance spectroscopy (NMR) we gained new insights about the complex impurity profile of the synthetic thyroid hormone. This resulted in the characterization of 24 compounds previously unknown to literature and the introduction of two new classes of Levothyroxine Sodium impurities. Five novel compounds were unambiguously identified via isolation or synthesis of reference substances and subsequent NMR spectroscopic investigation. Additionally, Collision-Induced Dissociation (CID)-type fragmentation of identified major impurities as well as neutral loss fragmentation patterns of many characterized impurities were discussed.

  8. 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.

  9. Combination of in vitro bioassays for the determination of cytotoxic and genotoxic potential of wastewater, surface water and drinking water samples.

    PubMed

    Zegura, Bojana; Heath, Ester; Cernosa, Andrej; Filipic, Metka

    2009-06-01

    In this study we evaluated genotoxicity and cytotoxicity of native samples of wastewaters (15 samples), surface waters (28 samples) and potable waters (8 samples) with the SOS/umuC assay with Salmonella typhimurium TA1535/pSK1002 and MTT assay with human hepatoma HepG2 cells. The genotoxicity of selected samples was confirmed with the comet assay with HepG2 cells. In the SOS/umuC assay 13 out of the 51 samples were genotoxic: two effluent samples from chemical industry; one sample of wastewater treatment plant effluent; two hospital wastewater samples; three river water samples and four lake water samples. Six samples were cytotoxic for HepG2 cells: both effluent samples of chemical industry, two wastewater treatment plant effluent samples, and two river water samples, however, only the chemical industry effluent samples were genotoxic and cytotoxic, indicating that different contaminants are responsible for genotoxic and toxic effects. Comparing genotoxicity of river and lake water samples with the chemical analytical data of the presence of the residues of pharmaceutical and personal care products (non-steroidal anti-inflammatory drugs, UV filters and disinfectants) in these samples, indicated that the presence of UV filters might be linked to the genotoxicity of these samples. The results showed that the application of the bacterial SOS/umuC assay and mammalian cell assays (MTT and comet assay) with HepG2 cells was suitably sensitive combination of assays to monitor genotoxicity and cytotoxicity of native samples of wastewaters and surface waters. With this study we also confirmed that the toxicity/genotoxicity bioassays should be an integral tool in the evaluation of toxicity of complex wastewaters before the release into environment, as well as for the monitoring of surface water quality, providing data useful in risk assessment.

  10. New perspectives and lessons learned in the identification of impurities in drug development.

    PubMed

    Sasaki, Ryan R; McGibbon, Graham; Lee, Mike S; Murray, Clare L; Pharr, Bruce

    2014-11-01

    Within the pharmaceutical industry, the rapid identification, elucidation and characterization of synthetic or process impurities or degradants form an intense and a comprehensive undertaking. Advances in laboratory hardware and software are changing the way in which scientists work together to help resolve impurities in a quick and efficient manner. Although the industry trend toward externalization and outsourcing of development tasks provides a cost-effective method, the demand for improved productivity in laboratory workflows in drug development continues to be a high priority. This brings a need for new approaches for communication, collaboration and data management.

  11. Ecotoxicity and genotoxicity assessment of cytotoxic antineoplastic drugs and their metabolites.

    PubMed

    Zounkova, Radka; Kovalova, Lubomira; Blaha, Ludek; Dott, Wolfgang

    2010-09-01

    In spite of growing scientific concern about pharmaceuticals in the environment, there is still a lack of information especially with regard to their metabolites. The present study investigated ecotoxicity and genotoxicity of three widely used cytostatic agents 5-fluorouracil (5-FU), cytarabine (CYT) and gemcitabine (GemC) and their major human metabolites, i.e. alpha-fluoro-beta-alanine (FBAL), uracil-1-beta-D-arabinofuranoside (AraU) and 2',2'-difluorodeoxyuridine (dFdU), respectively. Effects were studied in acute immobilization and reproduction assays with crustacean Daphnia magna and growth inhibition tests with alga Desmodesmus subspicatus and bacteria Pseudomonas putida. Genotoxicity was tested with umu-test employing Salmonella choleraesius subsp. chol. Toxicity was relatively high at parent compounds with EC(50) values ranging from 44 microg L(-1) (5-fluorouracil in the P. putida test) to 200 mg L(-1) (cytarabine in D. magna acute test). In general, the most toxic compound was 5-FU. Studied metabolites showed low or no toxicity; only FBAL (metabolite of 5-FU) showed low toxicity to D. subspicatus and P. putida with EC(50) values 80 and 140 mg L(-1), respectively. All parent cytostatics showed genotoxicity with minimum genotoxic concentrations (MGC) ranging from 40 to 330 mg L(-1). From metabolites, only FBAL was genotoxic in high concentrations. To our knowledge, the present study provides some of the first ecotoxicity data for both cytostatics and their metabolites, which might further serve for serious evaluation of ecological risks. The observed EC(50) values within the microg L(-1) range were fairly close to concentrations reported in hospital sewage water, which indicates further research needs, especially studies of chronic toxicity.

  12. Formation of peptide impurities in polyester matrices during implant manufacturing.

    PubMed

    Rothen-Weinhold, A; Oudry, N; Schwach-Abdellaoui, K; Frutiger-Hughes, S; Hughes, G J; Jeannerat, D; Burger, U; Besseghir, K; Gurny, R

    2000-05-01

    Most peptides are susceptible, in vivo, to proteolytic degradation, and it is difficult to formulate and to deliver them without loss of biological activity. In addition, it is often desirable to release them continuously and at a controlled rate over a period of weeks or months. For these reasons, a controlled release system is suitable. Poly(lactic acid) (PLA) is a biocompatible and biodegradable material that can be used for many applications, including the design of injectable controlled release systems for pharmaceutical agents. Development of these delivery systems presents challenges in the assessment of stability, specially for peptide drugs. By means of an extrusion method, long-acting poly(lactic acid) implants containing vapreotide, a somatostatin analogue, were prepared. The nature of the main degradation product obtained after implant manufacturing was elucidated. It was found that the main peptide impurity was a lactoyl lactyl-vapreotide conjugate. Because lactide are found in small quantities in most commercially available PLA, the influence of residual lactide in the polymeric matrix, on the formation of peptide impurities during manufacturing, was specially investigated. This work demonstrates that the degree of purity of the carrier is of great importance with regard to the formation of peptide impurities.

  13. Genotoxic potential evaluation of a cosmetic insoluble substance by the micronuclei assay.

    PubMed

    Dayan, N; Shah, V; Minko, T

    2011-01-01

    An optical brightener (OB) powder (INCI: sodium silicoaluminate (and) glycidoxypropyl trimethyloxysilane/PEI-250 cross fluorescent brightener 230 salt (and) polyvinylalcohol crosspolymer) that is used in cosmetic facial products was tested for its genotoxic potential using the micronuclei test (MNT). It is a solid dry powder with an average size of 5 microns that is insoluble but dispersible in water. This study describes the exposure of cell culture to positive controls with and without enzymatic activation and to the test compound in different concentrations. We evaluated three end points: microscopic observation and quantification of micronuclei formation, and cell viability and proliferation. Both positive controls induced significant changes that were observed under the microscope and quantified. Based on its chemical nature, it was not anticipated that the test substance will degrade under the conditions of the experiments. However, the test is required to make sure that when solublized, impurities that may be present, even at trace levels, will not induce a genotoxic effect. The test compound did not promote micronuclei formation or change the viability or proliferation rate of cells. During this study we faced challenges such as solubilization and correlating viability data to genotoxicity data. These are described in the body of the paper. We believe that with the emergence of the 7(th) European amendment that bans animal testing, sharing these data and the study protocol serves as a key in building the understanding of the utilization of in vitro studies in the safety assessment of cosmetic ingredients.

  14. 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.

  15. 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.

  16. [Studies on the food allergenic proteins contained in pharmaceutical excipients].

    PubMed

    Sakai, Shinobu; Adachi, Reiko; Miyazaki, Tamaki; Aso, Yukio; Okuda, Haruhiro; Teshima, Reiko

    2012-01-01

    Most drugs contain pharmaceutical excipients. These are pharmacologically inactive substances used as vehicles for the active ingredients of a medication. Some of these pharmaceutical excipients are produced from allergenic foods (e.g., milk, egg, peanut, soybean, and sesame) and removing proteins completely from such excipients is difficult. Therefore, if individuals with food allergy consume drugs containing allergenic food-derived excipients, eliminating the risk of developing specific allergic symptoms induced by them may not be possible. We determined the levels of proteins in pharmaceutical excipients and ethical drugs (inhalants and injections) by spectrophotometric analyses. The level of protein in the pharmaceutical excipient lactose in each sample was approximately 1 mg/g. In the case of oils from soybeans, peanuts, and sesame in pharmaceutical excipients, proteins were detected in the range 7-9 microg/g sample. We also determined levels of allergenic proteins in pharmaceutical excipients and ethical drugs using commercial enzyme-linked immunosorbent assay systems. The milk proteins in lactose were detected in the range 1.39-13.07 microg/g. The results of this study suggest that physicians, patients with food allergies, pharmacists, and healthcare providers must pay attention to presence of potential impurities those may cause allergic symptoms in pharmaceutical products.

  17. 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.

  18. Influence of Peroxide Impurities in Povidone on the Stability of Selected β-Blockers with the Help of HPLC.

    PubMed

    Prachi, Saklecha; Komal, Chaudhary; Priti, Mehta J

    2017-02-02

    A present study was conducted to investigate compatibility of β-blocker drugs( like atenolol, labetalol hydrochloride, bisoprolol fumarate, metoprolol succinate, carvedilol and propranolol hydrochloride) with the pharmaceutical excipient povidone. To check the influence of peroxide impurity present in povidone on the stability of β-blockers, a binary mixture technique has been adopted. The binary mixtures (1:1) of β-blockers with povidone excipient were stored for the duration of 6 months at accelerated conditions (40°C and 75% RH) and analyzed with the technique of high-performance liquid chromatography (HPLC). On analysis, HPLC results shows that, the percentage of total impurity for atenolol-2.15%, bisoprolol fumarate-3.55%, carvedilol-2.19%, and labetalol hydrochloride-1.89%, with respect to povidone. To verify the interaction of H2O2 present in povidone as an impurity, oxidative degradation of selected active pharmaceutical ingredients were performed and degradation profile were compared with that of degradation impurities generated in drug-excipient mixture at accelerated conditions. The relative retention time (RRT) of impurities generated in accelerated stability study samples resembles the RRT of degradation products generated by oxidative degradation of pure drugs. Thus, it confirms that degradation of β-blockers with povidone was mediated by organic peroxides present as an impurity in povidone.

  19. Pharmaceutical cocrystals: an overview.

    PubMed

    Qiao, Ning; Li, Mingzhong; Schlindwein, Walkiria; Malek, Nazneen; Davies, Angela; Trappitt, Gary

    2011-10-31

    Pharmaceutical cocrystals are emerging as a new class of solid drugs with improved physicochemical properties, which has attracted increased interests from both industrial and academic researchers. In this paper a brief and systematic overview of pharmaceutical cocrystals is provided, with particular focus on cocrystal design strategies, formation methods, physicochemical property studies, characterisation techniques, and recent theoretical developments in cocrystal screening and mechanisms of cocrystal formations. Examples of pharmaceutical cocrystals are also summarised in this paper.

  20. 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.

  1. 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.

  2. 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.

  3. Photoactivated hypericin is not genotoxic.

    PubMed

    Feruszová, Jana; Imreová, Petronela; Bodnárová, Kristína; Ševčovičová, Andrea; Kyzek, Stanislav; Chalupa, Ivan; Gálová, Eliška; Miadoková, Eva

    2016-04-01

    The study was designed to test the potential photogenotoxicity of hypericin (HYP) at three different levels: primary DNA damages, gene mutations and chromosome aberrations. Primary genetic changes were detected using the comet assay. The potential mutagenic activity of HYP was assessed using the Ames/Salmonella typhimurium assay. Finally, the ability of photoactivated HYP to induce chromosome aberrations was evaluated by the in vitro mammalian chromosome aberration test and compared to that of non-photoactivated HYP. The results have shown that photoactivated HYP can only induce primary DNA damages (single-strand DNA breaks), acting in a dose-response manner. This activity depended both on HYP concentrations and an intensity of the light energy needed for its photoactivation. However, mutagenic effect of photoactivated HYP evaluated in the Ames assay using three bacterial strains S. typhimurium (TA97, TA98 and TA100) was not confirmed. Moreover, photoactivated HYP in the range of concentrations (0.005-0.01 µg/ml) was not found to be clastogenic against HepG2 cells. Our findings from both the Ames assay and the chromosome aberrations test provide evidence that photoactivated HYP is not genotoxic, which might be of great importance mainly in terms of its use in the photodynamic therapy.

  4. Genotoxicity studies on green tea catechin.

    PubMed

    Ogura, R; Ikeda, N; Yuki, K; Morita, O; Saigo, K; Blackstock, C; Nishiyama, N; Kasamatsu, T

    2008-06-01

    The beneficial effects of tea catechins are well documented. We evaluated the genotoxic potential of a green tea catechin preparation using established genotoxicity assays, including a bacterial reverse mutation assay (Ames test), a chromosomal aberration assay in cultured Chinese hamster lung cells (CHL/IU), a mouse lymphoma L5178Y/tk assay, and a bone marrow micronucleus (MN) assay in ICR CD mice and SD rats. No significant increases in the number of revertant colonies were observed in the Ames test, but positive responses were observed in two in vitro assays: the chromosomal aberration assay and mouse lymphoma L5178/tk assay. However, the in vivo study demonstrated no significant increase in micronucleated polychromatic erythrocytes (MNPCE) in the bone marrow of both ICR CD mice and SD rats administered a high dose of the green tea catechin preparation up to 2000mg/kg. Combined with favorable epidemiological information suggesting a chemopreventive effect of tea catechins on carcinogenesis, we conclude that green tea catechin presents no significant genotoxic concern under the anticipated conditions of use. These results are consistent with other genotoxicity studies of tea catechins, which show minimal, if any, genotoxic potential.

  5. 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...

  6. Impurity-induced divertor plasma oscillations

    SciTech Connect

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

    2016-01-15

    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

    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.

  8. Impurity-induced divertor plasma oscillations

    SciTech Connect

    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 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. As a result, the implications of the impurity-induced plasma oscillations for divertor operation in the next generation tokamaks are also discussed.

  9. Impurity-induced divertor plasma oscillations

    DOE PAGES

    Smirnov, R. D.; Kukushkin, A. S.; Krasheninnikov, S. I.; ...

    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

  10. Pharmaceutical Education in Nigeria.

    ERIC Educational Resources Information Center

    Oyegbile, F. Rachel

    1988-01-01

    Nigeria has six pharmacy schools, most offering graduate programs. The undergraduate program is being expanded from four to five years. Although behavioral and clinical sciences are offered, emphasis is on the pharmaceutical sciences. Overall, pharmaceutical education is oriented toward hospice practice. (Author/MSE)

  11. 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.

  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. 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.

  15. 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

  16. Combining the in vivo comet and micronucleus assays: a practical approach to genotoxicity testing and data interpretation.

    PubMed

    Vasquez, Marie Z

    2010-03-01

    Despite regulatory directives requiring the reduction of animal use in safety testing, recent modifications to genotoxicity testing guidelines now propose the use of two in vivo genotoxicity assays as a follow-up to an in vitro positive (International Conference on Harmonization Consensus Draft Guidance S2[R1] released March, 2008). To address both goals, the in vivo comet and micronucleus (MN) assays can be successfully combined into one informative study. Combining these two assays with such differences in sensitivity, endpoints measured and the type of data generated significantly improves upon the current standard capabilities for detecting genotoxicity without requiring additional animals. But to take full advantage of the benefits of incorporating the comet assay in safety testing, these same differences must be recognized and considered. Developed from over 15 years experience using the in vivo comet and MN assays in genotoxicity testing of chemicals and pharmaceuticals, this paper presents guidelines for the appropriate experimental design, dose selection and data interpretation for combined in vivo comet/MN assay studies. To illustrate the approach, data from combined assay studies are presented and discussed.

  17. 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}

  18. Impure placebo is a useless concept.

    PubMed

    Louhiala, Pekka; Hemilä, Harri; Puustinen, Raimo

    2015-08-01

    Placebos are allegedly used widely in general practice. Surveys reporting high level usage, however, have combined two categories, 'pure' and 'impure' placebos. The wide use of placebos is explained by the high level usage of impure placebos. In contrast, the prevalence of the use of pure placebos has been low. Traditional pure placebos are clinically ineffective treatments, whereas impure placebos form an ambiguous group of diverse treatments that are not always ineffective. In this paper, we focus on the impure placebo concept and demonstrate problems related to it. We also show that the common examples of impure placebos are not meaningful from the point of view of clinical practice. We conclude that the impure placebo is a scientifically misleading concept and should not be used in scientific or medical literature. The issues behind the concept, however, deserve serious attention in future research.

  19. 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.

  20. 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.

  1. Development of Hydrophilic Interaction Liquid Chromatography Method for the Analysis of Moxonidine and Its Impurities

    PubMed Central

    2016-01-01

    Fast and simple hydrophilic interaction liquid chromatography (HILIC) method was developed and validated for the analysis of moxonidine and its four impurities (A, B, C, and D) in pharmaceutical dosage form. All experiments were performed on the Agilent Technologies 1200 high-performance liquid chromatography (HPLC) system using Zorbax RX-SIL, 250 mm × 4.6 mm, 5 μm column as stationary phase (T = 25°C, F = 1 mL/min, and λ = 255 nm), and mixture of acetonitrile and 40 mM ammonium formate buffer (pH 2.8) 80 : 20 (v/v) as mobile phase. Under the optimal chromatographic conditions, selected by central composite design, separation and analysis of moxonidine and its four impurities are enabled within 12 minutes. Validation of the method was conducted in accordance with ICH guidelines. Based on the obtained results selectivity, linearity (r ≥ 0.9976), accuracy (recovery: 93.66%–114.08%), precision (RSD: 0.56%–2.55%), and robustness of the method were confirmed. The obtained values of the limit of detection and quantification revealed that the method can be used for determination of impurities levels below 0.1%. Validated method was applied for determination of moxonidine and its impurities in commercially available tablet formulation. Obtained results confirmed that validated method is fast, simple, and reliable for analysis of moxonidine and its impurities in tablets. PMID:27847672

  2. Instabilities and bifurcations of nonlinear impurity modes.

    PubMed

    Kevrekidis, Panayotis G; Kivshar, Yuri S; Kovalev, Alexander S

    2003-04-01

    We study the structure and stability of nonlinear impurity modes in the discrete nonlinear Schrödinger equation with a single on-site nonlinear impurity emphasizing the effects of interplay between discreteness, nonlinearity, and disorder. We show how the interaction of a nonlinear localized mode (a discrete soliton or discrete breather) with a repulsive impurity generates a family of stationary states near the impurity site, as well as examine both theoretical and numerical criteria for the transition between different localized states via a cascade of bifurcations.

  3. 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.

  4. 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.

  5. An Experimental Design Approach for Impurity Profiling of Valacyclovir-Related Products by RP-HPLC

    PubMed Central

    Katakam, Prakash; Dey, Baishakhi; Hwisa, Nagiat T; Assaleh, Fathi H; Chandu, Babu R; Singla, Rajeev K; Mitra, Analava

    2014-01-01

    Abstract Impurity profiling has become an important phase of pharmaceutical research where both spectroscopic and chromatographic methods find applications. The analytical methodology needs to be very sensitive, specific, and precise which will separate and determine the impurity of interest at the 0.1% level. Current research reports a validated RP-HPLC method to detect and separate valacyclovir-related impurities (Imp-E and Imp-G) using the Box-Behnken design approach of response surface methodology. A gradient mobile phase (buffer: acetonitrile as mobile phase A and acetonitrile: methanol as mobile phase B) was used. Linearity was found in the concentration range of 50–150 μg/mL. The mean recovery of impurities was 99.9% and 103.2%, respectively. The %RSD for the peak areas of Imp-E and Imp-G were 0.9 and 0.1, respectively. No blank interferences at the retention times of the impurities suggest the specificity of the method. The LOD values were 0.0024 μg/mL for Imp-E and 0.04 μg/mL for Imp-G and the LOQ values were obtained as 0.0082 μg/mL and 0.136 μg/mL, respectively, for the impurities. The S/N ratios in both cases were within the specification limits. Proper peak shapes and satisfactory resolution with good retention times suggested the suitability of the method for impurity profiling of valacyclovir-related drug substances. PMID:25853072

  6. Identification and characterization of potential impurities in raloxifene hydrochloride.

    PubMed

    Reddy, Reguri Buchi; Goud, Thirumani Venkateshwar; Nagamani, Nagabushanam; Kumar, Nutakki Pavan; Alagudurai, Anandan; Murugan, Raman; Parthasarathy, Kannabiran; Karthikeyan, Vinayagam; Balaji, Perumal

    2012-01-01

    During the synthesis of the bulk drug Raloxifene hydrochloride, eight impurities were observed, four of which were found to be new. All of the impurities were detected using the gradient high performance liquid chromatographic (HPLC) method, whose area percentages ranged from 0.05 to 0.1%. LCMS was performed to identify the mass number of these impurities, and a systematic study was carried out to characterize them. These impurities were synthesized and characterized by spectral data, subjected to co-injection in HPLC, and were found to be matching with the impurities present in the sample. Based on their spectral data (IR, NMR, and Mass), these impurities were characterized as Raloxifene-N-Oxide [Impurity: 1]; EP impurity A [Impurity: 2]; EP impurity B [Impurity: 3]; Raloxifene Dimer [Impurity: 4]; HABT (6-Acetoxy-2-[4-hydroxyphenyl]-1-benzothiophene or 6-Hydroxy-2-[4-acetoxyphenyl]-1-benzothiophene) [Impurity: 5]; PEBE (Methyl[4-[2-(piperidin-1-yl)ethoxy

  7. Capillary electrophoresis determination of loratadine and related impurities.

    PubMed

    Fernández, H; Rupérez, F J; Barbas, C

    2003-03-10

    While HPLC has traditionally been the method of choice for purity determination of pharmaceutical substances, capillary electrophoresis (CE) offers a different selectivity and hence it is a complementary technique to HPLC. Loratadine, an antihistamine, could include in its raw material seven impurities that ought to be separated, identified and quantified for drug development and quality control. As a complementary tool for undoubtful identification, a CE method has been developed. The separation was carried out with an uncoated fused-silica capillary (57 cm x 50 microm ID) and was operated at 20 kV potential. Temperature was maintained at 25 degrees C. The final separation buffer was prepared with 100 mM H(3)PO(4) made up to pH 2.5 with NaOH and with 10% acetonitrile added (v/v). Impurities can be detected at the 0.1% level of the active and validation parameters for linearity accuracy and precision are adequate for all the analytes and that permits to consider the method reliable and suitable for application to long-term stability and purity studies.

  8. Genotoxic activity of halogenated phenylglycine derivatives.

    PubMed

    Boto, Alicia; Gallardo, Juan A; Hernández, Rosendo; Ledo, Francisco; Muñoz, Ana; Murguía, José R; Menacho-Márquez, Mauricio; Orjales, Aurelio; Saavedra, Carlos J

    2006-12-01

    The discovery of genotoxic amino acids derived from phenylglycine, and possessing halogen substituents, is described. The utility of hypervalent iodine reagents in the synthesis of this class of compounds is highlighted. The mechanism of action of the (haloaryl)glycines was studied in Saccharomyces cerevisiae.

  9. "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.

  10. 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 ...

  11. Amorphous pharmaceutical solids.

    PubMed

    Vranić, Edina

    2004-07-01

    Amorphous forms are, by definition, non-crystalline materials which possess no long-range order. Their structure can be thought of as being similar to that of a frozen liquid with the thermal fluctuations present in a liquid frozen out, leaving only "static" structural disorder. The amorphous solids have always been an essential part of pharmaceutical research, but the current interest has been raised by two developments: a growing attention to pharmaceutical solids in general, especially polymorphs and solvates and a revived interest in the science of glasses and the glass transition. Amorphous substances may be formed both intentionally and unintentionally during normal pharmaceutical manufacturing operations. The properties of amorphous materials can be exploited to improve the performance of pharmaceutical dosage forms, but these properties can also give rise to unwanted effects that need to be understood and managed in order for the systems to perform as required.

  12. Genotoxicity assessment of 4-methylimidazole: regulatory perspectives.

    PubMed

    Morita, Takeshi; Uneyama, Chikako

    2016-01-01

    4-Methylimidazole (4-MI) is formed as a result of the Maillard reaction process, and therefore is found in many foods and beverages. It is also found in soft drinks (i.e., cola) as a by-product in the production of some caramel colors. NTP bioassays revealed clear evidence of lung carcinogenicity of 4-MI in male and female mice, but not in rats and then IARC classified 4-MI as group 2B carcinogen. Genotoxicity studies with 4-MI were negative in the Ames tests and in the erythrocyte micronucleus tests with mice or rats. US California EPA (CEPA) evaluated the testing has not been adequately comprehensive to rule out a genotoxic mode of action; as target tissue of the carcinogenicity of 4-MI was lung, the lung should be used as a source tissue for in vitro metabolic activation system. Thus, CEPA defined the No Significant Risk Level (NSRL) for 10(-5) lifetime risk level of cancer by 4-MI as 29 μg/day based on the non-threshold approach. As higher levels of 4-MI than the NSRL were identified in some kinds of cola, health concerns of 4-MI were drawn the attention. On the other hand, other regulatory bodies (e.g., European Food Safety Authority, EFSA) showed no concerns of 4-MI from the use of caramel colors in food. EFSA evaluated 4-MI is not genotoxic, so, non-observed adverse effect level of 4-MI was considered to be 80 mg/kg/day. In this paper, genotoxic assessments of 4-MI in different regulatory bodies are presented and the risk evaluation of 4-MI is discussed based on new genotoxicity data.

  13. Ecotoxicology of human pharmaceuticals.

    PubMed

    Fent, Karl; Weston, Anna A; Caminada, Daniel

    2006-02-10

    Low levels of human medicines (pharmaceuticals) have been detected in many countries in sewage treatment plant (STP) effluents, surface waters, seawaters, groundwater and some drinking waters. For some pharmaceuticals effects on aquatic organisms have been investigated in acute toxicity assays. The chronic toxicity and potential subtle effects are only marginally known, however. Here, we critically review the current knowledge about human pharmaceuticals in the environment and address several key questions. What kind of pharmaceuticals and what concentrations occur in the aquatic environment? What is the fate in surface water and in STP? What are the modes of action of these compounds in humans and are there similar targets in lower animals? What acute and chronic ecotoxicological effects may be elicited by pharmaceuticals and by mixtures? What are the effect concentrations and how do they relate to environmental levels? Our review shows that only very little is known about long-term effects of pharmaceuticals to aquatic organisms, in particular with respect to biological targets. For most human medicines analyzed, acute effects to aquatic organisms are unlikely, except for spills. For investigated pharmaceuticals chronic lowest observed effect concentrations (LOEC) in standard laboratory organisms are about two orders of magnitude higher than maximal concentrations in STP effluents. For diclofenac, the LOEC for fish toxicity was in the range of wastewater concentrations, whereas the LOEC of propranolol and fluoxetine for zooplankton and benthic organisms were near to maximal measured STP effluent concentrations. In surface water, concentrations are lower and so are the environmental risks. However, targeted ecotoxicological studies are lacking almost entirely and such investigations are needed focusing on subtle environmental effects. This will allow better and comprehensive risk assessments of pharmaceuticals in the future.

  14. 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.

  15. 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.

  16. Cyto-genotoxicity and oxidative stress in common carp (Cyprinus carpio) exposed to a mixture of ibuprofen and diclofenac.

    PubMed

    Islas-Flores, Hariz; Manuel Gómez-Oliván, Leobardo; Galar-Martínez, Marcela; Michelle Sánchez-Ocampo, Esmeralda; SanJuan-Reyes, Nely; Ortíz-Reynoso, Mariana; Dublán-García, Octavio

    2017-05-01

    Thirty million people worldwide consume each day nonsteroidal anti-inflammatory drugs (NSAIDs), a heterogeneous group of pharmaceuticals used for its analgesic, antipyretic, and anti-inflammatory properties. Recent studies report high NSAID concentrations in wastewater treatment plant effluents, in surface, ground, and drinking water, and in sediments. NSAIDs are also known to induce toxicity on aquatic organisms. However, toxicity in natural ecosystems is not usually the result of exposure to a single substance but to a mixture of toxic agents, yet only a few studies have evaluated the toxicity of mixtures. The aim of this study was to evaluate the toxicity induced by diclofenac (DCF), ibuprofen (IBP), and their mixture on a species of commercial interest, the common carp Cyprinus carpio. The median lethal concentration of IBP and DCF was determined, and oxidative stress was evaluated using the following biomarkers: lipid peroxidation and activity of the antioxidant enzymes superoxide dismutase, catalase and glutathione peroxidase. Cyto-genotoxicity was evaluated by micronucleus test, comet assay, and the specific activity of caspase-3. Results show that DCF, IBP, and a mixture of these pharmaceuticals induced free radical production, oxidative stress and cyto-genotoxicity in tissues of C. carpio. However, a greater effect was elicited by the mixture than by either pharmaceutical alone in some biomarkers evaluated, particularly in gill. © 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 1637-1650, 2017.

  17. Analytical characterization of an orally-delivered peptide pharmaceutical product.

    PubMed

    Kelley, Wayne P; Chen, Shujun; Floyd, Philip D; Hu, Ping; Kapsi, Shiva G; Kord, Alireza S; Sun, Mingjiang; Vogt, Frederick G

    2012-05-15

    The characterization of orally-delivered peptide pharmaceuticals presents several challenges to analytical methods in comparison to characterization of conventional small-molecule drugs. These challenges include the analysis and characterization of difficult-to-separate impurities, secondary structure, the amorphous solid-state form, and the integrity of enteric-coated drug delivery systems. This work presents the multidisciplinary analytical characterization of a parathyroid hormone (PTH) peptide active pharmaceutical ingredient (API) and an oral formulation of this API within enteric-coated sucrose spheres. The analysis of impurities and degradation products in API and formulated drug product was facilitated by the development of an ultrahigh-performance liquid chromatography (UHPLC) method for analysis by high-resolution mass spectrometry (MS). The use of UHPLC allowed for additional resolution needed to detect impurities and degradation products of interest. The secondary structure was probed using a combination of solution-state NMR, infrared, and circular dichroism spectroscopic methods. Solid-state NMR is used to detect amorphous API in a nondestructive manner directly within the coated sucrose sphere formulation. Fluorescence and Raman microscopy were used in conjunction with Raman mapping to show enteric coating integrity and observe the distribution of API beneath the enteric-coating on the sucrose spheres. The methods are combined in a multidisciplinary approach to characterize the quality of the enteric-coated peptide product.

  18. 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.

  19. 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.

  20. 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.

  1. Direct Visualization of an Impurity Depletion Zone

    NASA Technical Reports Server (NTRS)

    Chernov, Alex A.; Garcia-Ruiz, Juan Ma; Thomas, Bill R.

    2000-01-01

    When a crystal incorporates more impurity per unit of its volume than the impurity concentration in solution, the solution in vicinity of the growing crystal is depleted with respect to the impurity I,2. With a stagnant solution, e. g. in microgravity or gels, an impurity depletion zone expands as the crystal grows and results in greater purity in most of the outer portion of the crystal than in the core. Crystallization in gel provides an opportunity to mimic microgravity conditions and visualize the impurity depletion zone. Colorless, transparent apoferritin (M congruent to 450 KDa) crystals were grown in the presence of red holoferritin dimer as a microheterogeneous impurity (M congruent to 900 KDa) within agarose gel by counterdiffusion with Cd(2+) precipitant. Preferential trapping of dimers, (distribution coefficient K = 4 (exp 1,2)) results in weaker red color around the crystals grown in the left tube in the figure as compared to the control middle tube without crystals. The left and the middle tubes contain colored ferritin dimers, the right tube contains colored trimers. The meniscus in the left tube separate gel (below) and liquid solution containing Cd(2+) (above). Similar solutions, though without precipitants, were present on top of the middle and right tube allowing diffusion of dimers and trimers. The area of weaker color intensity around crystals directly demonstrates overlapped impurity depletion zones.

  2. Development and validation of a sensitive GC-MS method for the determination of alkylating agent, 4-chloro-1-butanol, in active pharmaceutical ingredients.

    PubMed

    Harigaya, Koki; Yamada, Hiroyuki; Yaku, Koji; Nishi, Hiroyuki; Haginaka, Jun

    2014-01-01

    The analysis of genotoxic impurities (GTIs) in active pharmaceutical ingredients (APIs) is a challenging task. The target detection limit (DL) in an API is typically around 1 ppm (1 µg/g API). Therefore, a sensitive and selective analytical method is required for their analysis. 4-Chloro-1-butanol, an alkylating agent, is one of the GTIs. It is generated when tetrahydrofuran and hydrochloric acid are used during the synthesis of the APIs. In this study, a sensitive and robust gas chromatography-mass spectrometry (GC-MS) method was developed and validated for the identification of 4-chloro-1-butanol in APIs. In the GC-MS method, 3-chloro-1-butanol was employed as an internal standard to ensure accuracy and precision. Linearity was observed over the range 0.08 to 40 ppm (µg/g API), with a R(2) value of 0.9999. The DL and quantitation limit (QL) obtained were 0.05 ppm and 0.08 ppm (0.13 ng/mL and 0.20 ng/mL as the 4-chloro-1-butanol concentration), respectively. These DL and QL values are well over the threshold specified in the guidelines. The accuracy (recovery) of detection ranged from 90.5 to 108.7% between 0.4 ppm and 20 ppm of 4-chloro-1-butanol. The relative standard deviation in the repeatability of the spiked recovery test was 6.0%. These results indicate the validity of the GC-MS method developed in this study. The GC-MS method was applied for the determination of 4-chloro-1-butanol in the API (Compound A), which is under clinical trials. No 4-chloro-1-butanol was found in Compound A (below QL, 0.08 ppm).

  3. [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.

  4. 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.

  5. Inorganic arsenic: A non-genotoxic carcinogen.

    PubMed

    Cohen, Samuel M; Chowdhury, Aparajita; Arnold, Lora L

    2016-11-01

    Inorganic arsenic induces a variety of toxicities including cancer. The mode of action for cancer and non-cancer effects involves the metabolic generation of trivalent arsenicals and their reaction with sulfhydryl groups within critical proteins in various cell types which leads to the biological response. In epithelial cells, the response is cell death with consequent regenerative proliferation. If this continues for a long period of time, it can result in an increased risk of cancer. Arsenicals do not react with DNA. There is evidence for indirect genotoxicity in various in vitro and in vivo systems, but these involve exposures at cytotoxic concentrations and are not the basis for cancer development. The resulting markers of genotoxicity could readily be due to the cytotoxicity rather than an effect on the DNA itself. Evidence for genotoxicity in humans has involved detection of chromosomal aberrations, sister chromatid exchanges in lymphocytes and micronucleus formation in lymphocytes, buccal mucosal cells, and exfoliated urothelial cells in the urine. Numerous difficulties have been identified in the interpretation of such results, including inadequate assessment of exposure to arsenic, measurement of micronuclei, and potential confounding factors such as tobacco exposure, folate deficiency, and others. Overall, the data strongly supports a non-linear dose response for the effects of inorganic arsenic. In various in vitro and in vivo models and in human epidemiology studies there appears to be a threshold for biological responses, including cancer.

  6. 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.

  7. Cytotoxicity and genotoxicity of butyl cyclohexyl phthalate.

    PubMed

    Köksal, Çinel; Nalbantsoy, Ayse; Karabay Yavaşoğlu, N Ülkü

    2016-03-01

    Butyl cyclohexyl phthalate (BCP) is frequently used in personal care products, medical and household applications. The aim of this study is therefore to evaluate possible cytotoxicity and genotoxicity of BCP using in vitro and in vivo assays. The in vitro cytotoxic effect of BCP was investigated on mouse fibroblastic cell line (L929 cells) by MTT assay. The result showed that BCP inhibits cell proliferation in a concentration-dependent manner (IC50 value = 0.29 µg/mL). For genotoxicity assessment, tested concentrations of BCP demonstrated mutagenic activity in the presence of S9 mix with the Salmonella strain TA100 in the Ames test. Results showed that BCP is a secondary mutagenic substance even in low concentrations. The data obtained from 28-days repeated toxicity tests on mice revealed that BCP caused abnormalities of chromosome number, in a dose-dependent manner. Additionally, DNA damage, particularly DNA strand breaks, was assessed by Comet assay. The test result shows that BCP seemed to have genotoxic potential at a high level of exposure.

  8. 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.

  9. Mechanisms of fiber-induced genotoxicity.

    PubMed Central

    Jaurand, M C

    1997-01-01

    The mechanisms of particle-induced genotoxicity have been investigated mainly with asbestos fibers. The results are summarized and discussed in this paper. DNA damage can be produced by oxidoreduction processes generated by fibers. The extent of damage yield depends on experimental conditions: if iron is present, either on fibers or in the medium, damage is increased. However, iron reactivity does not explain all the results obtained in cell-free systems, as breakage of plasmid DNA was not directly associated with the amount of iron released by the fibers. The proximity of DNA to the site of generation of reactive oxygen species (ROS) is important because these species have an extremely short half-life. Damage to cellular DNA can be produced by oxidoreduction processes that originate from cells during phagocytosis. Secondary molecules that are more stable than ROS are probably involved in DNA damage. Oxidoreduction reactions originating from cells can induce mutations. Genotoxicity is also demonstrated by chromosomal damage associated with impaired mitosis, as evidenced by chromosome missegregation, spindle changes, alteration of cell cycle progression, formation of aneuploid and polyploid cells, and nuclear disruption. In some of these processes, the particle state and fiber dimensions are considered important parameters in the generation of genotoxic effects. PMID:9400703

  10. 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.

  11. Characterization of potential impurities and degradation products in electronic cigarette formulations and aerosols.

    PubMed

    Flora, Jason W; Meruva, Naren; Huang, Chorng B; Wilkinson, Celeste T; Ballentine, Regina; Smith, Donna C; Werley, Michael S; McKinney, Willie J

    2016-02-01

    E-cigarettes are gaining popularity in the U.S. as well as in other global markets. Currently, limited published analytical data characterizing e-cigarette formulations (e-liquids) and aerosols exist. While FDA has not published a harmful and potentially harmful constituent (HPHC) list for e-cigarettes, the HPHC list for currently regulated tobacco products may be useful to analytically characterize e-cigarette aerosols. For example, most e-cigarette formulations contain propylene glycol and glycerin, which may produce aldehydes when heated. In addition, nicotine-related chemicals have been previously reported as potential e-cigarette formulation impurities. This study determined e-liquid formulation impurities and potentially harmful chemicals in aerosols of select commercial MarkTen(®) e-cigarettes manufactured by NuMark LLC. The potential hazard of the identified formulation impurities and aerosol chemicals was also estimated. E-cigarettes were machine puffed (4-s duration, 55-mL volume, 30-s intervals) to battery exhaustion to maximize aerosol collection. Aerosols analyzed for carbonyls were collected in 20-puff increments to account for analyte instability. Tobacco specific nitrosamines were measured at levels observed in pharmaceutical grade nicotine. Nicotine-related impurities in the e-cigarette formulations were below the identification and qualification thresholds proposed in ICH Guideline Q3B(R2). Levels of potentially harmful chemicals detected in the aerosols were determined to be below published occupational exposure limits.

  12. Genotoxic activity of a technical toxaphene mixture and its photodegradation products in SOS genotoxicity tests.

    PubMed

    Bartos, Tomás; Skarek, Michal; Cupr, Pavel; Kosubová, Petra; Holoubek, Ivan

    2005-01-03

    Toxaphene (CAS No. 800-35-2) is a complex mixture of several hundred components that was used worldwide primarily as an agricultural pesticide with insecticide effects in the second half of the 20th century. In vitro investigations of the genotoxicity and mutagenicity of toxaphene were generally described in the literature, but they provided somewhat equivocal results. We re-evaluated the genotoxicity of technical toxaphene in two prokaryotic systems. The SOS Chromotest showed high sensitivity to toxaphene: three concentrations (40, 20 and 10 mg/l) were clearly positive and the dose-response effect was evident. In the umuC assay, a dose-dependent increase in genotoxic activity was observed at toxaphene concentrations from 2.5 to 40.0 mg/l, but these results were found to be not significant. The genotoxicity of toxaphene and its photodegradation products after UV-irradiation (3-6-9 h) at concentrations ranging from 7.5 to 60.0 mg/l was also examined in this study. An irradiated solution of technical toxaphene after 3 h showed no significant evidence of bacterial growth inhibition. However, exposure of Salmonella to 6 h UV-irradiated toxaphene showed a toxic effect compared with the negative control. After 9 h irradiation, a decrease of bacterial growth was observed. Activity of beta-galactosidase in the presence of a toxaphene solution was significantly increased after 6 and 9 h irradiation, reaching values that were 2.4- and 3.1-fold higher, respectively, than the control, which exceeded the criteria of significant genotoxicity. These results show that while technical toxaphene is a weak, direct-acting mutagen in some bacterial tests, a dose-dependent toxicity and genotoxicity of its photoproducts could be conclusively demonstrated by the umuC test.

  13. Identification of gliadin presence in pharmaceutical products.

    PubMed

    Miletic, I D; Miletic, V D; Sattely-Miller, E A; Schiffman, S S

    1994-07-01

    Celiac disease is characterized by hypersensitivity to the alcohol-soluble wheat proteins called gliadins. Total avoidance of gliadin is the lifelong treatment for such patients. However, wheat gliadins are often present as impurities in industrial starch commonly used in the preparation of different pharmaceutical products. Therefore, some drugs might contain gliadin, which can be dangerous for sensitive patients if taken in large amounts or used permanently. The purpose of this study was to develop a sensitive, reliable assay that is specific for the detection of gliadins in pharmaceutical products. Gliadins were extracted here using sodium dodecyl sulfate rather than 70% ethyl alcohol, which has been the traditional solvent. This gliadin extract was utilized in a dot-blot assay that incorporated an antigliadin antibody developed in rabbit and labeled with peroxidase. 4-Chloro-1-naphthol was used as a peroxidase-specific substrate. Isolated wheat gliadin was used as the positive control. Dilution experiments showed that the lower level of sensitivity for the assay was in the range of 0.0045 mg/ml of gliadin, which is a concentration level lower than that suggested for a gluten-free diet. The assay developed here revealed that 71.2% of 59 prescription and nonprescription drugs tested contained gliadin in the amount detected by our dot-blot assay. The prescription drugs tested were among the top 50 most frequently dispensed in U.S. community pharmacies. The nonprescription drugs were among those that constitute the largest sales in the United States. The results showed that the simple dot-blot assay developed here can be used for pharmaceutical testing performed either by hospital laboratories or by patients themselves.

  14. International Conference on Harmonisation; revised guidance on Q3B(R) Impurities in New Drug Products; Availability. Notice.

    PubMed

    2003-11-14

    The Food and Drug Administration (FDA) is announcing the availability of a revised guidance entitled "Q3B(R) Impurities in New Drug Products.'' The revised guidance, which updates a guidance on the same topic published in the Federal Register of May 19, 1997 (the 1997 guidance), was prepared under the auspices of the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH). The revised guidance is intended to provide guidance to applicants for drug marketing registration on the content and qualification of impurities in new drug products produced by chemically synthesized new drug substances not previously registered in a country, region, or member State. The revised guidance clarifies the 1997 guidance, adds information, and provides consistency with more recently published ICH guidances. The revised guidance complements the ICH guidance entitled "Q3A(R) Impurities in New Drug Substances.''

  15. Genotoxicity of nimesulide in Wistar rats.

    PubMed

    Borkotoky, Debojyoti; Panda, Sushen K; Sahoo, Gyana R; Parija, Subas C

    2014-04-01

    It is mandatory for all new drugs to be tested for their potential genotoxicity in addition to general toxicity testing. Some old drugs have not been tested adequately for their genotoxic effects because these were in use before the local regulations were enforced. According to the material safety database, the toxicological effect of nimesulide is not yet fully understood. The present study therefore aimed to explore the genotoxic potential of nimesulide in Wistar albino rats. Nimesulide at the dose level of 50 (Gr-50), 100 (Gr-100) and 200 (Gr-200) mg/kg body weight (b.w.) was given orally. Each rat in treated groups (Gr-50 to Gr-200; n = 10) and negative control group (Gr-NC; n = 10) were administered orally (p.o.) with nimesulide and normal saline, respectively, for 14 days. Similarly, rats of positive control (Gr-PC; n = 10) were administered with cyclophosphamide (CPA; 20 mg/kg b.w.) intraperitoneally. CPA served as positive control, whereas normal saline served as as negative control. Approximately 1-2 mL of blood was collected from retro-orbital sinus for comet assay and subsequently rats were sacrificed to aspirate the femoral bone marrow for the micronucleus test. Structural chromosomal aberration, micronucleated polychromatic erythrocytes (MnPCEs), polychromatic erythrocytes (PCEs) and comet tail length were calculated using micronucleus assay and comet assay, respectively, which served as markers of genotoxicity. In the present study, it was observed that a significant increase in (1) different classified structural chromosomal aberrations with increase in nimesulide dose, such as gaps (50 mg/kg), gaps, breaks and pulverizations (100 mg/kg) and gaps, breaks, fragments, rings and pulverizations (200 mg/kg) and (2) % MnPCE and comet tail length was observed in animals treated with CPA (p < 0.001) or 200 mg of nimesulide (p < 0.05), as compared to negative control. In conclusion, nimesulide (200 mg/kg b.w.) produced a

  16. Impurities and electronic localization in graphene bilayers

    NASA Astrophysics Data System (ADS)

    Ojeda Collado, H. P.; Usaj, Gonzalo; Balseiro, C. A.

    2015-01-01

    We analyze the electronic properties of bilayer graphene with Bernal stacking and a low concentration of adatoms. Assuming that the host bilayer lies on top of a substrate, we consider the case where impurities are adsorbed only on the upper layer. We describe nonmagnetic impurities as a single orbital hybridized with carbon's pz states. The effect of impurity doping on the local density of states with and without a gated electric field perpendicular to the layers is analyzed. We look for Anderson localization in the different regimes and estimate the localization length. In the biased system, the field-induced gap is partially filled by strongly localized impurity states. Interestingly, the structure, distribution, and localization length of these states depend on the field polarization.

  17. 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.

  18. Heavy metals testing in active pharmaceutical ingredients: an alternate approach.

    PubMed

    Raghuram, P; Soma Raju, I V; Sriramulu, J

    2010-01-01

    The principle of the pharmacopoeial heavy metals test is detection and estimation of the metallic impurities colored by sulfide ion by comparison against lead standard. The test suffers from a loss of analytes upon ashing and from having varied responses for various metals. An inductively coupled plasma-optical emission spectroscopy (ICP-OES) for estimating 23 metals in active pharmaceutical ingredients is being proposed. The method covers the metals listed in USP, Ph. Eur and EMEA guidance on "Residues of Metal Catalysts or Metal Reagents".

  19. Removal of some impurities from carbon nanotubes

    NASA Astrophysics Data System (ADS)

    Feng, Yongcheng; Zhou, Gumin; Wang, Guoping; Qu, Meizhen; Yu, Zuolong

    2003-07-01

    A non-destructive mild oxidation method of removing some impurities from as-grown carbon nanotubes (CNTs), including single-wall carbon nanotubes (SWNTs) and multi-wall carbon nanotubes (MWNTs), by H 2O 2 oxidation and HCl treatment, has been investigated, and somewhat pure carbon nanotubes have been prepared. The CNTs from which some impurities were removed have been evaluated by transmission electron microscopy (TEM) and temperature programmed oxidation and gas chromatography (TPO-GC).

  20. 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.

  1. An improved validated ultra high pressure liquid chromatography method for separation of tacrolimus impurities and its tautomers.

    PubMed

    Subasranjan, Acharya; C, Srinivasulu; Hemant, Raoutray

    2010-03-01

    A selective, specific and sensitive ultra high pressure liquid chromatography (UHPLC) method was developed for determination of tacrolimus degradation products and tautomers in the preparation of pharmaceuticals. The chromatographic separation was performed on Waters ACQUITY UPLC system and BEH C₈ column using gradient elution of mobile phase A (90:10 v/v of 0.1% v/v triflouroacetic acid solution and Acetonitrile) and mobile phase B (90:10 v/v acetonitrile and water) at a flow rate of 0.6 mL min⁻¹. Ultraviolet detection was performed at 210 nm. Tacrolimus, tautomers and impurities were chromatographed with a total run time of 25 min. Calibration showed that the response of impurity was a linear function of concentration over the range 0.3-6 µg mL⁻¹ (r² ≥ 0.999) and the method was validated over this range for precision, intermediate precision, accuracy, linearity and specificity. For precision study, percentage relative standard deviation of each impurity was < 15% (n = 6). The method was found to be precise, accurate, linear and specific. The proposed method was successfully employed for estimation of tacrolimus impurities in pharmaceutical preparations.

  2. Impurity profiling of trandolapril under stress testing: Structure elucidation of by-products and development of degradation pathway.

    PubMed

    Dendeni, M; Cimetiere, N; Amrane, A; Hamida, N Ben

    2012-11-15

    Various regulatory authorities like International Conference on Harmonization (ICH), US Food and Drug Administration, Canadian Drug and Health Agency are emphasizing on the purity requirements and the identification of impurities in active pharmaceutical drugs. Qualification of the impurities is the process of acquiring and evaluating data that establishes biological safety of an individual impurity; thus, revealing the need and scope of impurity profiling of drugs in pharmaceutical research. As no stability-indicating method is available for identification of degradation products of trandolapril, a new angiotensin converting enzyme inhibitor (ACEI), under stress testing, the development of an accurate method is needed for quantification and qualification of degradation products. Ultra high performance liquid chromatography (UPLC) coupled to electrospray tandem mass spectrometry was used for the rapid and simultaneous analysis of trandolapril and its degradation products. Chromatographic separation was achieved in less than 4 min, with improved peak resolution and sensitivity. Thanks to this method, the kinetics of trandolapril degradation under various operating conditions and the characterization of the structure of the by-products formed during stress testing have been determined. Thereafter, a mechanism of trandolapril degradation in acid and neutral conditions, including all the identified products, was then proposed.

  3. Reflections on Pharmaceutical Education.

    ERIC Educational Resources Information Center

    Smith, Robert E.

    1992-01-01

    A discussion of the implications of adopting a new example for pharmaceutical education focuses on the need to develop a new pharmacy college culture and on the faculty's role in addressing stated educational goals. Anticipated changes in staffing and faculty development and difficulties in reorganizing curricula are examined. (MSE)

  4. 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.

  5. Comparison of ultra-high performance methods in liquid and supercritical fluid chromatography coupled to electrospray ionization - mass spectrometry for impurity profiling of drug candidates.

    PubMed

    Lemasson, Elise; Bertin, Sophie; Hennig, Philippe; Lesellier, Eric; West, Caroline

    2016-11-11

    Impurity profiling of organic products synthesized as possible drug candidates represents a major analytical challenge. Complementary analytical methods are required to ensure that all impurities are detected. Both high-performance liquid chromatography (HPLC) and supercritical fluid chromatography (SFC) can be used for this purpose. In this study, we compared ultra-high performance HPLC (UHPLC) and ultra-high performance SFC (UHPSFC) using a large dataset of 140 pharmaceutical compounds. Four previously optimized methods (two on each technique) were selected to ensure fast high-resolution separations. The four methods were evaluated based on response rate, peak capacity, peak shape and capability to detect impurities (UV). The orthogonality between all methods was also assessed. The best UHPLC method and UHPSFC methods provided comparable quality for the 140 compounds included in this study. Moreover, they were found to be highly orthogonal. At last, the potential of the combined use of UHPLC and UHPSFC for impurity profiling is illustrated with practical examples.

  6. 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.

  7. p53 induction and cell viability modulation by genotoxic individual chemicals and mixtures.

    PubMed

    Di Paolo, Carolina; Müller, Yvonne; Thalmann, Beat; Hollert, Henner; Seiler, Thomas-Benjamin

    2017-03-16

    The binding of the p53 tumor suppression protein to DNA response elements after genotoxic stress can be quantified by cell-based reporter gene assays as a DNA damage endpoint. Currently, bioassay evaluation of environmental samples requires further knowledge on p53 induction by chemical mixtures and on cytotoxicity interference with p53 induction analysis for proper interpretation of results. We investigated the effects of genotoxic pharmaceuticals (actinomycin D, cyclophosphamide) and nitroaromatic compounds (4-nitroquinoline 1-oxide, 3-nitrobenzanthrone) on p53 induction and cell viability using a reporter gene and a colorimetric assay, respectively. Individual exposures were conducted in the absence or presence of metabolic activation system, while binary and tertiary mixtures were tested in its absence only. Cell viability reduction tended to present direct correlation with p53 induction, and induction peaks occurred mainly at chemical concentrations causing cell viability below 80%. Mixtures presented in general good agreement between predicted and measured p53 induction factors at lower concentrations, while higher chemical concentrations gave lower values than expected. Cytotoxicity evaluation supported the selection of concentration ranges for the p53 assay and the interpretation of its results. The often used 80% viability threshold as a basis to select the maximum test concentration for cell-based assays was not adequate for p53 induction assessment. Instead, concentrations causing up to 50% cell viability reduction should be evaluated in order to identify the lowest observed effect concentration and peak values following meaningful p53 induction.

  8. Toxic and genotoxic impact of fibrates and their photoproducts on non-target organisms.

    PubMed

    Isidori, Marina; Nardelli, Angela; Pascarella, Luigia; Rubino, Maria; Parrella, Alfredo

    2007-07-01

    Lipid regulators have been detected in effluents from sewage treatment plants and surface waters from humans via excretion. This study was designed to assess the ecotoxicity of fibrates, lipid regulating agents. The following compounds were investigated: Bezafibrate, Fenofibrate and Gemfibrozil and their derivatives obtained by solar simulator irradiation. Bioassays were performed on bacteria, algae, rotifers and microcrustaceans to assess acute and chronic toxicity, while SOS Chromotest and Ames test were utilized to detect the genotoxic potential of the investigated compounds. The photoproducts were identified by their physical features and for the first risk evaluation, the environmental impact of parental compounds was calculated by Measured Environmental Concentrations (MEC) using the available data from the literature regarding drug occurrence in the aquatic environment and the Predicted No Effect Concentrations (PNEC) based on our toxicity data. The results showed that acute toxicity was in the order of dozens of mg/L for all the trophic levels utilized in bioassays (bacteria, rotifers, crustaceans). Chronic exposure to these compounds caused inhibition of growth population on rotifers and crustaceans while the algae seemed to be slightly affected by this class of pharmaceuticals. Genotoxic and mutagenic effects were especially found for the Gemfibrozil photoproduct suggesting that also byproducts have to be considered in the environmental risk of drugs.

  9. 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

  10. 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

  11. Challenges in the analytical method development and validation for an unstable active pharmaceutical ingredient.

    PubMed

    Sajonz, Peter; Wu, Yan; Natishan, Theresa K; McGachy, Neil T; Detora, David

    2006-03-01

    A sensitive high-performance liquid chromatography (HPLC) impurity profile method for the antibiotic ertapenem is developed and subsequently validated. The method utilizes an Inertsil phenyl column at ambient temperature, gradient elution with aqueous sodium phosphate buffer at pH 8, and acetonitrile as the mobile phase. The linearity, method precision, method ruggedness, limit of quantitation, and limit of detection of the impurity profile HPLC method are found to be satisfactory. The method is determined to be specific, as judged by resolving ertapenem from in-process impurities in crude samples and degradation products that arise from solid state thermal and light stress, acid, base, and oxidative stressed solutions. In addition, evidence is obtained by photodiode array detection studies that no degradate or impurity having a different UV spectrum coeluted with the major component in stressed or unstressed samples. The challenges during the development and validation of the method are discussed. The difficulties of analyzing an unstable active pharmaceutical ingredient (API) are addressed. Several major impurities/degradates of the API have very different UV response factors from the API. These impurities/degradates are synthesized or prepared by controlled degradation and the relative response factors are determined.

  12. 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

  13. Genotoxicity Expert Panel review: weight of evidence evaluation of the genotoxicity of glyphosate, glyphosate-based formulations, and aminomethylphosphonic acid.

    PubMed

    Brusick, David; Aardema, Marilyn; Kier, Larry; Kirkland, David; Williams, Gary

    2016-09-01

    In 2015, the International Agency for Research on Cancer (IARC) published a monograph concluding there was strong evidence for genotoxicity of glyphosate and glyphosate formulations and moderate evidence for genotoxicity of the metabolite aminomethylphosphonic acid (AMPA). These conclusions contradicted earlier extensive reviews supporting the lack of genotoxicity of glyphosate and glyphosate formulations. The IARC Monograph concluded there was strong evidence of induction of oxidative stress by glyphosate, glyphosate formulations, and AMPA. The Expert Panel reviewed the genotoxicity and oxidative stress data considered in the IARC Monograph, together with other available data not considered by IARC. The Expert Panel defined and used a weight of evidence (WoE) approach that included ranking of studies and endpoints by the strength of their linkage to events associated with carcinogenic mechanisms. Importantly, the Expert Panel concluded that there was sufficient information available from a very large number of regulatory genotoxicity studies that should have been considered by IARC. The WoE approach, the inclusion of all relevant regulatory studies, and some differences in interpretation of individual studies led to significantly different conclusions by the Expert Panel compared with the IARC Monograph. The Expert Panel concluded that glyphosate, glyphosate formulations, and AMPA do not pose a genotoxic hazard and the data do not support the IARC Monograph genotoxicity evaluation. With respect to carcinogenicity classification and mechanism, the Expert Panel concluded that evidence relating to an oxidative stress mechanism of carcinogenicity was largely unconvincing and that the data profiles were not consistent with the characteristics of genotoxic carcinogens.

  14. 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.

  15. 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

  16. 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

  17. Gray marketing of pharmaceuticals.

    PubMed

    Chaudhry, P E; Walsh, M G

    1995-01-01

    Pharmaceutical marketers in the European Union are constrained by regulated prices, opening up opportunities for gray marketers. The authors investigate the legal framework that regulates gray markets by summarizing and analyzing relevant European Court of Justice decisions that favor gray marketers and actually foster parallel trade. Before marketing managers can develop effective strategies in this marketplace, they must first understand the precedents of the legal system in which they will be operating.

  18. Derivative spectrophotometric analysis of benzophenone (as an impurity) in phenytoin.

    PubMed

    Walash, Mohamed Ibrahim; Rizk, Mohamed Salem; Sheribah, Zeinab Awad; Salim, Mohamed Mansour

    2011-12-12

    Three simple and rapid spectrophotometric methods were developed for detection and trace determination of benzophenone (the main impurity) in phenytoin bulk powder and pharmaceutical formulations. The first method, zero-crossing first derivative spectrophotometry, depends on measuring the first derivative trough values at 257.6 nm for benzophenone. The second method, zero-crossing third derivative spectrophotometry, depends on measuring the third derivative peak values at 263.2 nm. The third method, ratio first derivative spectrophotometry, depends on measuring the peak amplitudes of the first derivative of the ratio spectra (the spectra of benzophenone divided by the spectrum of 5.0 μg/mL phenytoin solution) at 272 nm. The calibration graphs were linear over the range of 1-10 μg/mL. The detection limits of the first and the third derivative methods were found to be 0.04 μg/mL and 0.11 μg/mL and the quantitation limits were 0.13 μg/mL and 0.34 μg/mL, respectively, while for the ratio derivative method, the detection limit was 0.06 μg/mL and the quantitation limit was 0.18 μg/mL. The proposed methods were applied successfully to the assay of the studied drug in phenytoin bulk powder and certain pharmaceutical preparations. The results were statistically compared to those obtained using a polarographic method and were found to be in good agreement.

  19. 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.

  20. Transport analysis of tungsten impurity in ITER

    NASA Astrophysics Data System (ADS)

    Murakami, Y.; Amano, T.; Shimizu, K.; Shimada, M.

    2003-03-01

    The radial distribution of tungsten impurity in ITER is calculated by using the 1.5D transport code TOTAL coupled with NCLASS, which can solve the neo-classical impurity flux considering arbitrary aspect ratio and collisionality. An impurity screening effect is observed when the density profile is flat and the line radiation power is smaller than in the case without impurity transport by a factor of 2. It is shown that 90 MW of line radiation power is possible without significant degradation of plasma performance ( HH98( y,2) ˜1) when the fusion power is 700 MW (fusion gain Q=10). The allowable tungsten density is about 7×10 15/m 3, which is 0.01% of the electron density and the increase of the effective ionic charge Zeff is about 0.39. In this case, the total radiation power is more than half of the total heating power 210 MW, and power to the divertor region is less than 100 MW. This operation regime gives an opportunity for high fusion power operation in ITER with acceptable divertor conditions. Simulations for the case with an internal transport barrier (ITB) are also performed and it is found that impurity shielding by an ITB is possible with density profile control.

  1. 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.

  2. Magnetic impurity in a Weyl semimetal

    NASA Astrophysics Data System (ADS)

    Sun, Jin-Hua; Xu, Dong-Hui; Zhang, Fu-Chun; Zhou, Yi

    2015-11-01

    We utilize the variational method to study the Kondo screening of a spin-1 /2 magnetic impurity in a three-dimensional (3D) Weyl semimetal with two Weyl nodes along the kz axis. The model reduces to a 3D Dirac semimetal when the separation of the two Weyl nodes vanishes. When the chemical potential lies at the nodal point, μ =0 , the impurity spin is screened only if the coupling between the impurity and the conduction electron exceeds a critical value. For finite but small μ , the impurity spin is weakly bound due to the low density of states, which is proportional to μ2, contrary to that in a 2D Dirac metal such as graphene and 2D helical metal, where the density of states is proportional to |μ | . The spin-spin correlation function Ju v(r ) between the spin v component of the magnetic impurity at the origin and the spin u component of a conduction electron at spatial point r is found to be strongly anisotropic due to the spin-orbit coupling, and it decays in the power law. The main difference of the Kondo screening in 3D Weyl semimetals and in Dirac semimetals is in the spin x (y ) component of the correlation function in the spatial direction of the z axis.

  3. Application of genetically altered models as replacement for the lifetime mouse bioassay in pharmaceutical development.

    PubMed

    Alden, Carl; Smith, Peter; Morton, Dan

    2002-01-01

    The international pharmaceutical regulatory academic and industrial toxicology communities are collaborating to improve the efficiency and effectiveness of cancer hazard identification based on dramatic improvements in our understanding of the cancer process. Guidelines emanating from the International Conference on Harmonization provide for use of in vivo alternatives. Standard practices utilizing lifetime rat and mouse studies are recognized as seriously flawed with over 80% false positive rates. Furthermore, tobacco, the most important human carcinogen commercialized by industry, is negative in these traditional lifetime studies. The lifetime mouse bioassay is generally recognized in pharmaceutical development as not adding value in safety assessment. An international consortium under the aegis of ILSI has recently completed an evaluation of alternative mouse cancer models. Transgenic models are less expensive, use fewer animals and take less time than traditional lifetime bioassays. These alternative models have now been sufficiently evaluated to be considered useful in the safety assessment plan for pharmaceuticals in development. Specifically for example, the rasH2 appears useful in detecting nongenotoxic as well as genotoxic rodent tumorigens with improved concordance with human response. The p53+/- heterozygous mouse apparently identifies hormonal carcinogenic mechanisms, immunosuppressive carcinogens, and genotoxic carcinogens. The TG:AC predicts for rodent tumorigens applied topically. Recent experiences at FDA, CPMP, and MHW indicate that with good planning and agency interactions, regulatory acceptability can be anticipated.

  4. Genotoxicity evaluation of sesamin and episesamin.

    PubMed

    Hori, Hisako; Takayanagi, Tomomi; Kamada, Yoko; Shimoyoshi, Satomi; Ono, Yoshiko; Kitagawa, Yoshinori; Shibata, Hiroshi; Nagao, Minako; Fujii, Wataru; Sakakibara, Yutaka

    2011-02-03

    Sesamin is a major lignan that is present in sesame seeds and oil. Sesamin is partially converted to its stereoisomer, episesamin, during the refining process of non-roasted sesame seed oil. We evaluated the genotoxicity of these substances through the following tests: a bacterial reverse mutation assay (Ames test), a chromosomal aberration test in cultured Chinese hamster lung cells (CHL/IU), a bone marrow micronucleus (MN) test in Crlj:CD1 (ICR) mice, and a comet assay using the liver of Sprague-Dawley (SD) rats. Episesamin showed negative results in the Ames test with and without S9 mix, in the in vitro chromosomal aberration test with and without S9 mix, and in the in vivo comet assay. Sesamin showed negative results in the Ames test with and without S9 mix. In the in vitro chromosomal aberration test, sesamin did not induce chromosomal aberrations in the absence of S9 mix, but induced structural abnormalities at cytotoxic concentrations in the presence of S9 mix. Oral administration of sesamin at doses up to 2.0g/kg did not cause a significant increase in either the percentage of micronucleated polychromatic erythrocytes in the in vivo bone marrow MN test or in the % DNA in the comet tails in the in vivo comet assay of liver cells. These findings indicate that sesamin does not damage DNA in vivo and that sesamin and episesamin have no genotoxic activity.

  5. Forskolin: genotoxicity assessment in Allium cepa.

    PubMed

    Mohammed, Khalid Pasha; Aarey, Archana; Tamkeen, Shayesta; Jahan, Parveen

    2015-01-01

    Forskolin, a diterpene, 7β-acetoxy-8,13-epoxy-1α,6β,9α-trihydroxy-labd-14-en-11-one (C22H34O7) isolated from Coleus forskohlii, exerts multiple physiological effects by stimulating the enzyme adenylate cyclase and increasing cyclic adenosine monophosphate (cAMP) concentrations. Forskolin is used in the treatment of hypertension, congestive heart failure, eczema, and other diseases. A cytogenetic assay was performed in Allium cepa to assess possible genotoxic effects of forskolin. Forskolin was tested at concentrations 5-100 μM for exposure periods of 24 or 48 h. Treated samples showed significant reductions in mitotic index (p < 0.05) and increases in the frequency of chromosome aberrations (p < 0.01) at both exposure times. The treated meristems showed chromosome aberrations including sticky metaphases, sticky anaphases, laggard, anaphase bridges, micronuclei, polyploidy, fragments, breaks, and C-mitosis. Forskolin may cause genotoxic effects and further toxicological evaluations should be conducted to ensure its safety.

  6. Genotoxicity of silver nanoparticles in Allium cepa.

    PubMed

    Kumari, Mamta; Mukherjee, A; Chandrasekaran, N

    2009-09-15

    Potential health and environmental effects of nanoparticles need to be thoroughly assessed before their widespread commercialization. Though there are few studies on cytotoxicity of nanoparticles on mammalian and human cell lines, there are hardly any reports on genotoxic and cytotoxic behavior of nanoparticles in plant cells. This study aims to investigate cytotoxic and genotoxic impacts of silver nanoparticles using root tip cells of Allium cepa as an indicator organism. A.cepa root tip cells were treated with four different concentrations (25, 20, 75, and 100 ppm) of engineered silver nanoparticles (below 100 nm size) dispersion, to study endpoints like mitotic index, distribution of cells in mitotic phases, different types of chromosomal aberrations, disturbed metaphase, sticky chromosome, cell wall disintegration, and breaks. For each concentration five sets of microscopic observations were carried out. No chromosomal aberration was observed in the control (untreated onion root tips) and the mitotic index (MI) value was 60.3%. With increasing concentration of the nanoparticles decrease in the mitotic index was noticed (60.30% to 27.62%). The different cytological effects including the chromosomal aberrations were studied in detail for the treated cells as well as control. We infer from this study that silver nanoparticles could penetrate plant system and may impair stages of cell division causing chromatin bridge, stickiness, disturbed metaphase, multiple chromosomal breaks and cell disintegration. The findings also suggest that plants as an important component of the ecosystems need to be included when evaluating the overall toxicological impact of the nanoparticles in the environment.

  7. 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

  8. Strong quantum scarring by local impurities

    NASA Astrophysics Data System (ADS)

    Luukko, Perttu J. J.; Drury, Byron; Klales, Anna; Kaplan, Lev; Heller, Eric J.; Räsänen, Esa

    2016-11-01

    We discover and characterise strong quantum scars, or quantum eigenstates resembling classical periodic orbits, in two-dimensional quantum wells perturbed by local impurities. These scars are not explained by ordinary scar theory, which would require the existence of short, moderately unstable periodic orbits in the perturbed system. Instead, they are supported by classical resonances in the unperturbed system and the resulting quantum near-degeneracy. Even in the case of a large number of randomly scattered impurities, the scars prefer distinct orientations that extremise the overlap with the impurities. We demonstrate that these preferred orientations can be used for highly efficient transport of quantum wave packets across the perturbed potential landscape. Assisted by the scars, wave-packet recurrences are significantly stronger than in the unperturbed system. Together with the controllability of the preferred orientations, this property may be very useful for quantum transport applications.

  9. Magnetic impurities in small metal clusters

    NASA Astrophysics Data System (ADS)

    Pastor, G. M.

    2005-09-01

    [Dedicated to Bernhard Mühlschlegel on the occasion of his 80th birthday]Magnetic impurities in small metallic clusters are investigated in the framework of the Anderson model by using exact diagonalization and geometry optimization methods.The singlet-triplet spin gap E shows a remarkable dependence as a function of band-filling, cluster structure, and impurity position that can be interpreted in terms of the environment-specific conduction-electron spectrum. The low-energy spin excitations involve similar energies as isomerizations. Interesting correlations between cluster structure and magnetic behavior are revealed. Finite-temperature properties such as specific heat, effective impurity moment, and magnetic susceptibility are calculated exactly in the canonical ensemble. A finite-size equivalent of the Kondo effect is identified and its structural dependence is discussed.

  10. Strong quantum scarring by local impurities

    PubMed Central

    Luukko, Perttu J. J.; Drury, Byron; Klales, Anna; Kaplan, Lev; Heller, Eric J.; Räsänen, Esa

    2016-01-01

    We discover and characterise strong quantum scars, or quantum eigenstates resembling classical periodic orbits, in two-dimensional quantum wells perturbed by local impurities. These scars are not explained by ordinary scar theory, which would require the existence of short, moderately unstable periodic orbits in the perturbed system. Instead, they are supported by classical resonances in the unperturbed system and the resulting quantum near-degeneracy. Even in the case of a large number of randomly scattered impurities, the scars prefer distinct orientations that extremise the overlap with the impurities. We demonstrate that these preferred orientations can be used for highly efficient transport of quantum wave packets across the perturbed potential landscape. Assisted by the scars, wave-packet recurrences are significantly stronger than in the unperturbed system. Together with the controllability of the preferred orientations, this property may be very useful for quantum transport applications. PMID:27892510

  11. Characteristics of impurity-induced pseudogap

    NASA Astrophysics Data System (ADS)

    Numata, Yoshinori; Uto, Tatsuro; Matuda, Azusa

    2016-05-01

    We have performed STM/STS measurements on a single crystal of Bi2.1Sr1.9Ca (Cu1-xCox) 2O8+δ (Co-Bi2212), to reveal impurity effects on the pseudogap in cuprate high-Tc superconductors. We report a drastic change in the temperature dependence of a pseudogap and in the density of states (DOS) modulation with a 4a period, in a certain doping range. In the Co 4% substituted samples, the pseudogap gradually closed like a gap of a BCS superconductor for slightly overdoped and overdoped regime, while their low temperature values were enhanced due to impurity. In addition, a disappearance of a 4a periodic modulation and a development of new modulation were observed in the DOS spatial distribution. These results indicate an intimate relation between the DOS modulation and the pseudogap, and qualitative difference in the impurity enhanced pseudogap and conventional one.

  12. 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

  13. Impurities in nonlinear optical oxide crystals

    NASA Astrophysics Data System (ADS)

    Morris, Patricia A.

    1990-11-01

    Impurities in nonlinear optical oxide crystals can affect many of the properties for device applications. The structures of typical crystals are tolerant with respect to occupancy and are nonstoichiometric on the cation sublattices (e.g. the A sublattice in crystals with the general formula AMO 3). This may, at least in part, be due to the presence of the relatively strong covalent nature of the acentric oxide groups determining the nonlinear optical properties. These circumstances make the incorporation of impurities into the lattice relatively easy and result in large distribution coefficients for many impurities. Generally, little purification during growth will occur with respect to these impurities and therefore, it is usually necessary to purify the starting materials of any unwanted ions. Chemical or powder processing and firing procedures can be used to prevent any contamination of the crystal growth precursors by common impurities (e.g. Si, Al, Fe, Ca, Na, K, Mg, Cl, and S) at a level of <10 parts per million total concentration. A combination of analytical techniques, including those which require little or no sample preparation (e.g. secondary ion mass spectrometry, neutron activation analysis, or laser microprobe mass spectrometry), should be used to determine the impurities present in a material. For example, the effects of protons incorporated (OH -) in the lattice of these crystals can be very detrimental and can be detected using infrared spectroscopy. The growth of many of these crystals requires flux techniques, but the temperature dependence of any nonstoichiometry present and of the distribution coefficients make the use of slow cooling techniques generally not recommended when uniformity of properties is required.

  14. Magnetic impurities in spin-split superconductors

    NASA Astrophysics Data System (ADS)

    van Gerven Oei, W.-V.; Tanasković, D.; Žitko, R.

    2017-02-01

    Hybrid semiconductor-superconductor quantum dot devices are tunable physical realizations of quantum impurity models for a magnetic impurity in a superconducting host. The binding energy of the localized subgap Shiba states is set by the gate voltages and external magnetic field. In this work we discuss the effects of the Zeeman spin splitting, which is generically present both in the quantum dot and in the (thin-film) superconductor. The unequal g factors in semiconductor and superconductor materials result in respective Zeeman splittings of different magnitude. We consider both classical and quantum impurities. In the first case we analytically study the spectral function and the subgap states. The energy of bound states depends on the spin-splitting of the Bogoliubov quasiparticle bands as a simple rigid shift. For the case of collinear magnetization of impurity and host, the Shiba resonance of a given spin polarization remains unperturbed when it overlaps with the branch of the quasiparticle excitations of the opposite spin polarization. In the quantum case, we employ numerical renormalization group calculations to study the effect of the Zeeman field for different values of the g factors of the impurity and of the superconductor. We find that in general the critical magnetic field for the singlet-doublet transition changes nonmonotonically as a function of the superconducting gap, demonstrating the existence of two different transition mechanisms: Zeeman splitting of Shiba states or gap closure due to Zeeman splitting of Bogoliubov states. We also study how in the presence of spin-orbit coupling, modeled as an additional noncollinear component of the magnetic field at the impurity site, the Shiba resonance overlapping with the quasiparticle continuum of the opposite spin gradually broadens and then merges with the continuum.

  15. Steviol glycoside safety: is the genotoxicity database sufficient?

    PubMed

    Urban, J D; Carakostas, M C; Brusick, D J

    2013-01-01

    The safety of steviol glycoside sweeteners has been extensively reviewed in the literature. National and international food safety agencies and approximately 20 expert panels have concluded that steviol glycosides, including the widely used sweeteners stevioside and rebaudioside A, are not genotoxic. However, concern has been expressed in recent publications that steviol glycosides may be mutagenic based on select studies representing a small fraction of the overall database, and it has been suggested that further in vivo genotoxicity studies are required to complete their safety profiles. To address the utility of conducting additional in vivo genotoxicity studies, this review evaluates the specific genotoxicity studies that are the sources of concern, and evaluates the adequacy of the database including more recent genotoxicity data not mentioned in those publications. The current database of in vitro and in vivo studies for steviol glycosides is robust and does not indicate that either stevioside or rebaudioside A are genotoxic. This, combined with a lack of evidence for neoplasm development in rat bioassays, establish the safety of all steviol glycosides with respect to their genotoxic/carcinogenic potential.

  16. 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.

  17. Fractional impurity moments in two-dimensional noncollinear magnets.

    PubMed

    Wollny, Alexander; Fritz, Lars; Vojta, Matthias

    2011-09-23

    We study dilute magnetic impurities and vacancies in two-dimensional frustrated magnets with noncollinear order. Taking the triangular-lattice Heisenberg model as an example, we use quasiclassical methods to determine the impurity contributions to the magnetization and susceptibility. Most importantly, each impurity moment is not quantized but receives nonuniversal screening corrections due to local relief of frustration. At finite temperatures, where bulk long-range order is absent, this implies an impurity-induced magnetic response of Curie form, with a prefactor corresponding to a fractional moment per impurity. We also discuss the behavior in an applied magnetic field, where we find a singular linear-response limit for overcompensated impurities.

  18. Identification, Characterization, and Quantification of Impurities of Safinamide Mesilate: Process-Related Impurities and Degradation Products.

    PubMed

    Zou, Liang; Sun, Lili; Zhang, Hui; Hui, Wenkai; Zou, Qiaogen; Zhu, Zheying

    2017-02-02

    The characterization of process-related impurities and degradation products of safinamide mesilate (SAFM) in bulk drugand a stability-indicating HPLC method for the separation and quantification of all the impurities were investigated. Four process-related impurities (Imp-B, Imp-C, Imp-D, and Imp-E) were found in the SAFM bulk drug. Five degradation products (Imp-A, Imp-C, Imp-D, Imp-E, and Imp-F) were observed in SAFM under oxidative conditions. Imp-C, Imp-D, and Imp-E were also degradation products and process-related impurities. Remarkably, one new compound, identified as (S)-2-[4-(3-fluoro-benzyloxy) benzamido] propanamide (i.e., Imp-D), is being reported here as an impurity for the first time. Furthermore, the structures of the aforementioned impurities were characterized and confirmed via IR, NMR, and MS techniques, and the most probable formation mechanisms of all impurities proposed according to the synthesis route. Optimum separation was achieved on an Inertsil ODS-3 column (250 × 4.6 mm, 5 μm), using 0.1% formic acid in water (pH adjusted to 5.0) and acetonitrile as the mobile phase in gradient mode. The proposed method was found to be stability-indicating, precise, linear, accurate, sensitive, and robust for the quantitation of SAFM and its process-related substances, including its degradation products.

  19. Differential genotoxicity mechanisms of silver nanoparticles and silver ions.

    PubMed

    Li, Yan; Qin, Taichun; Ingle, Taylor; Yan, Jian; He, Weiwei; Yin, Jun-Jie; Chen, Tao

    2017-01-01

    In spite of many reports on the toxicity of silver nanoparticles (AgNPs), the mechanisms underlying the toxicity are far from clear. A key question is whether the observed toxicity comes from the silver ions (Ag(+)) released from the AgNPs or from the nanoparticles themselves. In this study, we explored the genotoxicity and the genotoxicity mechanisms of Ag(+) and AgNPs. Human TK6 cells were treated with 5 nM AgNPs or silver nitrate (AgNO3) to evaluate their genotoxicity and induction of oxidative stress. AgNPs and AgNO3 induced cytotoxicity and genotoxicity in a similar range of concentrations (1.00-1.75 µg/ml) when evaluated using the micronucleus assay, and both induced oxidative stress by measuring the gene expression and reactive oxygen species in the treated cells. Addition of N-acetylcysteine (NAC, an Ag(+) chelator) to the treatments significantly decreased genotoxicity of Ag(+), but not AgNPs, while addition of Trolox (a free radical scavenger) to the treatment efficiently decreased the genotoxicity of both agents. In addition, the Ag(+) released from the highest concentration of AgNPs used for the treatment was measured. Only 0.5 % of the AgNPs were ionized in the culture medium and the released silver ions were neither cytotoxic nor genotoxic at this concentration. Further analysis using electron spin resonance demonstrated that AgNPs produced hydroxyl radicals directly, while AgNO3 did not. These results indicated that although both AgNPs and Ag(+) can cause genotoxicity via oxidative stress, the mechanisms are different, and the nanoparticles, but not the released ions, mainly contribute to the genotoxicity of AgNPs.

  20. 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.

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

    PubMed Central

    Hose, J E

    1994-01-01

    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

  2. Large-scale genotoxicity assessments in the marine environment

    SciTech Connect

    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. 31 refs., 2 tabs.

  3. 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

  4. Defects and impurities in mercuric iodine processing

    SciTech Connect

    van Scyoc, J.M.; James, R.B.; Schlesinger, T.E.; Gilbert, T.S.

    1996-03-01

    In the fabrication of mercuric iodide HgI{sub 2} room temperature radiation detectors, as in any semiconductor process, the quality of the final device is very sensitive to the impurities and defects present. Each process step can change the effects of existing defects, reduce the number of defects, or introduce new defects. In HgI{sub 2} detectors these defects act as trapping and recombination centers, thereby degrading immediate performance and leading to unstable devices. In this work we characterized some of the defects believed to strongly affect detector operation. Specifically, we studied impurities that are known to be present in typical HgI{sub 2} materials. Leakage current measurements were used to study the introduction and characteristics of these impurities, as such experiments reveal the mobile nature of these defects. In particular, we found that copper, which acts as a hole trap, introduces a positively charged center that diffuses and drifts readily in typical device environments. These measurements suggest that Cu, and related impurities like silver, may be one of the leading causes of HgI{sub 2} detector failures.

  5. Process and system for removing impurities from a gas

    SciTech Connect

    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.

  6. Development of Impurity Profiling Methods Using Modern Analytical Techniques.

    PubMed

    Ramachandra, Bondigalla

    2017-01-02

    This review gives a brief introduction about the process- and product-related impurities and emphasizes on the development of novel analytical methods for their determination. It describes the application of modern analytical techniques, particularly the ultra-performance liquid chromatography (UPLC), liquid chromatography-mass spectrometry (LC-MS), high-resolution mass spectrometry (HRMS), gas chromatography-mass spectrometry (GC-MS) and high-performance thin layer chromatography (HPTLC). In addition to that, the application of nuclear magnetic resonance (NMR) spectroscopy was also discussed for the characterization of impurities and degradation products. The significance of the quality, efficacy and safety of drug substances/products, including the source of impurities, kinds of impurities, adverse effects by the presence of impurities, quality control of impurities, necessity for the development of impurity profiling methods, identification of impurities and regulatory aspects has been discussed. Other important aspects that have been discussed are forced degradation studies and the development of stability indicating assay methods.

  7. 40 CFR 158.340 - Discussion of formation of impurities.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... and products produced by an integrated system. (1) Each impurity associated with the active ingredient...) Products not produced by an integrated system. Each impurity associated with the active ingredient...

  8. Pharmaceutical Education and the Translation of Pharmaceutical Care into Practice.

    ERIC Educational Resources Information Center

    Newton, Gail D.

    1991-01-01

    A systematic approach to reform of pharmaceutical education is seen as necessary to link intended outcomes of reform to a progressive and generally accepted mission of professional practice. Cooperation between pharmaceutical education, professional organizations, and regulatory agencies is viewed as necessary and refinement of professional…

  9. Deliquescence of pharmaceutical systems.

    PubMed

    Mauer, Lisa J; Taylor, Lynne S

    2010-12-01

    Deliquescence is a first order phase transition from solid to solution that occurs at a relative humidity (RH) that is characteristic to the crystalline compound. Such dissolution of active pharmaceutical ingredients and excipients can lead to detrimental physical and chemical instabilities. Furthermore, in systems containing more than one deliquescent component, the RH of the solid-solution transition will be lowered, leading to some level of dissolution at unexpectedly low RH conditions. Deliquescence lowering is independent of the ratio of the deliquescent components and therefore is of concern for any formulation containing two or more deliquescent compounds. Because chemical reactions occur much more readily in solution, deliquescence will enhance the degradation of labile APIs. RH fluctuations will lead to cycles of deliquescence and efflorescence (crystallization), which will contribute to particle agglomeration and caking. This review will address the phenomenon of deliquescence, the significance of deliquescence to pharmaceutical systems, measurement techniques, the kinetics and thermodynamics of deliquescence, the behavior of mixtures of deliquescent compounds (including phase diagrams and thermodynamics of binary systems), and consequences of deliquescence on chemical and physical stability.

  10. 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

  11. Genotoxicity evaluation of Isaria sinclairii (ISE) extract.

    PubMed

    Ahn, Mi Young; Ryu, Kang Sun; Jee, Sang Duck; Kim, Iksoo; Kim, Jin Won; Kim, Yeong Shik; Kim, Hyung Sik; Kim, In Sun; Kang, Se C; Koo, Hyun Jung; Park, Yo An; Choi, Sul Min; Yoo, Eun Jeong; Kwack, Seung Jun; Yoo, Sun Dong; Lee, Byung Mu

    2004-12-01

    The mutagenic potential Isaria sinclairii, a traditional Chinese medicine composed of the fruiting bodies of I. sinclairii and its parasitic host larva, was evaluated using short-term genotoxicity tests, namely, the Ames test, chromosome aberration (CA), and micronuclei (MN) tests. In a Salmonella typhimurium assay, I. sinclairii extract (ISE) did not produce any mutagenic response in the absence or presence of 59 mix with TA98, TA100, TA1535, and TA1537. In the chromosome aberration (CA) test, ISE induced no significant effect on Chinese hamster ovary (CHO) cells compared with control. In the MN test, no significant change in the occurrence of micronucleated polychromatic erythrocytes was observed in male ICR mice intraperitoneally administered ISE at doses of 15, 150, or 1500 mg/kg. These results indicate that ISE has no mutagenic potential in these in vitro and in vivo systems.

  12. Monitoring genotoxic exposure in uranium mines.

    PubMed Central

    Srám, R J; Dobiás, L; Rössner, P; Veselá, D; Veselý, D; Rakusová, R; Rericha, V

    1993-01-01

    Recent data from deep uranium mines in Czechoslovakia indicated that mines 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 B1 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 vitro. These data suggest that mycotoxins produced by molds in uranium mines are a new genotoxic factor for uranium miners. PMID:8143610

  13. 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.

  14. Materials in Manufacturing and Packaging Systems as Sources of Elemental Impurities in Packaged Drug Products: A Literature Review.

    PubMed

    Jenke, Dennis R; Stults, Cheryl L M; Paskiet, Diane M; Ball, Douglas J; Nagao, Lee M

    Elemental impurities in drug products can arise from a number of different sources and via a number of different means, including the active pharmaceutical ingredient, excipients, the vehicle, and leaching of elemental entities that are present in the drug product's manufacturing or packaging systems. Thus, knowledge about the presence, level, and likelihood of leaching of elemental entities in manufacturing and packaging systems is relevant to understanding how these systems contribute to a drug product's total elemental impurity burden. To that end, a joint team from the Extractables and Leachables Safety Information Exchange (ELSIE) Consortium and the International Pharmaceutical Aerosol Consortium on Regulation and Science (IPAC-RS) has conducted a review of the available literature on elemental entities in pharmaceutically relevant polymers and the presence of these elemental entities in material extracts and/or drug products. This review article contains the information compiled from the available body of literature and considers two questions: (1) What elemental entities are present in the relevant polymers and materials and at what levels are they present? (2) To what extent are these elemental entities leached from these materials under conditions relevant to the manufacturing and storage/distribution of solution drug products? Conclusions drawn from the compiled data are as follows: (1) Elemental entities are present in the materials used to construct packaging and manufacturing systems as these materials either contain these elemental entities as additives or are exposed to elemental entities during their production. (2) Unless the elemental entities are parts of the materials themselves (for example, SiO2 in glass) or intentionally added to the materials (for example, metal stearates in polymers), their incidental amounts in the materials are generally low. (3) When elemental entities are present in materials and systems, generally only a very small

  15. Parallel Impurity Spreading During Massive Gas Injection

    NASA Astrophysics Data System (ADS)

    Izzo, V. A.

    2016-10-01

    Extended-MHD simulations of disruption mitigation in DIII-D demonstrate that both pre-existing islands (locked-modes) and plasma rotation can significantly influence toroidal spreading of impurities following massive gas injection (MGI). Given the importance of successful disruption mitigation in ITER and the large disparity in device parameters, empirical demonstrations of disruption mitigation strategies in present tokamaks are insufficient to inspire unreserved confidence for ITER. Here, MHD simulations elucidate how impurities injected as a localized jet spread toroidally and poloidally. Simulations with large pre-existing islands at the q = 2 surface reveal that the magnetic topology strongly influences the rate of impurity spreading parallel to the field lines. Parallel spreading is largely driven by rapid parallel heat conduction, and is much faster at low order rational surfaces, where a short parallel connection length leads to faster thermal equilibration. Consequently, the presence of large islands, which alter the connection length, can slow impurity transport; but the simulations also show that the appearance of a 4/2 harmonic of the 2/1 mode, which breaks up the large islands, can increase the rate of spreading. This effect is seen both for simulations with spontaneously growing and directly imposed 4/2 modes. Given the prevalence of locked-modes as a cause of disruptions, understanding the effect of large islands is of particular importance. Simulations with and without islands also show that rotation can alter impurity spreading, even reversing the predominant direction of spreading, which is toward the high-field-side in the absence of rotation. Given expected differences in rotation for ITER vs. DIII-D, rotation effects are another important consideration when extrapolating experimental results. Work supported by US DOE under DE-FG02-95ER54309.

  16. 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.

  17. Chromium genotoxicity: a double-edged sword

    PubMed Central

    Nickens, Kristen P.; Patierno, Steven R.; Ceryak, Susan

    2010-01-01

    Certain forms of hexavalent chromium [Cr(VI)] are known respiratory carcinogens that induce a broad spectrum of DNA damage. Cr(VI)-carcinogenesis may be initiated or promoted through several mechanistic processes including, the intracellular metabolic reduction of Cr(VI) producing chromium species capable of interacting with DNA to yield genotoxic and mutagenic effects, Cr(VI)-induced inflammatory/immunological responses, and alteration of survival signaling pathways. Cr(VI) enters the cell through nonspecific anion channels, and is metabolically reduced by agents including ascorbate, glutathione, and cysteine to Cr(V), Cr(IV), and Cr(III). Cr(III) has a weak membrane permeability capacity and is unable to cross the cell membrane, thereby trapping it within the cell where it can bind to DNA and produce genetic damage leading to genomic instability. Structural genetic lesions produced by the intracellular reduction of Cr(VI) include DNA adducts, DNA strand breaks, DNA-protein crosslinks, oxidized bases, abasic sites, and DNA inter- and intrastrand crosslinks. The damage induced by Cr(VI) can lead to dysfunctional DNA replication and transcription, aberrant cell cycle checkpoints, dysregulated DNA repair mechanisms, microsatelite instability, inflammatory responses, and the disruption of key regulatory gene networks responsible for the balance of cell survival and cell death, which may all play an important role in Cr(VI) carcinogenesis. Several lines of evidence have indicated that neoplastic progression is a result of consecutive genetic/epigenetic changes that provide cellular survival advantages, and ultimately lead to the conversion of normal human cells to malignant cancer cells. This review is based on studies that provide a glimpse into Cr(VI) carcinogenicity via mechanisms including Cr(VI)-induced death-resistance, the involvement of DNA repair mechanisms in survival after chromium exposure, and the activation of survival signaling cascades in response to Cr

  18. 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.

  19. No cytotoxicity or genotoxicity of graphene and graphene oxide in murine lung epithelial FE1 cells in vitro.

    PubMed

    Bengtson, Stefan; Kling, Kirsten; Madsen, Anne Mette; Noergaard, Asger W; Jacobsen, Nicklas Raun; Clausen, Per Axel; Alonso, Beatriz; Pesquera, Amaia; Zurutuza, Amaia; Ramos, Raphael; Okuno, Hanako; Dijon, Jean; Wallin, Håkan; Vogel, Ulla

    2016-07-01

    Graphene and graphene oxide receive much attention these years, because they add attractive properties to a wide range of applications and products. Several studies have shown toxicological effects of other carbon-based nanomaterials such as carbon black nanoparticles and carbon nanotubes in vitro and in vivo. Here, we report in-depth physicochemical characterization of three commercial graphene materials, one graphene oxide (GO) and two reduced graphene oxides (rGO) and assess cytotoxicity and genotoxicity in the murine lung epithelial cell line FE1. The studied GO and rGO mainly consisted of 2-3 graphene layers with lateral sizes of 1-2 µm. GO had almost equimolar content of C, O, and H while the two rGO materials had lower contents of oxygen with C/O and C/H ratios of 8 and 12.8, respectively. All materials had low levels of endotoxin and low levels of inorganic impurities, which were mainly sulphur, manganese, and silicon. GO generated more ROS than the two rGO materials, but none of the graphene materials influenced cytotoxicity in terms of cell viability and cell proliferation after 24 hr. Furthermore, no genotoxicity was observed using the alkaline comet assay following 3 or 24 hr of exposure. We demonstrate that chemically pure, few-layered GO and rGO with comparable lateral size (> 1 µm) do not induce significant cytotoxicity or genotoxicity in FE1 cells at relatively high doses (5-200 µg/ml). Environ. Mol. Mutagen. 57:469-482, 2016. © 2016 The Authors. Environmental and Molecular Mutagenesis Published by Wiley Periodicals, Inc.

  20. No cytotoxicity or genotoxicity of graphene and graphene oxide in murine lung epithelial FE1 cells in vitro

    PubMed Central

    Bengtson, Stefan; Kling, Kirsten; Madsen, Anne Mette; Noergaard, Asger W.; Jacobsen, Nicklas Raun; Clausen, Per Axel; Alonso, Beatriz; Pesquera, Amaia; Zurutuza, Amaia; Ramos, Raphael; Okuno, Hanako; Dijon, Jean; Wallin, Håkan

    2016-01-01

    Graphene and graphene oxide receive much attention these years, because they add attractive properties to a wide range of applications and products. Several studies have shown toxicological effects of other carbon‐based nanomaterials such as carbon black nanoparticles and carbon nanotubes in vitro and in vivo. Here, we report in‐depth physicochemical characterization of three commercial graphene materials, one graphene oxide (GO) and two reduced graphene oxides (rGO) and assess cytotoxicity and genotoxicity in the murine lung epithelial cell line FE1. The studied GO and rGO mainly consisted of 2–3 graphene layers with lateral sizes of 1–2 µm. GO had almost equimolar content of C, O, and H while the two rGO materials had lower contents of oxygen with C/O and C/H ratios of 8 and 12.8, respectively. All materials had low levels of endotoxin and low levels of inorganic impurities, which were mainly sulphur, manganese, and silicon. GO generated more ROS than the two rGO materials, but none of the graphene materials influenced cytotoxicity in terms of cell viability and cell proliferation after 24 hr. Furthermore, no genotoxicity was observed using the alkaline comet assay following 3 or 24 hr of exposure. We demonstrate that chemically pure, few‐layered GO and rGO with comparable lateral size (> 1 µm) do not induce significant cytotoxicity or genotoxicity in FE1 cells at relatively high doses (5–200 µg/ml). Environ. Mol. Mutagen. 57:469–482, 2016. © 2016 The Authors. Environmental and Molecular Mutagenesis Published by Wiley Periodicals, Inc. PMID:27189646

  1. Divertor impurity sources; effects of hot surfaces and thin films on impurity production

    NASA Astrophysics Data System (ADS)

    Stamp, M. F.; Andrew, P.; Brezinsek, S.; Huber, A.; JET EFDA Contributors

    2005-03-01

    Strong continuum emission has been observed from divertor tiles at visible wavelengths and identified as Planck radiation from surfaces with temperatures of typically ˜ 2600 K. Such hot spots (which are not tile edges) can persist for several seconds and are more common at the inner divertor, than the outer. Surprisingly, these hot spots do not usually produce significant impurity fluxes. In contrast, ELMs may produce a significant enhancement of impurity fluxes, depending on strike point location and ELM size.

  2. 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...

  3. Genotoxicity guidelines recommended by International Conference of Harmonization (ICH).

    PubMed

    Kamath, Gireesh H; Rao, K S

    2013-01-01

    Genotoxicity tests are designed to detect the genetic damage by various mechanisms. Several guidelines have provided various tests to be conducted for testing the genotoxicity and each of the regulatory agencies around the world have developed their own requirements for mutagenicity, without realizing that the products developed or registered in one country are also going to be registered and marketed around the world. The ICH guideline of genotoxicity helps to optimize the standard battery for genetic toxicology and to provide guidance on interpretation of results. These suggested standard set of tests does not imply that other genotoxicity tests are inadequate or inappropriate, but they help in improving risk characterization for carcinogenic effects that have their basis in changes in the genetic material.

  4. Genotoxicity of the fungicide dichlofluanide in seven assays

    SciTech Connect

    Heil, J.; Reifferscheid, G.; Hellmich, D.; Hergenroeder, M.; Zahn, R.K. )

    1991-01-01

    Seven different endpoints for detection of genotoxicity have been used to demonstrate the DNA-altering properties of Dichlofluanid, a fungicide commonly used in viticulture pest control. Each endpoint (DNA synthesis inhibition test, alkaline viscosimetry, umu-test, alkaline filter elution, FADU-test, {sup 32}P-postlabeling, and electron microscopy) shows clear evidence of genotoxicity. These data indicate that application of the fungicide dichlofluanid may be mutagenic and/or carcinogenic for exposed humans.

  5. Are genotoxic carcinogens more potent than nongenotoxic carcinogens?

    PubMed Central

    Parodi, S; Malacarne, D; Romano, P; Taningher, M

    1991-01-01

    In this report we have raised the question whether genotoxic carcinogens are more potent than nongenotoxic carcinogens when studied in long-term carcinogenicity assays in rodents. To build a large database of compounds for which both carcinogenicity and genotoxicity had been investigated, we have used a database produced by Gold and co-workers for carcinogenic potency data (975 chemicals) and a database produced by Würgler for genotoxicity data (2834 chemicals). Considering compounds positive or negative in at least three short-term tests and in at least 75% of available tests, we could define 67 genotoxic carcinogens and 46 nongenotoxic carcinogens. Carcinogenic potency of genotoxic carcinogens was about 50 times higher than carcinogenic potency of nongenotoxic carcinogens. Our results are different from the results of Tennant et al.; their database (24 genotoxic carcinogens and 12 nongenotoxic carcinogens compatible with our definition) seems to suggest that there is practically no difference in potency between genotoxic and nongenotoxic carcinogens. The two databases have only four compounds in common and are also different in terms of number of elements for different chemical classes. Nitrosocompounds, nitrogen mustards, hydrazine derivatives, and polycyclic aromatic hydrocarbons are not represented in the database of Tennant. The overall impression from our analysis is that the usefulness of short-term tests of genotoxicity could be significantly better than what has been suggested by the previous work of Tennant et al. because these tests tend to detect, at least for many important chemical classes, the most potent carcinogens. This consideration may not be valid for certain classes of chemicals. PMID:1821372

  6. Low doses and thresholds in genotoxicity: from theories to experiments.

    PubMed

    Zito, R

    2001-09-01

    The absence of threshold in the action of genotoxic carcinogens was theoretically postulated more than thirty years ago, but continuously challenged for scientific and practical reasons. The direct experimental demonstration of the presence of a threshold for genotoxic damage is precluded by the insufficient sensitivity of the biological methods presently available. In the last twenty years the sensitivity of the methods for quantitative determination of the DNA adducts of the carcinogens was enormously improved, demonstrating linearity of the dose/adducts pattern over dose intervals of more than million-fold. The arguments more often advanced for the presence of a threshold for genotoxic carcinogens were mainly based on the action of intracellular scavengers, detoxification enzymes and repair systems, being able to block completely the genotoxic carcinogens at very low doses. This hypothesis is disproved by the constant presence of DNA adducts at extremely low doses of different carcinogens, whatever their chemical structure can be. On the other hand if genotoxic damage results from damage to proteins involved in cell division, like tubulin, there is a threshold dose for such genotoxic effects. The detailed knowledge of the genotoxicity mechanism is therefore needed for a sound carcinogenic risk assessment. Most of the genotoxic carcinogens, or their metabolites, damage directly the DNA. In this case the absence of threshold must be assumed, not only for theoretical reasons, but for the results of the experiments quantitatively relating DNA damage and very low doses of carcinogens. For the sake of clarity the "adjectivated" thresholds, like practical pragmatic, apparent and operational, must disappear from documents analysing the carcinogenic risk.

  7. 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.

  8. Shape of impurity electronic absorption bands in nematic liquid crystal

    SciTech Connect

    Aver`yanov, E.M.

    1994-11-01

    The impurity-matrix anisotropic static intermolecular interactions, orientation-statistical properties, and electronic structure of uniaxial impurity molecules are shown to have a significant influence on spectral moments of the electronic absorption bands of impurities in the nematic liquid crystal. 14 refs., 3 figs.

  9. Development and validation of a specific and sensitive GC-FID method for the determination of impurities in 5-chlorovaleroyl chloride.

    PubMed

    Tang, Liya; Kim, Alexandre; Miller, Scott A; Lloyd, David K

    2010-11-02

    5-Chlorovaleroyl chloride (5-CVC) is commonly used as an alkylating agent in the synthesis of pharmaceutical intermediates, active ingredients, as well as other specialty chemicals. It is critical to monitor the impurities present in 5-CVC as they may have a direct impact on the impurity profile and quality of the final product. This paper describes the development and validation of a GC-FID method for the analysis of low level impurities of 5-CVC. This is the first method reported in the literature for the impurity determination of 5-CVC. The results of GC method development, with and without sample derivatization, are presented. The final method uses methanol for derivatization and separates methyl esters of 5-CVC and the key impurities, 4-pentenoyl chloride, 4-chlorovaleroyl chloride, 5-chlorohexanoyl chloride, and 4-methyl-5-chlorovaleroyl chloride. 3-Methoxypyridine was used in the sample solvent to enable the detection of 5-chlorovaleric acid (5-CVA) which is the major degradant of 5-CVC. The method was validated for specificity, linearity, accuracy, precision, sensitivity, and robustness. This simple and robust GC approach may be applicable to impurity analysis of other acid chlorides or acid halides.

  10. Isolation, Identification, and Characterisation of Degradation Products and the Development and Validation of a Stability-Indicating Method for the Estimation of Impurities in the Tolterodine Tartrate Formulation.

    PubMed

    Prakash, Lakkireddy; Himaja, Malipeddi; Vasudev, Rudraraju

    2015-01-01

    A short and sensitive stability-indicating gradient RP-UPLC method was developed for the quantitative determination of process-related impurities and degradation products of tolterodine tartrate in pharmaceutical formulations. The method was developed by using the Waters ACQUITY UPLC™ BEH shield RP18 (2.1 × 100 mm, 1.7 μm) column with a mobile phase containing a gradient mixture of solvent A and B at a detection wavelength of 210 nm. During the stress study, the degradation products of tolterodine tartrate were well-resolved from tolterodine and its impurities and the mass balances were found to be satisfactory in all the stress conditions, thus proving the stability-indicating capability of the method. The developed method was validated as per ICH guidelines with respect to specificity, linearity, limit of detection and quantification, accuracy, precision, ruggedness, and robustness. During the stability (40°C/75% RH, 3 months) analysis of the drug product, one unknown impurity was detected by the above stability-indicating method. The unknown impurity was isolated by preparative HPLC and subjected to mass and NMR studies. Based on the spectral data, the unknown impurity was characterised as 2-(3-amino-1-phenylpropyl)-4-methylphenol (des-N,N-diisopropyl tolterodine). Structural elucidation of the impurity by spectral data is discussed in detail.

  11. Designing a Pharmaceutical Care Curriculum.

    ERIC Educational Resources Information Center

    Perrier, Donald G.; And Others

    1995-01-01

    Guidelines for developing a pharmacy school curriculum based on the principle of pharmaceutical care and professional responsibility are offered, beginning with mission statements for profession, practice, and pharmaceutical education in general. The University of Toronto experience in designing such a curriculum is chronicled as an illustration…

  12. Evaluation of protective effect of amifostine on dacarbazine induced genotoxicity.

    PubMed

    Etebari, M; Jafarian-Dehkordi, A; Lame, V

    2015-01-01

    Anticancer therapy with alkylating agents has been used for many years. Dacarbazine (DTIC) as an alkylating agent is used alone or in combination with other chemotherapy drugs. In order to inhibit the formation of secondary cancers resulting from chemotherapy with DTIC, preventional strategies is necessary. The present study was undertaken to evaluate the genoprotective effect of amifostine on the genotoxic effects of DTIC in cell culture condition. To determine the optimum genotoxic concentration of DTIC, HepG2 cells were incubated with various DTIC concentrations including 5, 10 and 20 μg/ml for 2 h and the genotoxic effects were evaluated by the comet assay. The result of this part of the study showed that incubation of HepG2 cells with DTIC at 5 μg/ml was sufficient to produce genotoxic effect. In order to determine the protective effects of amifostine on genotoxicity induced by DTIC, HepG2 cells were incubated with different concentrations of amifostine (2, 3 and 5 mg/ml) for 1 h which was followed by incubation with DTIC at 5 μg/ml for 2 h. One hour incubation of cells with different concentrations of amifostine before incubation with DITC indicated that at least 5 mg/ml concentration of amifostine can prevent genotoxic effects induced by DTIC on HepG2 cells under described condition. In conclusion amifostine could prevent DNA damage induced by DTIC on HepG2 cells.

  13. Update on the genotoxicity and carcinogenicity of cobalt compounds

    PubMed Central

    Lison, D; De Boeck, M; Verougstraete, V; Kirsch-Volders, M

    2001-01-01

    OBJECTIVE—To integrate recent understandings of the mechanisms of genotoxicity and carcinogenicity of the different cobalt compounds.
METHOD—A narrative review of the studies published since the last IARC assessment in 1991 (genotoxicity, experimental carcinogenesis, and epidemiology).
RESULTS—Two different mechanisms of genotoxicity, DNA breakage induced by cobalt metal and especially hard metal particles, and inhibition of DNA repair by cobalt (II) ions contribute to the carcinogenic potential of cobalt compounds. There is evidence that soluble cobalt (II) cations exert a genotoxic and carcinogenic activity in vitro and in vivo in experimental systems but evidence in humans is lacking. Experimental data indicate some evidence of a genotoxic potential for cobalt metal in vitro in human lymphocytes but there is no evidence available of a carcinogenic potential. There is evidence that hard metal particles exert a genotoxic and carcinogenic activity in vitro and in human studies, respectively. There is insufficient information for cobalt oxides and other compounds.
CONCLUSION—Although many areas of uncertainty remain, an assessment of the carcinogenicity of cobalt and its compounds requires a clear distinction between the different compounds of the element and needs to take into account the different mechanisms involved.


Keywords: cobalt; DNA breakage; inhibition of DNA repair PMID:11555681

  14. Evaluation of protective effect of amifostine on dacarbazine induced genotoxicity

    PubMed Central

    Etebari, M.; Jafarian-Dehkordi, A.; Lame, V.

    2015-01-01

    Anticancer therapy with alkylating agents has been used for many years. Dacarbazine (DTIC) as an alkylating agent is used alone or in combination with other chemotherapy drugs. In order to inhibit the formation of secondary cancers resulting from chemotherapy with DTIC, preventional strategies is necessary. The present study was undertaken to evaluate the genoprotective effect of amifostine on the genotoxic effects of DTIC in cell culture condition. To determine the optimum genotoxic concentration of DTIC, HepG2 cells were incubated with various DTIC concentrations including 5, 10 and 20 μg/ml for 2 h and the genotoxic effects were evaluated by the comet assay. The result of this part of the study showed that incubation of HepG2 cells with DTIC at 5 μg/ml was sufficient to produce genotoxic effect. In order to determine the protective effects of amifostine on genotoxicity induced by DTIC, HepG2 cells were incubated with different concentrations of amifostine (2, 3 and 5 mg/ml) for 1 h which was followed by incubation with DTIC at 5 μg/ml for 2 h. One hour incubation of cells with different concentrations of amifostine before incubation with DITC indicated that at least 5 mg/ml concentration of amifostine can prevent genotoxic effects induced by DTIC on HepG2 cells under described condition. In conclusion amifostine could prevent DNA damage induced by DTIC on HepG2 cells. PMID:26430459

  15. Stability-indicating UPLC method for determination of Valsartan and their degradation products in active pharmaceutical ingredient and pharmaceutical dosage forms.

    PubMed

    Krishnaiah, Ch; Reddy, A Raghupathi; Kumar, Ramesh; Mukkanti, K

    2010-11-02

    A simple, precise, accurate stability-indicating gradient reverse phase ultra-performance liquid chromatographic (RP-UPLC) method was developed for the quantitative determination of purity of Valsartan drug substance and drug products in bulk samples and pharmaceutical dosage forms in the presence of its impurities and degradation products. The method was developed using Waters Aquity BEH C18 (100 mm x 2.1 mm, 1.7 microm) column with mobile phase containing a gradient mixture of solvents A and B. The eluted compounds were monitored at 225 nm, the run time was within 9.5 min, which Valsartan and its seven impurities were well separated. Valsartan was subjected to the stress conditions of oxidative, acid, base, hydrolytic, thermal and photolytic degradation. Valsartan was found to degrade significantly in acid and oxidative stress conditions and stable in base, hydrolytic and photolytic degradation conditions. The degradation products were well resolved from main peak and its impurities, proving the stability-indicating power of the method. The developed method was validated as per international conference on harmonization (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 Valsartan in pharmaceutical dosage forms.

  16. 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

  17. 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.

  18. 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

  19. 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.

  20. Incorporation of impurity to a tetragonal lysozyme crystal

    NASA Astrophysics Data System (ADS)

    Kurihara, Kazuo; Miyashita, Satoru; Sazaki, Gen; Nakada, Toshitaka; Durbin, Stephen D.; Komatsu, Hiroshi; Ohba, Tetsuhiko; Ohki, Kazuo

    1999-01-01

    Concentration of a phosphor-labeled impurity (ovalbumin) incorporated into protein (hen egg white lysozyme) crystals during growth was measured by fluorescence.This technique enabled us to measure the local impurity concentration in a crystal quantitatively. Impurity concentration increased with growth rate, which could not be explained by two conventional models (equilibrium adsorption model and Burton-Prim-Slichter model); a modified model is proposed. Impurity concentration also increased with the pH of the solution. This result is discussed considering the electrostatic interaction between the impurity and the crystallizing species.

  1. [Pharmaceutical logistic in turnover of pharmaceutical products of Azerbaijan].

    PubMed

    Dzhalilova, K I

    2009-11-01

    Development of pharmaceutical logistic system model promotes optimal strategy for pharmaceutical functioning. The goal of such systems is organization of pharmaceutical product's turnover in required quantity and assortment, at preset time and place, at a highest possible degree of consumption readiness with minimal expenses and qualitative service. Organization of the optimal turnover chain in the region is offered to start from approximate classification of medicaments by logistic characteristics. Supplier selection was performed by evaluation of timeliness of delivery, quality of delivered products (according to the minimum acceptable level of quality) and time-keeping of time spending for orders delivery.

  2. A new, rapid, stability-indicating UPLC method for separation and determination of impurities in amlodipine besylate, valsartan and hydrochlorothiazide in their combined tablet dosage form.

    PubMed

    Vojta, Jiří; Jedlička, Aleš; Coufal, Pavel; Janečková, Lucie

    2015-05-10

    A new rapid stability-indicating UPLC method for separation and determination of impurities in amlodipine besylate, valsartan and hydrochlorothiazide in their combined tablet dosage form was developed. The separation of Ph. Eur. related substances of amlodipine besylate (A, B, D, E, F, G), hydrochlorothiazide (A, B, C), valsartan (B, C), two other valsartan impurities (S)-2-(N-{[2'-cyanobiphenyl-4-yl]methyl}pentanamido)-3-methylbutanoic acid and (S)-3-methyl-2-{[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methylamino}butanoic acid and several unknown impurities was achieved by reversed phase liquid chromatography with UV detection. The detection wavelengths were set as follows: 225nm for valsartan, its impurities and for the impurity D of amlodipine, 271nm for hydrochlorothiazide and its impurities and 360nm for amlodipine and its impurities except for impurity D. Zorbax Eclipse C8 RRHD (100mm×3.0mm, 1.8μm) was used as a separation column and the analytes were eluted within 11min by a programmed gradient mixture of 0.01M phosphate buffer pH 2.5 and acetonitrile. The method was successfully validated in accordance to the International Conference of Harmonization (ICH) guidelines for amlodipine besylate and its impurity D, valsartan and its impurity C and hydrochlorothiazide and its impurities A, B and C. The triple-combined tablets were exposed to thermal, higher humidity, acid, alkaline, oxidative and photolytic stress conditions. Stressed samples were analyzed by the proposed method. All the significant degradation products and impurities were satisfactory separated from each other and from the principal peaks of drug substances. The peak purity test complied for peaks of amlodipine, valsartan and hydrochlorothiazide in all the stressed samples and indicated no co-elution of degradation products. The method was found to be precise, linear, accurate, sensitive, specific, robust and stability-indicating and could be used as a routine purity test method for amlodipine

  3. A novel validated ultra-performance liquid chromatography Method for separation of eszopiclone impurities and its degradants in drug products.

    PubMed

    Sharma, Nitish; Rao, Surendra Singh; Kumar, Namala Durga Atchuta; Reddy, Annarapu Malleswara

    2013-01-01

    A selective, specific, and sensitive ultra-performance LC (UPLC) method was developed for determination of eszopiclone and its degradation products. The chromatographic separation was performed with a Waters ACQUITY UPLC system and BEH C18 column using gradient elution with mobile phases A and B. Mobile phase A was 0.01 M phosphate buffer with 0.2% (w/v) 1-octane sulfonic acid sodium salt as an ion pair reagent, adjusted pH 2.2 with orthophosphoric acid-acetonitrile (85 + 15, v/v). Mobile phase B was pH 2.2 buffer-acetonitrile (20 + 80, v/v). UV detection was performed at 303 nm. Eszopiclone and its impurities were chromatographed with a total run time of 13 min. A calibration study showed that the response for each of the impurities A, B, C, and D was linear between concentrations of 0.02 and 7.2 microg/mL (r2 > or = 0.999). The method was validated over this range for precision, intermediate precision, accuracy, linearity, and specificity. For the precision study, RSD of each impurity was <5% (n = 6). The method was found to be precise, accurate, linear, and specific. The proposed method was successfully used for determination of eszopiclone impurities in pharmaceutical preparations.

  4. Kinetic neoclassical calculations of impurity radiation profiles

    SciTech Connect

    Stotler, D. P.; Battaglia, D. J.; Hager, R.; Kim, K.; Koskela, T.; Park, G.; Reinke, M. L.

    2016-12-30

    Modifications of the drift-kinetic transport code XGC0 to include the transport, ionization, and recombination of individual charge states, as well as the associated radiation, are described. The code is first applied to a simulation of an NSTX H-mode discharge with carbon impurity to demonstrate the approach to coronal equilibrium. The effects of neoclassical phenomena on the radiated power profile are examined sequentially through the activation of individual physics modules in the code. Orbit squeezing and the neoclassical inward pinch result in increased radiation for temperatures above a few hundred eV and changes to the ratios of charge state emissions at a given electron temperature. As a result, analogous simulations with a neon impurity yield qualitatively similar results.

  5. Kinetic neoclassical calculations of impurity radiation profiles

    DOE PAGES

    Stotler, D. P.; Battaglia, D. J.; Hager, R.; ...

    2016-12-30

    Modifications of the drift-kinetic transport code XGC0 to include the transport, ionization, and recombination of individual charge states, as well as the associated radiation, are described. The code is first applied to a simulation of an NSTX H-mode discharge with carbon impurity to demonstrate the approach to coronal equilibrium. The effects of neoclassical phenomena on the radiated power profile are examined sequentially through the activation of individual physics modules in the code. Orbit squeezing and the neoclassical inward pinch result in increased radiation for temperatures above a few hundred eV and changes to the ratios of charge state emissions atmore » a given electron temperature. As a result, analogous simulations with a neon impurity yield qualitatively similar results.« less

  6. Global migration of impurities in tokamaks

    NASA Astrophysics Data System (ADS)

    Hakola, A.; Airila, M. I.; Björkas, C.; Borodin, D.; Brezinsek, S.; Coad, J. P.; Groth, M.; Järvinen, A.; Kirschner, A.; Koivuranta, S.; Krieger, K.; Kurki-Suonio, T.; Likonen, J.; Lindholm, V.; Makkonen, T.; Mayer, M.; Miettunen, J.; Müller, H. W.; Neu, R.; Petersson, P.; Rohde, V.; Rubel, M.; Widdowson, A.; the ASDEX Upgrade Team; Contributors, JET-EFDA

    2013-12-01

    The migration of impurities in tokamaks has been studied with the help of tracer-injection (13C and 15N) experiments in JET and ASDEX Upgrade since 2001. We have identified a common pattern for the migrating particles: scrape-off layer flows drive impurities from the low-field side towards the high-field side of the vessel. Migration is also sensitive to the density and magnetic configuration of the plasma, and strong local variations in the resulting deposition patterns require 3D treatment of the migration process. Moreover, re-erosion of the deposited particles has to be taken into account to properly describe the migration process during steady-state operation of the tokamak.

  7. 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.

  8. Phase Shift of the Asymmetric Friedel-Anderson Impurity

    NASA Astrophysics Data System (ADS)

    Bergmann, Gerd

    2013-04-01

    The ground state of the asymmetric Friedel-Anderson (aFA) impurity is calculated within the FAIR (Friedel artificially inserted resonance) theory. Its properties are investigated by means of the fidelity with different Friedel impurities and by its Friedel oscillations. Friedel impurities with a specific phase shift δ at the Fermi level possess a finite fidelity with the aFA impurity. This phase shift δ determines other properties of the aFA impurity such as the amplitude and displacement of its Friedel oscillations. One can find the parameters of a Friedel impurity which coincides in its Friedel oscillations almost perfectly with the aFA impurity, thereby avoiding an Anderson orthogonality catastrophe.

  9. Phyllanthus orbicularis aqueous extract: cytotoxic, genotoxic, and antimutagenic effects in the CHO cell line.

    PubMed

    Sànchez-Lamar, A; Fiore, M; Cundari, E; Ricordy, R; Cozzi, R; De Salvia, R

    1999-12-15

    The present work evaluates the cytotoxic, genotoxic, and antimutagenic effects of Phyllanthus orbicularis (plant of genus Phyllantus) aqueous extract in Chinese hamster ovary (CHO) cells. P. orbicularis aqueous extracts are used in Cuban traditional medicine for their antiviral activity against Hepatitis B virus and A and B flu virus. The cytotoxicity of the extract was tested by means of colony-forming ability and growth-inhibition assays as well as by measuring the mitotic index. Apoptosis induction and cell-cycle kinetics were analyzed by cytofluorimetric methods. Chromosome aberration assays were performed to study the genotoxic and antimutagenic activity of the extract. Results show that doses of up to 100 microg/ml of the extract did not induce any cytotoxic effects. Cell survival and mitotic index decreased significantly at doses higher than 100 microg/ml as a function of dose as well as of treatment time. Moreover, continuous treatments of up to 18 h induced the appearance of a significant number of apoptotic cells. Following a 3-h exposure to a dose of 750 microg/ml, cells accumulated significantly in G(2)-M phase and remained blocked in G(1-) and G(2)-M phases after several posttreatments in fresh growth medium. The aqueous extract alone did not induce chromosome aberrations but, in combined treatment with H(2)O(2), significantly reduced H(2)O(2)-induced chromosome aberrations. Flow cytometric analysis of DCFH intracellular oxidation showed that the extract decreased the oxidizing power of H(2)O(2.) This ability could possibly explain the extract's antigenotoxic activity. Absence of cytotoxicity at the lower tested doses and the antimutagenic properties of the extract stimulate the interest in studying possible new pharmaceutical uses of P. orbicularis.

  10. 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.

  11. Development and validation of an UPLC method for rapid determination of ibuprofen and diphenhydramine citrate in the presence of impurities in combined dosage form.

    PubMed

    Rao, Dantu Durga; Sait, Shakil S; Mukkanti, K

    2011-04-01

    A novel, stability-indicating gradient reverse-phase ultra-performance liquid chromatographic method was developed for the simultaneous determination of ibuprofen and diphenhydramine citrate in the presence of degradation products and process related impurities in combined dosage form. The method was developed using C18 column with mobile phase containing a gradient mixture of solvent A and B. The eluted compounds were monitored at 220 nm. Ibuprofen and diphenhydramine citrate were subjected to the stress conditions of oxidative, acid, base, hydrolytic, thermal, and photolytic degradation. Major unknown impurity formed under oxidative degradation was identified using LC-MS-MS study. The developed method was validated as per ICH guidelines with respect to specificity, linearity, limit of detection, limit of quantitation, accuracy, precision and robustness. The described method was linear over the range of 0.20-6.00 μg/mL (r>0.998) for Ibuprofen and 0.084-1.14 μg/mL for diphenhydramine citrate (r>0.998). The limit of detection results were ranged from 0.200-0.320 μg/mL for ibuprofen impurities and 0.084-0.099 μg/mL for diphenhydramine citrate impurities. The limit of quantitation results were ranged from 0.440 to 0.880 μg/mL for ibuprofen impurities and 0.258 to 0.372 μg/mL for diphenhydramine citrate impurities. The recovery of ibuprofen impurities were ranged from 98.1% to 100.5% and the recovery of diphenhydramine citrate impurities were ranged from 97.5% to 102.1%. This method is also suitable for the simultaneous assay determination of ibuprofen and diphenhydramine citrate in pharmaceutical dosage forms.

  12. [Pharmaceuticals: a strategic national industry].

    PubMed

    Hollender, Louis

    2004-01-01

    Asked by Mme Nicole Fontaine, Delegate Minister of Industry, to help the government with its ongoing reflections on pharmaceutical industrial strategy, and the necessary autonomy of our country in the face of major commercial threats, a working group of the French National Academy of Medicine consulted representatives of five French and two foreign major drug companies. Their statements can be classified in four categories:--the first concerns new medications, which must be approved successively by three commissions, whose opinions are often delayed and influenced by economic considerations;--second, public and private research are both insufficient and are sometimes hindered by procedural restrictions,--third, the pharmaceutical industry is unable to deal with frequent and unforseeable political upheavals,--France does not adequately recognize the strategic importance of the pharmaceutical industry in the national economy. The Academy makes several recommendations: the French pharmaceutical industry should be considered as a national priority, the strategic importance of national pharmaceutical companies should be recognized, a multi-annual contract should be signed with manufacturers, clinical trials should be facilitated in France, relationships between the national pharmaceutical industry and public research structures should be reinforced, and an inter-ministerial Council on Pharmaceuticals should be created. This study was supplemented by a survey of veterinary medications, the results and conclusions of which are very similar to those outlined above for human medicines.

  13. Electrophobic interaction induced impurity clustering in metals

    SciTech Connect

    Zhou, Hong-Bo; Wang, Jin-Long; Jiang, W.; Lu, Guang-Hong; Aguiar, J. A.; Liu, Feng

    2016-10-01

    We introduce the concept of electrophobic interaction, analogous to hydrophobic interaction, for describing the behavior of impurity atoms in a metal, a 'solvent of electrons'. We demonstrate that there exists a form of electrophobic interaction between impurities with closed electron shell structure, which governs their dissolution behavior in a metal. Using He, Be and Ar as examples, we predict by first-principles calculations that the electrophobic interaction drives He, Be or Ar to form a close-packed cluster with a clustering energy that follows a universal power-law scaling with the number of atoms (N) dissolved in a free electron gas, as well as W or Al lattice, as Ec is proportional to (N2/3-N). This new concept unifies the explanation for a series of experimental observations of close-packed inert-gas bubble formation in metals, and significantly advances our fundamental understanding and capacity to predict the solute behavior of impurities in metals, a useful contribution to be considered in future material design of metals for nuclear, metallurgical, and energy applications.

  14. International Conference on Harmonisation; revised guidance on Q3A impurities in new drug substances; availability. Notice.

    PubMed

    2003-02-11

    The Food and Drug Administration (FDA) is announcing the availability of a revised guidance entitled "Q3A(R) Impurities in New Drug Substances." The revised guidance, which updates a guidance on the same topic published in the Federal Register of January 4, 1996 (the 1996 guidance), was prepared under the auspices of the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH). The revised guidance clarifies the 1996 guidance, adds information, and provides consistency with more recently published ICH guidances. The revised guidance is intended to provide guidance to applicants for drug marketing registration on the content and qualification of impurities in new drug substances produced by chemical syntheses and not previously registered in a country, region, or member State.

  15. [Study on genotoxicity of aldicarb and methomyl].

    PubMed

    Sun, Xiao-Yu; Jin, Yong-Tang; Wu, Bin; Wang, Wei-Qin; Pang, Xiao-Lu; Wang, Jing

    2010-12-01

    Genotoxicity of aldicarb and methomyl was explored. The aldicarb and methomyl were diluted by the deionized water respectively, and then five concentrations of aldicarb were generated as 0.002, 0.02, 0.2, 2, 20 microg/L, methomyl as 0.02, 0.2, 2, 20, 200 microg/L. The micronucleus of carp erythrocyte was counted by micronucleus test. The mutation of bacteria was assessed by Ames test. The DNA damage of human lymphocytes was tested by comet assay. The genotoxicity of aldicarb and methomyl was estimated by the three toxicology tests mentioned above. The results showed that, in the micronucleus test, both any concentration of two pesticides were not able to induce higher frequency of micronucleus in carp erythrocyte (p > 0.05). Under condition of metabolic inactivation, although the number of colony with back mutation in any concentration of two pesticides did not exceed the double number of those with spontaneous mutation, the revertants of TA97 strains in the aldicarb 2-20 microg/L and the methomyl 20-200 microg/L were (129.17 +/- 17.00), (129.50 +/- 18.28), (109.83 +/- 10.80) and (114.17 +/- 9.37) entries/plate, respectively, they were significantly greater than those in spontaneous mutation (p < 0.05, p < 0.01). In the methomyl 200 microg/L group, the revertants of TA100 and TA102 strains were (147.83 +/- 23.29) and (275.83 +/- 20.63) entries/plate, respectively, they are significantly higher than that of the control group under condition of metabolic activation (p < 0.05). In comet assay, both the high concentration groups of aldicarb and methomyl resulted in different degrees of DNA damage of human peripheral blood lymphocytes. Compared with deionized water group, all of three indexes of comet assay in the aldicarb 20 microg/L groups and the methomyl 200 microg/L groups were significantly higher (p < 0.01). Despite that both aldicarb and methomyl did not results in damaging chromosome carp erythrocyte and producing apparent mutagenicity, the effect of

  16. Synthesis of the impurities during the manufacture of bulk drug midazolam and separation of these impurities by HPLC.

    PubMed

    Sati, Bhawana; Sati, Hemlata; Saklani, Sarla; Bhatt, Prakash Chandra; Mishra, Ravinesh

    2013-09-01

    During the manufacture of bulk drug midazolam various impurities arised that can be the related products or degradation products. Structures of eight impurities that can arise during the manufacture of bulk drug midazolam were proposed. In the present work, synthesis of these impurities and their characterization by different spectroscopic techniques have been done. HPLC method was developed for the separation of impurities from the bulk drug. The developed method separates midazolam from its eight impurities/degradation products within a run time of 45 min.

  17. 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

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

    PubMed

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

    2015-07-01

    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.

  19. GMK (Progenics Pharmaceuticals).

    PubMed

    Knutson, Keith L

    2002-01-01

    Progenics Pharmaceuticals is developing GMK vaccine (a ganglioside conjugate vaccine coupled to keyhole limpet hemocyanin and formulated with the adjuvant QS-21), licensed from the Memorial Sloan-Kettering Cancer Center, for the potential treatment of melanoma and other cancers [194258], [325284]. It was previously under co-development with Bristol-Myers Squibb, but in May 2001, all rights to the GMK vaccine were returned to Progenics [409168]. It was the first of a new class of ganglioside conjugate vaccine evaluated by Progenics [194258]. GMK vaccination induces antibodies against GM2 ganglioside capable of specifically killing melanoma cells. Melanoma patients with antibodies against GM2 ganglioside have significantly improved disease-free and overall survival compared to antibody-negative subjects. The vaccine is undergoing two phase III trials, the first comparing GMK to high-dose IFNalpha in melanoma patients with more serious disease and at a high risk of relapse, and the second, in collaboration with the European Organization for Research and Treatment of Cancer, comparing GMK (14 doses of GMK over three years) to no treatment other than close monitoring of malignant melanoma patients at immediate risk of relapse [409168]. In February 1999, Lehman Brothers predicted that the vaccine had a 50% probability of reaching market, with an estimated first launch date in 2002. The analysts predicted potential peak sales in 2008 of $150 million in the US and $100 million in the rest of the world at that time [319225]. In January 2000, Lehman Brothers expected that an NDA filing would take place in 2002, with possible launch of the vaccine in 2003. In addition, Lehman Brothers estimated potential peak sales at $500 million [357788]. In August 2000, Punk, Ziegel & Company predicted that Progenics Pharmaceuticals will become sustainably profitable in 2003 following the launch of GMK and PRO-542 in 2002 [390063]. In July 2001, Ladenburg Thalmann predicted a $257 million

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

    SciTech Connect

    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, 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.

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

    DOE PAGES

    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

  2. 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.

  3. 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.

  4. Cells behaviors and genotoxicity on topological surface.

    PubMed

    Yang, N; Yang, M K; Bi, S X; Chen, L; Zhu, Z Y; Gao, Y T; Du, Z

    2013-08-01

    To investigate different cells behaviors and genotoxicity, which were driven by specific microenvironments, three patterned surfaces (pillars, wide grooves and narrow grooves) and one smooth surface were prepared by template-based technique. Vinculin is a membrane-cytoskeletal protein in focal adhesion plaques and associates with cell-cell and cell-matrix junctions, which can promote cell adhesion and spreading. The immunofluorescence staining of vinculin revealed that the narrow grooves patterned substrate was favorable for L929 cell adhesion. For cell multiplication, the narrow grooves surface was fitted for the proliferation of L929, L02 and MSC cells, the pillars surface was only in favor of L929 cells to proliferate during 7 days of cell cultivation. Cell genetic toxicity was evaluated by cellular micronuclei test (MNT). The results indicated that topological surfaces were more suitable for L929 cells to proliferate and maintain the stability of genome. On the contrary, the narrow grooves surface induced higher micronuclei ratio of L02 and MSC cells than other surfaces. With the comprehensive results of cell multiplication and MNT, it was concluded that the wide grooves surface was best fitted for L02 cells to proliferate and have less DNA damages, and the smooth surface was optimum for the research of MSC cells in vitro.

  5. DNA Dosimetry Assessment for Sunscreen Genotoxic Photoprotection

    PubMed Central

    Schuch, André Passaglia; Lago, Juliana Carvalhães; Yagura, Teiti; Menck, Carlos Frederico Martins

    2012-01-01

    Background Due to the increase of solar ultraviolet radiation (UV) incidence over the last few decades, the use of sunscreen has been widely adopted for skin protection. However, considering the high efficiency of sunlight-induced DNA lesions, it is critical to improve upon the current approaches that are used to evaluate protection factors. An alternative approach to evaluate the photoprotection provided by sunscreens against daily UV radiation-induced DNA damage is provided by the systematic use of a DNA dosimeter. Methodology/Principal Findings The Sun Protection Factor for DNA (DNA-SPF) is calculated by using specific DNA repair enzymes, and it is defined as the capacity for inhibiting the generation of cyclobutane pyrimidine dimers (CPD) and oxidised DNA bases compared with unprotected control samples. Five different commercial brands of sunscreen were initially evaluated, and further studies extended the analysis to include 17 other products representing various formulations and Sun Protection Factors (SPF). Overall, all of the commercial brands of SPF 30 sunscreens provided sufficient protection against simulated sunlight genotoxicity. In addition, this DNA biosensor was useful for rapidly screening the biological protection properties of the various sunscreen formulations. Conclusions/Significance The application of the DNA dosimeter is demonstrated as an alternative, complementary, and reliable method for the quantification of sunscreen photoprotection at the level of DNA damage. PMID:22768281

  6. 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.

  7. 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.

  8. Industry viewpoint on thresholds for genotoxic carcinogens.

    PubMed

    Morelli, M A

    2000-01-01

    Modern chemical control of pests has contributed to a dramatic improvement in public welfare since its introduction 50 years ago. Millions of lives have been saved through the control of disease vectors, and millions more have been improved by the use of chemicals to produce an inexpensive and abundant food supply. Hundreds of pesticidally active ingredients are in commercial use today, and among these are found genotoxic and nongenotoxic carcinogens. In the United States, the Environmental Protection Agency regulates carcinogens using threshold and nonthreshold approaches depending upon the outcome of a weight-of-evidence determination. More than one-half of all pesticides with some evidence of carcinogenic potential are regulated by the nonthreshold approach. The limitations on product use imposed by this approach have restricted the number of products available to growers and to the public. This restriction has had a direct impact on industry with respect to commercial success and financial returns on investment as well as an indirect impact on the industry's ability to fund the discovery and development of new compounds. This paper explores the question of how well regulation by the nonthreshold approach has achieved the goal of protecting public health, whether it does this better than the alternative use of the threshold approach, and whether the incremental protection it affords is a meaningful public benefit that justifies the aforementioned impacts on industry.

  9. Monitoring genotoxic exposure in uranium miners

    SciTech Connect

    Sram, R.J.; Binkova, B.; Dobias, L.; Roessner, P.T.; Topinka, J.; Vesela, D.; Vesely, D.; Stejskalova, J.; Bavorova, H.; Rericha, V. )

    1993-03-01

    Recent data from deep uranium mines in Czechoslovakia indicated that in addition to radon daughter products, miners are also exposed to chemical mutagens. Mycotoxins were identified as a possible source of mutagenicity present in the mines. Various methods of biomonitoring were used to examine three groups of miners from different uranium mines. Cytogenetic analysis of peripheral lymphocytes, unscheduled DNA synthesis (UDS) in lymphocytes, and lipid peroxidation (LPO) in both plasma and lymphocytes were studied on 66 exposed miners and 56 controls. Throat swabs were taken from 116 miners and 78 controls. Significantly increased numbers of aberrant cells were found in all groups of miners, as well as decreased UDS values in lymphocytes and increased LPO plasma levels in comparison to controls. Molds were detected in throat swabs from 27% of miners, and 58% of these molds were embryotoxic. Only 5% of the control samples contained molds and none of them was embryotoxic. The following mycotoxins were isolated from miners' throat swab samples: rugulosin, sterigmatocystin, mycophenolic acid, brevianamid A, citreoviridin, citrinin, penicilic acid, and secalonic acid. These data suggest that mycotoxins are a genotoxic factor affecting uranium miners.

  10. 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

  11. 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.

  12. 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...

  13. 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...

  14. ENVIRONMENTAL STEWARDSHIP OF PHARMACEUTICALS ...

    EPA Pesticide Factsheets

    There is no abstract available for this product. If further information is requested, please refer to the bibliographic citation and contact the person listed under Contact field. The research focused on in the subtasks is the development and application of state-of the-art technologies to meet the needs of the public, Office of Water, and ORD in the area of Water Quality. Located In the subtasks are the various research projects being performed in support of this Task and more in-depth coverage of each project. Briefly, each project's objective is stated below.Subtask 1: To integrate state-of-the-art technologies (polar organic chemical integrative samplers, advanced solid-phase extraction methodologies with liquid chromatography/electrospray/mass spectrometry) and apply them to studying the sources and fate of a select list of PPCPs. Application and improvement of analytical methodologies that can detect non-volatile, polar, water-soluble pharmaceuticals in source waters at levels that could be environmentally significant (at concentrations less than parts per billion, ppb). IAG with USGS ends in FY05. APM 20 due in FY05.Subtask 2: Coordination of interagency research and public outreach activities for PPCPs. Participate on NSTC Health and Environment subcommittee working group on PPCPs. Web site maintenance and expansion, invited technical presentations, invited articles for peer-reviewed journals, interviews for media, responding to public inquiries. S

  15. ENVIRONMENTAL STEWARDSHIP OF PHARMACEUTICALS ...

    EPA Pesticide Factsheets

    The occurrence of pharmaceuticals and personal care products (PPCPS) as environmental pollutants is a multifaceted issue whose scope continues to become better delineated since the escalation of conceited attention beginning in the 1980s. PPCPs typically occur as trace environmental pollutants (primarily in surface but also in ground waters) as a result of their widespread, continuous, combined usage in a broad range of human and veterinary therapeutic activities and practices. With respect to the risk-assessment paradigm the growing body of published work has focused primarily on the origin and occurrence of these substances. Comparatively less is known about human and ecological exposure, and even less about the documented or potential hazards associated with trace exposure to these anthropogenic substances, many of which are highly bioactive and perpetually present in many aquatic locales. The research focused on in the subtasks is the development and application of state-of the-art technologies to meet the needs of the public, Office of Water, and ORD in the area of Water Quality. Located In the subtasks are the various research projects being performed in support of this Task and more in-depth coverage of each project. Briefly, each project's objective is stated below.Subtask 1: To integrate state-of-the-art technologies (polar organic chemical integrative samplers, advanced solid-phase extraction methodologies with liquid chromatography/electrospray/m

  16. Biricodar. Vertex Pharmaceuticals.

    PubMed

    Dey, Saibal

    2002-05-01

    Vertex is developing biricodar as a chemosensitizing agent designed to restore the effectiveness of chemotherapeutic agents in tumor multidrug resistance. By November 1998, phase II trials had commenced for biricodar, in combination with chemotherapy, for five common cancer indications: breast, ovarian, soft-tissue sarcomas, small cell lung cancer and prostate cancer. Phase II trials were ongoing in January 2002. By March 2000, Vertex was the sole developer of biricodar, as an agreement made in 1996 with BioChem Pharma (now Shire Pharmaceuticals), for the development and marketing of biricodar in Canada was terminated. Biricodar is the free base compound, which also has a citrate salt analog known as VX-710-3. Vertex has published three patents, WO-09615101, WO-09636630 and WO-09736869, disclosing derivatives of biricodar that are claimed for the treatment of multidrug resistant protein and P-glycoprotein-mediated multidrug resistant tumors. In January 2002, a Banc of America analyst report forecast that biricodar had a 30% chance of reaching the market with a launch date in the second half of 2005, with peak sales estimated at $250 million.

  17. OSI-774 OSI Pharmaceuticals.

    PubMed

    Norman, P

    2001-02-01

    OSI-774 (formerly CP-358774), a quinazoline derivative, is an orally active epidermal growth factor receptor (EGFR) inhibitor which was originally under joint development by Pfizer and OSI Pharmaceuticals (formerly Oncogene Science) for the potential treatment of cancer (eg, ovarian, non-small cell lung cancer (NSCLC) and head and neck). It is being evaluated in phase II trials [304305], [372201]. On 8 January 2001, OSI announced that it had signed an agreement with Roche and Genentech for the global co-development and marketing of OSI-774. The agreement with Genentech covers the United States, that with Roche the rest of the world [395371], [395526]. In June 2000, OSI gained all development and marketing rights for OSI-774 following Pfizer's merger with Warner-Lambert [371439]. In September 2000, Pfizer transferred the IND dossierfor OSI-774 to OSI ahead of the timeline agreed in the June 2000 development and marketing rights agreement [383786]. The phase II trials will assess OSI-774 both as a single agent and in combination with existing chemotherapy regimens [347783]. Phase III trials are expected to be initiated in 2001 [347783]. In October 2000, Lehman Brothers predicted that OSI-774 would move into pivotal trials in thefirst half of 2001 and that the drug would be launched in 2003. The analysts also estimated worldwide sales of US $66 million, $285 million and $461 million in 2003, 2004 and 2005, respectively, and peak sales in excess of US $500 million [395189].

  18. PHARMACEUTICALS AS ENVIRONMENTAL ...

    EPA Pesticide Factsheets

    There is no abstract available for this product. If further information is requested, please refer to the bibliographic citation and contact the person listed under Contact field. The research focused on in the subtasks is the development and application of state-of the-art technologies to meet the needs of the public, Office of Water, and ORD in the area of Water Quality. Located In the subtasks are the various research projects being performed in support of this Task and more in-depth coverage of each project. Briefly, each project's objective is stated below.Subtask 1: To integrate state-of-the-art technologies (polar organic chemical integrative samplers, advanced solid-phase extraction methodologies with liquid chromatography/electrospray/mass spectrometry) and apply them to studying the sources and fate of a select list of PPCPs. Application and improvement of analytical methodologies that can detect non-volatile, polar, water-soluble pharmaceuticals in source waters at levels that could be environmentally significant (at concentrations less than parts per billion, ppb). IAG with USGS ends in FY05. APM 20 due in FY05.Subtask 2: Coordination of interagency research and public outreach activities for PPCPs. Participate on NSTC Health and Environment subcommittee working group on PPCPs. Web site maintenance and expansion, invited technical presentations, invited articles for peer-reviewed journals, interviews for media, responding to public inquiries. S

  19. PHARMACEUTICALS AS UBIQUITOUS POLLUTANTS ...

    EPA Pesticide Factsheets

    Those chemical pollutants that are regulated under various international, federal, and state programs represent but a small fraction of the universe of chemicals that occur in the environment as a result of both natural processes and human influence. Although this galaxy of targeted chemicals might be minuscule compared with the universe of both known and yet-to-be identified chemicals, an implicit assumption is that these selective lists of chemicals are responsible for the most significant share of risk with respect to environmental or economic impairment or to human health. Pharmaceuticals and personal care products (PPCPs) comprise a particularly large and diverse array of unregulated pollutants that occur in the environment from the combined activities and actions of multitudes of individuals as well as from veterinary and agricultural use. Although the concentration of any individual PPCP rarely ever exceeds the sub-ppm level (if present in drinking water, concentrations of individual PPCPs are generally less than the ppt-ppb level), evidence is accumulating that these trace-Ievel pollutants are ubiquitous, they can have a continuous presence regardless of environmental half-lives ( e.g., where sanitary wastewaters enter the environment), and the numbers of distinct and varied chemical entities could be extremely large (given that thousands are in commercial use). The research focused on in the subtasks is the development and application of state-of the-ar

  20. 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...

  1. 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.

  2. [PICS: pharmaceutical inspection cooperation scheme].

    PubMed

    Morénas, J

    2009-01-01

    The pharmaceutical inspection cooperation scheme (PICS) is a structure containing 34 participating authorities located worldwide (October 2008). It has been created in 1995 on the basis of the pharmaceutical inspection convention (PIC) settled by the European free trade association (EFTA) in1970. This scheme has different goals as to be an international recognised body in the field of good manufacturing practices (GMP), for training inspectors (by the way of an annual seminar and experts circles related notably to active pharmaceutical ingredients [API], quality risk management, computerized systems, useful for the writing of inspection's aide-memoires). PICS is also leading to high standards for GMP inspectorates (through regular crossed audits) and being a room for exchanges on technical matters between inspectors but also between inspectors and pharmaceutical industry.

  3. Spectrofluorimetric determination of 2-aminopyridine as a potential impurity in piroxicam and tenoxicam within the pharmacopoeial limit.

    PubMed

    Barary, Magda H; Abdel-Hay, Mohamed H; Sabry, Suzy M; Belal, Tarek S

    2004-01-27

    The British Pharmacopoeia defines 2-aminopyridine (2-AP) as a potential impurity in piroxicam (PX) and tenoxicam (TX). Selective spectrofluorimetric determination of 2-AP in PX and TX, within or near the pharmacopoeial level, 0.2%, was developed, based on the measurement of the native fluorescence either in aqueous 0.1N sulfuric acid or in dioxane. Accordingly, this approach was followed for confirming purity of PX and TX in bulk and pharmaceutical preparations. The study was also extended to include simultaneous determinations of PX/2-AP and TX/2-AP systems based on selective fluorescence measurements in the cited solvents.

  4. Theoretical explanation for strong poloidal impurity asymmetry in tokamak pedestals

    NASA Astrophysics Data System (ADS)

    Espinosa, Silvia

    2016-10-01

    Stronger impurity density in-out poloidal asymmetries than predicted by the most comprehensive neoclassical models have been measured in H-mode tokamak pedestals during the last decade. However, these pioneering theories neglect the impurity diamagnetic drift, while recent measurements indicate that it can be of the same order as the ExB drift that is retained. In order to keep both drifts self-consistently, stronger radial gradients of the impurity density must be allowed. As a result, radial impurity flow effects need to be included for the first time. These effects substantially alter the parallel impurity flow. The resulting modification in the impurity friction with the banana regime background ions then allows stronger poloidal variation of the impurity density, temperature and potential. Even the six-fold high field side accumulation of boron density measured on Alcator C-Mod can be explained without invoking anomalous transport. Moreover, the potential can no longer be assumed to be a flux function since the impurity density variation gives a poloidally varying potential that results in strong poloidal variation of the radial electric field. The fact that the magnitude of the negative radial electric field and the impurity temperature are both larger on the low field side is also correctly predicted. Finally, this pedestal neoclassical model with radial flows may provide insight on how to control impurity accumulation in JET. Supported by DOE Grant DE-FG0291ER54109 and La Caixa Fellowship.

  5. 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.

  6. The influence of thermal desorption on genotoxicity of multipolluted soil.

    PubMed

    Bonnard, M; Devin, S; Leyval, C; Morel, J-L; Vasseur, P

    2010-07-01

    A multipolluted soil sampled from a former coking plant in Lorraine (France) was evaluated for its genotoxic effects on coelomocytes of the Eisenia fetida earthworm using the comet assay. The biological efficiency of thermal desorption of the contaminated soil was also investigated. The untreated polluted soil was shown to be genotoxic to earthworms. Although thermal desorption reduced the concentration of PAHs by 94% (Sigma(16 PAHs)=1846 and 101 mg/kg before and after thermal desorption, respectively), the treatment did not eliminate the genotoxicity of soil pollutants to earthworms but increased it. The concentration of non-volatile metals did not change after thermal desorption. Among metals found in the treated soil, cadmium, chromium and nickel could explain the genotoxicity of the contaminated soil after thermal desorption. The treatment could increase the bioavailability and genotoxicity of heavy metals, through a modification of the soil's organic matter, the speciation of heavy metals and their binding to organic matter. This study underlines the importance of measuring biological effects, in order to evaluate the risk associated with formerly contaminated soils and the efficiency of remediation.

  7. 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.

  8. Combined genotoxicity of chlorinated products from tyrosine and benzophenone-4.

    PubMed

    Chang, Yangyang; Bai, Yaohui; Ji, Qinghua; Huo, Yang; Liu, Huijuan; Crittenden, John C; Qu, Jiuhui

    2017-01-15

    The toxicity of disinfection by-products (DBPs) from a single precursor was studied intensively. Here we examined the genotoxicity when two precursors (tyrosine (Tyr) and benzophenone-4 (BP-4)) were chlorinated together and separately. We sought to examine whether the genotoxicity of the mixture (GCM) could be estimated from the sum of the genotoxicities of the individual precursors (GCI), which were chlorinated separately. We determined the genotoxicity using the SOS/umu test. The results revealed that GCM was not identical to GCI. The difference in genotoxicity between GCM and GCI (GΔ) was observed to decrease with increasing pH. GCM was higher than GCI (GΔ>0) at pH 5.0-6.1, and lower than GCI (GΔ<0) at pH 6.3-8.0. We found that nitrogen-containing DBPs played a dominant role in determining GCM and GCI. We propose that the total organic nitrogen (TON) ratio, TON(chlorinatedmixture)/TON(thesumofchlorinatedindividuals), is useful to estimate GΔ.

  9. 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

  10. Assessment of cytotoxic and genotoxic activity of alcohol extract of Polyscias filicifolia shoot, leaf, cell biomass of suspension culture and saponin fraction.

    PubMed

    Marczewska, Jadwiga; Karwicka, Ewa; Drozd, Janina; Anuszewskal, Elzbieta; Sliwińska, Anita; Nosov, Aleksander; Olszowska, Olga

    2011-01-01

    Some medicinal plants are the object of biotechnologists' special interest owing to their content of secondary metabolites, which have a strong pharmacological effect. Polyscias filicifolia is a plant known for long in traditional medicine of the Southeast Asia. Literature data suggest that it acts on the endocrine system, has adaptogenic and antiulcerative activity, shows bactericidal and insecticidal properties, restores the activity of the protein synthesis system in the conditions of long- and short-term anoxia, as well as reduces the effect of many mutagens in vitro. The purpose of the studies was to assess the cytotoxic and genotoxic effect of ethanol extracts from Polyscias filicifolia dry shoots and leaves obtained in vitro, as well as cell biomass from suspension culture. Saponin fraction from dried shoots was also tested. Initially, the cytotoxic effect was evaluated using the murine connective tissue cell line C3H/AN - L929. The genotoxic properties of the extracts were assessed using standard screening tests: the Ames test and the micronucleus test. Based on the obtained results it can be concluded that none of the extracts increases the number of revertants, both in tests with and without metabolic activation. The lack of in vitro genotoxic and mutagenic activity of tested shoot, dried leaf, cell biomass extracts, as well as the saponin fraction from dried shoots allows us to hope that Polyscias filicifolia could be used as a possible pharmaceutical raw material showing therapeutic properties.

  11. Facilitating the use of counter-current chromatography in pharmaceutical purification through use of organic solvent nanofiltration.

    PubMed

    Rundquist, Elin; Pink, Christopher; Vilminot, Elsa; Livingston, Andrew

    2012-03-16

    This paper demonstrates a combined approach for separating an active pharmaceutical ingredient (API) from a heavily contaminated waste stream. The approach uses organic solvent nanofiltration (OSN) to improve the application of counter-current chromatography (CCC) in an industrial process. OSN provides an efficient route for exchanging solutes from the process solvent into the desired mobile phase for CCC, generating a CCC feed containing less than 0.01% (area % by GC) of the original process solvents. The high solvent burden of CCC was additionally reduced through recovery of mobile phase using OSN, with the recovered solvent containing less than 1% (area % by HPLC) impurities. The recovered solvent was then successfully recycled into a subsequent CCC run with no indication of impurity build-up. Coupling OSN with CCC improved the mass-intensity of the CCC process, reducing the solvent use by 56%. OSN can be a useful tool in facilitating the application of CCC to pharmaceutical process streams.

  12. 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.

  13. 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

  14. DNA damage as an indicator of pollutant-induced genotoxicity

    SciTech Connect

    Shugart, L.R.

    1989-01-01

    Biological monitoring is an approach of considerable interest to scientists in the field of environmental genotoxicity who are investigating the effects of hazardous substances on the biota. In essence the technique involves an evaluation of various types of responses in living organisms for their potential to identify exposure to dangerous substances and to define or to predict subsequent deleterious effects. The rationale for the selection of DNA damage as an indicator of exposure to genotoxic agents is based mainly on the mechanisms of action of chemicals that are known mutagens and carcinogens. An alkaline unwinding assay that detects excess strand breakage within the DNA polymer was applied to sunfish in a local stream as a biological monitor for environmental genotoxicity due to industrial pollution. The study was conducted over a period of 15 months and the temporal and spatial aspects of the data were evaluated for the effect of remedial action. 16 refs., 4 figs., 4 tabs.

  15. Genotoxic potential of glyphosate formulations: mode-of-action investigations.

    PubMed

    Heydens, William F; Healy, Charles E; Hotz, Kathy J; Kier, Larry D; Martens, Mark A; Wilson, Alan G E; Farmer, Donna R

    2008-02-27

    A broad array of in vitro and in vivo assays has consistently demonstrated that glyphosate and glyphosate-containing herbicide formulations (GCHF) are not genotoxic. Occasionally, however, related and contradictory data are reported, including findings of mouse liver and kidney DNA adducts and damage following intraperitoneal (ip) injection. Mode-of-action investigations were therefore undertaken to determine the significance of these contradictory data while concurrently comparing results from ip and oral exposures. Exposure by ip injection indeed produced marked hepatic and renal toxicity, but oral administration did not. The results suggest that ip injection of GCHF may induce secondary effects mediated by local toxicity rather than genotoxicity. Furthermore, these results continue to support the conclusion that glyphosate and GCHF are not genotoxic under exposure conditions that are relevant to animals and humans.

  16. In vivo genotoxic interactions among three phenolic benzene metabolites.

    PubMed

    Marrazzini, A; Chelotti, L; Barrai, I; Loprieno, N; Barale, R

    1994-11-01

    Three benzene metabolites, hydroquinone (HQ), cathecol (CAT) and phenol (PHE) were studied to define their possible interaction in inducing micronuclei (Mn) in mouse bone marrow polychromatic erythrocytes (PCEs). HQ and CAT, administered separately, induced Mn while PHE showed no genotoxic effects. Binary and ternary mixtures of two or three metabolites gave different results, causing considerable increase or decrease in Mn induction. HQ and PHE, in binary mixtures, as well as PHE and CAT, increased Mn synergistically, while HQ and CAT interacted negatively. The genotoxicity of ternary mixtures was mainly the consequence of two metabolites: HQ and CAT. The maximal effect obtained is far below the induction of Mn consequent to benzene treatment. These data suggest that toxic and genotoxic effects of benzene alone could be the result of more complex interactions among these and other metabolites.

  17. Identification, isolation and characterization of process related impurities in ezetimibe.

    PubMed

    Guntupalli, Srikanth; Ray, Uttam Kumar; Murali, N; Gupta, P Badrinadh; Kumar, Vundavilli Jagadeesh; Satheesh, D; Islam, Aminul

    2014-01-01

    During the synthesis of ezetimibe, two process related impurities were detected were HPLC analysis at levels ranging from 0.05 to 0.8%. These two impurities were isolated by column chromatography and co-injected with ezetimibe sample to confirm the retention times in HPLC. These two impurities were characterized as 2-(4-hydroxybenzyl)-N,5-bis(4-fluorophenyl) pentanamide (impurity-I) and 1-(4-fluorophenyl)-3(3-(4-fluorophenyl)propyl)-4-(4-hydroxyphenyl)azetidin-2-one (impurity-II). Isolation, structural elucidation of these impurities by spectral data ((1)H NMR, (13)C NMR, MS and IR) and probable mechanism of their formation have been discussed.

  18. Investigation of reduction process and related impurities in ezetimibe.

    PubMed

    Zhang, Dengfeng; Su, Jiangtao

    2015-03-25

    During the synthesis of ezetimibe bulk drug, research for the impurities which especially come from the last two steps of synthetic route is of great significance for the quality by design (QbD) concept. The design spaces of last two steps of reduction reaction were established. The critical parameters were discussed under the QbD concept, which have noticeable impact on the impurity profile such as the new process related impurities mentioned in this paper. Three novel reduction process related impurities were prepared by designed synthetic route and co-injected with ezetimibe sample for identification. These novel process related impurities were also detected in different laboratory batches of ezetimibe bulk drug and characterized using MS, (1)H, (13)C, 2D NMR and IR techniques. The synthesis, isolation, identification, structural elucidation and formation of impurities were also discussed in detail.

  19. 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.

  20. 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)].

  1. 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

  2. Genotoxicity of diuron and glyphosate in oyster spermatozoa and embryos.

    PubMed

    Akcha, F; Spagnol, C; Rouxel, J

    2012-01-15

    We investigated the effects of genotoxicant exposure in gametes and embryos to find a possible link between genotoxicity and reproduction/developmental impairment, and explore the impact of chemical genotoxicity on population dynamics. Our study focused on the genotoxic effects of two herbicides on oyster gametes and embryos: glyphosate (both as an active substance and in the Roundup formulation) and diuron. France is Europe's leading consumer of agrochemical substances and as such, contamination of France's coastal waters by pesticides is a major concern. Glyphosate and diuron are among the most frequently detected herbicides in oyster production areas; as oyster is a specie with external reproduction, its gametes and embryos are in direct contact with the surrounding waters and are hence particularly exposed to these potentially dangerous substances. In the course of this study, differences in genotoxic and embryotoxic responses were observed in the various experiments, possibly due to differences in pollutant sensitivity between the tested genitor lots. Glyphosate and Roundup had no effect on oyster development at the concentrations tested, whereas diuron significantly affected embryo-larval development from the lowest tested concentration of 0.05 μg L⁻¹, i.e. an environmentally realistic concentration. Diuron may therefore have a significant impact on oyster recruitment rates in the natural environment. Our spermiotoxicity study revealed none of the tested herbicides to be cytotoxic for oyster spermatozoa. However, the alkaline comet assay showed diuron to have a significant genotoxic effect on oyster spermatozoa at concentrations of 0.05 μg L⁻¹ upwards. Conversely, no effects due to diuron exposure were observed on sperm mitochondrial function or acrosomal membrane integrity. Although our initial results showed no negative effect on sperm function, the possible impact on fertilization rate and the consequences of the transmission of damaged DNA for

  3. Genotoxicity and cytotoxicity of 2-hydroxyethyl methacrylate.

    PubMed

    Pawlowska, Elzbieta; Poplawski, Tomasz; Ksiazek, Dominika; Szczepanska, Joanna; Blasiak, Janusz

    2010-02-01

    Resin-based methacrylate materials are widely used in restorative dentistry. They are viscous substances that are converted into solid material via polymerization. This process, however, may be incomplete, leading to the release of monomers into the oral cavity and the pulp, which can be reached through the dentin micro-channels. This opens the opportunity for the monomers to reach the bloodstream. Monomers can reach concentrations in the millimolar range, high enough to cause cellular damage, so it is justified to study their potential toxic effects. In the present work we investigated the cytotoxicity and genotoxicity of 2-hydroxyethyl methacrylate (HEMA) in human peripheral blood lymphocytes and A549 lung-tumour cells. HEMA at concentrations up to 10mM neither affected the viability of the cells nor interacted with isolated plasmid DNA during a 1h exposure. However, HEMA induced concentration-dependent DNA damage in lymphocytes, as assessed by alkaline and pH 12.1 versions of the comet assay. HEMA did not cause double-strand breaks, as assessed by the neutral version of the comet assay and pulsed-field gel electrophoresis. The use of DNA repair enzymes, spin traps and vitamin C produced results suggesting that HEMA induced oxidative modifications to DNA bases. DNA damage caused by HEMA at 10mM was removed within 120min. HEMA induced apoptosis in a concentration-dependent manner and caused cell-cycle delay at the G0/G1-checkpoint. Methylglycol chitosan displayed a protective effect against the DNA-damaging action of HEMA. The results obtained in this study suggest that HEMA induces adverse biological effects, mainly via reactive oxygen species, which can lead to DNA damage, apoptosis and cell-cycle delay. Chitosan and its derivatives can be considered as additional components of dental restoration to decrease the harmful potency of HEMA.

  4. 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).

  5. Impurity Correction Techniques Applied to Existing Doping Measurements of Impurities in Zinc

    NASA Astrophysics Data System (ADS)

    Pearce, J. V.; Sun, J. P.; Zhang, J. T.; Deng, X. L.

    2017-01-01

    Impurities represent the most significant source of uncertainty in most metal fixed points used for the realization of the International Temperature Scale of 1990 (ITS-90). There are a number of different methods for quantifying the effect of impurities on the freezing temperature of ITS-90 fixed points, many of which rely on an accurate knowledge of the liquidus slope in the limit of low concentration. A key method of determining the liquidus slope is to measure the freezing temperature of a fixed-point material as it is progressively doped with a known amount of impurity. Recently, a series of measurements of the freezing and melting temperature of `slim' Zn fixed-point cells doped with Ag, Fe, Ni, and Pb were presented. Here, additional measurements of the Zn-X system are presented using Ga as a dopant, and the data (Zn-Ag, Zn-Fe, Zn-Ni, Zn-Pb, and Zn-Ga) have been re-analyzed to demonstrate the use of a fitting method based on Scheil solidification which is applied to both melting and freezing curves. In addition, the utility of the Sum of Individual Estimates method is explored with these systems in the context of a recently enhanced database of liquidus slopes of impurities in Zn in the limit of low concentration.

  6. Current Studies into the Genotoxic Effects of Nanomaterials

    PubMed Central

    Ng, Cheng-Teng; Li, Jasmine J.; Bay, Boon-Huat; Yung, Lin-Yue Lanry

    2010-01-01

    Nanotechnology has created opportunities for engineers to manufacture superior and more efficient devices and products. Nanomaterials (NMs) are now widely used in consumer products as well as for research applications. However, while the lists of known toxic effects of nanomaterials and nanoparticles (NPs) continue to grow, there is still a vast gap in our knowledge about the genotoxicity of NMs. In this paper, we highlight some NMs of interest and discuss the current in vivo and in vitro studies into genotoxic effects of NMs. PMID:20936181

  7. Genotoxicity of ibuprofen in mouse bone marrow cells in vivo.

    PubMed

    Tripathi, Rina; Pancholi, Shyam S; Tripathi, Pankaj

    2012-10-01

    Genotoxicity of ibuprofen was evaluated by employing the mouse in vivo chromosomal aberration (CA) test. Ibuprofen administered orally at doses of 10, 20, 40, and 60 mg/kg body weight to mice resulted in mitotic depression and induction of CAs. A dose-related decrease in mitotic index (MI) and an increase in the frequencies of chromosomal aberrations per cell (CAs/cell) were recorded in bone marrow cells. However, a statistically significant reduction in MI and an increase in CAs/cell were found for both the higher doses. The results obtained indicate that ibuprofen is capable of inducing dose-dependent genotoxicity in bone marrow cells of mice.

  8. An evaluation of the genotoxic potential of glyphosate.

    PubMed

    Li, A P; Long, T J

    1988-04-01

    The potential genotoxicity of glyphosate, the active ingredient in Roundup herbicide, was tested in a variety of well-established in vitro and in vivo assays including the Salmonella typhimurium and Escherichia coli WP-2 reversion assays, recombination (rec-assay) with Bacillus subtilis. Chinese hamster ovary cell gene mutation assay at the hypoxanthine/guanine phosphoribosyl transferase gene locus, hepatocyte primary culture/DNA repair assay, and in vivo cytogenetics assay in rat bone marrow. No genotoxic activity was observed in the assays performed. The data suggest that glyphosate should not pose a genetic risk to man.

  9. Separation and analysis of trace degradants in a pharmaceutical formulation using on-line capillary isotachophoresis-NMR.

    PubMed

    Eldridge, Stacie L; Almeida, Valentino K; Korir, Albert K; Larive, Cynthia K

    2007-11-15

    NMR spectroscopy is widely used in the pharmaceutical industry for the structure elucidation of pharmaceutical impurities, especially when coupled to a separation method, such as HPLC. However, NMR has relatively poor sensitivity compared with other techniques such as mass spectrometry, limiting its applicability in impurity analyses. This limitation is addressed here through the on-line coupling of microcoil NMR with capillary isotachophoresis (cITP), a separation method that can concentrate dilute components by 2-3 orders of magnitude. With this approach, 1H NMR spectra can be acquired for microgram (nanomole) quantities of trace impurities in a complex sample matrix. cITP-NMR was used in this work to isolate and detect 4-aminophenol (PAP) in an acetaminophen sample spiked at the 0.1% level, with no interference from the parent compound. Analysis of an acetaminophen thermal degradation sample revealed resonances of several degradation products in addition to PAP, confirming the effectiveness of on-line cITP-NMR for trace analyses of pharmaceutical formulations. Subsequent LC-MS/MS analysis provided complementary information for the structure elucidation of the unknown degradation products, which were dimers formed during the degradation process.

  10. Gas chromatographic analysis of trace gas impurities in tungsten hexafluoride.

    PubMed

    Laurens, J B; de Coning, J P; Swinley, J M

    2001-03-09

    Highly reactive fluorinated gaseous matrices require special equipment and techniques for the gas chromatographic analysis of trace impurities in these gases. The impurities that were analysed at the low-microg/l levels included oxygen, nitrogen, carbon dioxide, carbon monoxide, sulfur hexafluoride and hydrogen. This paper describes the use of a system utilising backflush column switching to protect the columns and detectors in the analysis of trace gas impurities in tungsten hexafluoride. Two separate channels were used for the analysis of H2, O2, N2, CO, CO2 and SF6 impurities with pulsed discharge helium ionisation detection.

  11. HPLC-MS Examination of Impurities in Pentaerythritol Tetranitrate

    NASA Astrophysics Data System (ADS)

    Brown, Geoffrey W.; Giambra, Anna M.

    2014-04-01

    Pentaerythritol tetranitrate (PETN) has trace homolog impurities that can be detected by high-performance liquid chromatography-mass spectrometry. Consideration of observed impurity masses and candidate structures based on known pentaerythritol impurities allows identification of 22 compounds in the data. These are all consistent with either fully nitrated homologs or derivatives substituted with methyl, methoxy, or hydroxyl groups in place of a nitric ester. Examining relative impurity concentrations in three starting batches of PETN and six subsequently processed batches shows that it is possible to use relative concentration profiles as a fingerprint to differentiate batches and follow them through recrystallization steps.

  12. On impurity handling in high performance stellarator/heliotron plasmas

    NASA Astrophysics Data System (ADS)

    Burhenn, R.; Feng, Y.; Ida, K.; Maassberg, H.; McCarthy, K. J.; Kalinina, D.; Kobayashi, M.; Morita, S.; Nakamura, Y.; Nozato, H.; Okamura, S.; Sudo, S.; Suzuki, C.; Tamura, N.; Weller, A.; Yoshinuma, M.; Zurro, B.

    2009-06-01

    The Large Helical Device (LHD) and Wendelstein 7-X (W7-X, under construction) are experiments specially designed to demonstrate long-pulse (quasi steady state) operation, which is an intrinsic property of stellarators and heliotrons. Significant progress has been made in establishing high performance plasmas. A crucial point is the increasing impurity confinement at high density observed at several machines (TJ-II, W7-AS, LHD) which can lead to impurity accumulation and early pulse termination by radiation collapse. In addition, theoretical predictions for non-axisymmetric configurations predict the absence of impurity screening by ion temperature gradients in standard ion-root plasmas. Nevertheless, scenarios were found where impurity accumulation was successfully avoided in LHD and W7-AS due to the onset of friction forces in the (high density and low temperature) scrape-off-layer (SOL), the generation of magnetic islands at the plasma boundary and to a certain degree also by edge localized modes, flushing out impurities and reducing the net impurity influx into the core. In both the W7-AS high density H-mode regime and in the case of application of sufficient electron cyclotron radiation heating power a reduction in impurity core confinement was observed. The exploration of such purification mechanisms is a demanding task for successful steady-state operation. Impurity transport at the plasma edge/SOL was identified to play a major role for the global impurity behaviour in addition to the core confinement.

  13. Oxygen impurity radiation from Tokamak-like plasmas

    NASA Technical Reports Server (NTRS)

    Rogerson, J. E.; Davis, J.; Jacobs, V. L.

    1977-01-01

    We have constructed a nonhydrodynamic coronal model for calculating radiation from impurity atoms in a heated plasma. Some recent developments in the calculation of dielectronic recombination rate coefficients and collisional excitation rate coefficients are included. The model is applied to oxygen impurity radiation during the first few milliseconds of a TFR Tokamak plasma discharge, and good agreement with experimental results is obtained. Estimates of total line and continuum radiation from the oxygen impurity are given. It is shown that impurity radiation represents a considerable energy loss.

  14. Impurity Role In Mechanically Induced Defects

    SciTech Connect

    Howell, R.H.; Asoka-Kumar, P.; Hartley, J.; Sterne, P.

    2000-02-25

    An improved understanding of dislocation dynamics and interactions is an outstanding problem in the multi scale modeling of materials properties, and is the current focus of major theoretical efforts world wide. We have developed experimental and theoretical tools that will enable us to measure and calculate quantities defined by the defect structure. Unique to the measurements is a new spectroscopy that determines the detailed elemental composition at the defect site. The measurements are based on positron annihilation spectroscopy performed with a 3 MeV positron beam [1]. Positron annihilation spectroscopy is highly sensitive to dislocations and associated defects and can provide unique elements of the defect size and structure. Performing this spectroscopy with a highly penetrating positron beam enables flexibility in sample handling. Experiments on fatigued and stressed samples have been done and in situ measurement capabilities have been developed. We have recently performed significant upgrades to the accelerator operation and novel new experiments have been performed [2-4] To relate the spectrographic results and the detailed structure of a defect requires detailed calculations. Measurements are coupled with calculated results based on a description of positions of atoms at the defect. This gives an atomistic view of dislocations and associated defects including impurity interactions. Our ability to probe impurity interactions is a unique contribution to defect understanding not easily addressed by other atomistic spectroscopies.

  15. Impurity pellet injection experiments at TFTR

    SciTech Connect

    Marmar, E.S.

    1992-01-01

    Impurity (Li and C) pellet injection experiments on TFTR have produced a number of new and significant results. (1) We observe reproducible improvements of TFTR supershots after wall-conditioning by Li pellet injection ( lithiumization'). (2) We have made accurate measurements of the pitch angle profiles of the internal magnetic field using two novel techniques. The first measures the internal field pitch from the polarization angles of Li[sup +] line emission from the pellet ablation cloud, while the second measures the pitch angle profiles by observing the tilt of the cigar-shaped Li[sup +] emission region of the ablation cloud. (3) Extensive measurements of impurity pellet penetration into plasmas with central temperatures ranging from [approximately]0.3 to [approximately]7 keV have been made and compared with available theoretical models. Other aspects of pellet cloud physics have been investigated. (4) Using pellets as a well defined perturbation has allowed study of transport phenomena. In the case of small pellet perturbations, the characteristics of the background plasmas are probed, while with large pellets, pellet induced effects are clearly observed. These main results are discussed in more detail in this paper.

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

    PubMed

    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.

  17. Exposure to siRNA-GalNAc Conjugates in Systems of the Standard Test Battery for Genotoxicity.

    PubMed

    Janas, Maja M; Jiang, Yongfeng; Duncan, Richard G; Hayes, Antoinette N; Liu, Ju; Kasperkovitz, Pia V; Placke, Michael E; Barros, Scott A

    2016-12-01

    Registration of pharmaceuticals requires an assessment of their genotoxic potential using in vitro and in vivo tests outlined in the International Conference on Harmonisation (ICH) guidance S2(R1). We have evaluated numerous siRNA-N-acetylgalactosamine (GalNAc) conjugates containing phosphorothioate linkages and various combinations of 2'-fluoro and 2'-O-methyl ribose modifications of multiple nucleotides in the ICH battery of assays, all of which have uniformly yielded negative results. To verify these negative genotoxicity results, in this study we confirm test article exposure using toolkit small interfering RNAs (siRNAs) representative of those in the clinic. In the Ames test, the highest uptake of the siRNA-GalNAc conjugates occurred at 1 h postdose in all bacterial strains independent of siRNA sequence or chemistry (up to ∼14,000 siRNA molecules per cell), followed by metabolic degradation of the parent siRNA at 6, 24, and 48 h postdose. siRNA-GalNAc conjugates were internalized by bacteria as assessed by protection from the addition of nucleases to the culture media following uptake and by the requirement of cell lysis for detection of the siRNA. In the in vitro chromosome aberration assay, uptake was observed in Chinese hamster ovary cells (up to ∼5,500 siRNA molecules per cell at 21 h postdose) and in CD3(+) human peripheral blood lymphocytes (up to ∼500 siRNA molecules per cell at 21 h postdose). In the in vivo micronucleus assay in rat bone marrow, exposure to parent siRNA was 100-350 μg of antisense strand per gram of protein at 24 and 48 h postlimit dose of 2 g/kg. Loss of terminal nucleotides was detected in bone marrow by mass spectrometry, indicating exposure to monomer metabolites as well. Negative genotoxicity results were also confirmed in an in vitro double-strand DNA break assay in HeLa and HepG2 cells where exposure was maximized using transfection reagents. Thus negative genotoxicity assay results for si

  18. Effects of electron-impurity scattering on density of states in silicene: Impurity bands and band-gap narrowing

    NASA Astrophysics Data System (ADS)

    Liu, S. Y.; Zeng, Y. C.; Lei, X. L.

    2016-12-01

    Considering the interband correlation, we present a generalized multiple-scattering approach of Green's function to investigate the effects of electron-impurity scattering on the density of states in silicene at zero temperature. The reduction of energy gaps in the case of relatively high chemical potential and the transformation of split-off impurity bands into band tails for low chemical potential are found. The dependency of optical conductivity on the impurity concentration is also discussed for frequency within the terahertz regime.

  19. [Bioequivalence studies of pharmaceutical preparations].

    PubMed

    Vetchý, D; Frýbortová, K; Rabisková, M; Danecková, H

    2007-01-01

    Bioequivalence studies are very important for the development of a pharmaceutical preparation in the pharmaceutical industry. Their rationale is the monitoring of pharmacokinetic and pharmacodynamic parameters after the administration of tested drugs. The target of such study is to evaluate the therapeutic compatibility of tested drugs (pharmaceutical equivalents or pharmaceutical alternatives). The importance of bioequivalence studies is increasing also due to the large growth of the production and consumption of generic products. Generic products represent approximately 50 % of the whole consumption in many European countries and USA. The search output of bioequivalence study is together with the pharmaceutical quality data of medical product one of the main part of the registration file submitted to a national regulatory authorities. The registration of generic products does not demand complicated and expensive clinical study contrary to original product. The comparison of the original and the generic product via bioequivalence study is suggested as sufficient. The aim of this article is to provide to a medical public a summary about the types of bioequivalence studies, their range, rules of their practise and let them gain their own attitude to this question.

  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. Cyto/Genotoxicity study of polyoxyethylene (20) sorbitan monolaurate (tween 20).

    PubMed

    Eskandani, Morteza; Hamishehkar, Hamed; Ezzati Nazhad Dolatabadi, Jafar

    2013-09-01

    Polyoxyethylene (20) sorbitan monolaurate (tween 20) is a non-ionic surfactant that is widely used as an emulsifier and stabilizer in pharmaceutical formulations, food and cosmetic industries. Although a number of studies have showed its non-toxic impacts on target cells, still, it is essential to investigate its effect on target cells. Therefore, in the present study, the anti-cell proliferation and cyto/genotoxicity effects of tween 20 are reported to address the possible mechanism for induction of apoptosis. At 40%-50% confluency, A549 cells and human umbilical vein endothelial cells were exposed to tween 20 at a recommended concentration for 24 h. After 24 h, to detect apoptosis and DNA damage, the treated cells were subjected to 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, fluorescein isothiocyanate (FITC)-labeled annexin V flow cytometry, DAPI staining, comet, and DNA ladder assays. Tween 20 decreased the growth of treated cells dose and time dependently, and single-strand DNA cleavage has been confirmed by comet assay. In addition, morphological alteration of DAPI-stained cells showed clear fragmentation in the chromatin and DNA rings within the nucleus of tween 20-treated cells. In addition, flow cytometry and DNA fragmentation assays confirmed DAPI staining assay results and indicated the occurrence of a programmed cell death (apoptosis) in the treated cells. These results demonstrate that, despite consideration of tween 20 as a safe non-ionic surfactant, it can induce apoptosis in target cells.

  2. Tartrazine induces structural and functional aberrations and genotoxic effects in vivo.

    PubMed

    Khayyat, Latifa; Essawy, Amina; Sorour, Jehan; Soffar, Ahmed

    2017-01-01

    Tartrazine is a synthetic organic azo dye widely used in food and pharmaceutical products. The current study aimed to evaluate the possible adverse effect of this coloring food additive on renal and hepatic structures and functions. Also, the genotoxic potential of tartrazine on white blood cells was investigated using comet assay. Twenty adult male Wistar rats were grouped into two groups of 10 each, control- and tartrazine-treated groups. The control group was administered orally with water alone. The experimental group was administered orally with tartrazine (7.5 mg/kg, b.wt.). Our results showed a marked increase in the levels of ALT, AST, ALP, urea, uric acid, creatinine, MDA and NO, and a decreased level of total antioxidants in the serum of rats dosed with tartrazine compared to controls. On the other hand, administration of tartrazine was associated with severe histopathological and cellular alterations of rat liver and kidney tissues and induced DNA damage in leucocytes as detected by comet assay. Taken together, the results showed that tartrazine intake may lead to adverse health effects.

  3. Tartrazine induces structural and functional aberrations and genotoxic effects in vivo

    PubMed Central

    Khayyat, Latifa; Sorour, Jehan; Soffar, Ahmed

    2017-01-01

    Tartrazine is a synthetic organic azo dye widely used in food and pharmaceutical products. The current study aimed to evaluate the possible adverse effect of this coloring food additive on renal and hepatic structures and functions. Also, the genotoxic potential of tartrazine on white blood cells was investigated using comet assay. Twenty adult male Wistar rats were grouped into two groups of 10 each, control- and tartrazine-treated groups. The control group was administered orally with water alone. The experimental group was administered orally with tartrazine (7.5 mg/kg, b.wt.). Our results showed a marked increase in the levels of ALT, AST, ALP, urea, uric acid, creatinine, MDA and NO, and a decreased level of total antioxidants in the serum of rats dosed with tartrazine compared to controls. On the other hand, administration of tartrazine was associated with severe histopathological and cellular alterations of rat liver and kidney tissues and induced DNA damage in leucocytes as detected by comet assay. Taken together, the results showed that tartrazine intake may lead to adverse health effects. PMID:28243541

  4. 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.

  5. Macro trends in pharmaceutical innovation.

    PubMed

    Cohen, Fredric J

    2005-04-01

    Extract: A lately recycled criticism of the pharmaceutical industry is that it is failing in its mission to innovate. In particular, critics question the industry's incentives to innovate, and they deride those innovations the industry makes as imitative. Industry advocates contend the opposite. The truth is that there are no generally accepted measures of innovation that would conclusively prove either side's point. However, I have found trends in several measures that support both sides of the innovation debate. Overall, the bulk of evidence suggests that the pharmaceutical industry continues to regard pioneering innovations as important (evidenced by the motivation, effort and ability of the industry to create such innovations). However, like other mature manufacturing industries, the pharmaceutical industry relies heavily on incremental innovations (what critics call "me-too" drugs) to sustain its profits. To a large extent, these incremental innovations are themselves medically beneficial and should be encouraged rather than dismissed as merely imitative.

  6. Planning and coordinating pharmaceutical purchasing.

    PubMed

    Buchanan, E C

    1984-09-01

    The planning and coordination of the pharmaceutical purchasing process are discussed. Planning for pharmaceutical purchasing should begin with decisions regarding why a purchasing policy is needed, what the institution's purchasing policy will be, and what departments will be involved in purchasing. General goals of purchasing and procedures for revising purchasing functions are presented, and the role of the pharmacy department, materials management, and other hospital departments in purchasing is discussed. Coordinating input on purchasing decisions from medical staff, administration, and clinical and technical pharmacy personnel to achieve purchasing goals and objectives is discussed. A well-designed pharmaceutical purchasing system provides for planned and scheduled purchases, competitive bidding, product standardization, group purchasing, information sharing, internal accountability, and quality assurance.

  7. Comparative genotoxicity of aluminium and cadmium in embryonic zebrafish cells.

    PubMed

    Pereira, Sandrine; Cavalie, Isabelle; Camilleri, Virginie; Gilbin, Rodolphe; Adam-Guillermin, Christelle

    2013-01-20

    Aluminium is a toxic metal whose genotoxicity has been scarcely studied in aquatic species and more generally in mammals. Recently, human and ecological disaster caused by the discharge of red mud in Hungary has revived questions about the toxicity of this metal particularly for the environment. On the contrary, cadmium is a highly toxic metal whose genotoxicity has been well characterized in various mammalian cells. However on non-human cells, little is known about its impact on DNA damage and repair. In this study, the genotoxic potential of both metals on embryonic zebrafish cells ZF4 was analyzed and particularly the impairment of the major DNA double strand breaks (DSB)-repair pathway, i.e. non-homologous end-joining (NHEJ). To this aim, DNA single strand breaks (SSB) and DSB were evaluated using the comet assay and the immunodetection of γ-H2AX proteins, respectively, in AlCl(3) or CdCl(2) exposed ZF4 cells. These exposures result in the production of DSBs a few hours after incubation. The DNA-PK kinase activity, essential for NHEJ, is more affected by the presence of aluminium than cadmium. Altogether our data provide evidence of the high toxicity induced by aluminium in zebrafish and indicates the pertinence of genotoxicity evaluation in organisms living in contaminated water.

  8. 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 ...

  9. 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.

  10. 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.

  11. Intracellular STING inactivation sensitizes breast cancer cells to genotoxic agents

    PubMed Central

    Gaston, Julie; Cheradame, Laura; Yvonnet, Vanessa; Deas, Olivier; Poupon, Marie-France; Judde, Jean-Gabriel

    2016-01-01

    Activation of the IFN/STAT1 pathway is closely associated with drug response and recurrence of breast cancer treated by chemotherapy. The aim of the current study was to elucidate the molecular mechanisms involved upstream and downstream of this pathway in order to identify distinct entities that might be manipulated to improve treatment efficacy. Four breast cancer cell lines (T-47D, MCF7, MDA-MB-231 and HBCx-19 established from the eponymous PDX) were treated in vitro with mafosfamide, a DNA damage inducer. In two of these cell lines (MCF7 and HBCx-19), genotoxic treatment upregulated type I IFN expression leading to paracrine activation of IFN/STAT1 signaling pathway after 6–8 days. We show that STING, a well-characterized inducer of IFN in immune cells, is rapidly triggered in MCF7 cells under genotoxic stress and forms nuclear foci that co-localize with phosphorylated IRF-3 and γH2AX. STING silencing abrogated chemotherapy-induced type I IFN production and signaling and potentiated genotoxic treatment efficacy as it promoted cell death extent and delayed cell colony regrowth. Similar results were obtained after silencing PARP12, one selected gene of the IFN/STAT1 pathway fingerprint. In summary, this study provides the first demonstration of STING activation in breast cancer cells. Our data suggest that genotoxic-induced, STING-mediated type I IFN signaling is a cell-intrinsic mechanism of breast cancer cell survival and regrowth. PMID:27791205

  12. 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.

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

    PubMed Central

    Kier, Larry D.

    2015-01-01

    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. PMID:25687244

  14. 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

  15. Relevance of the mouse spot test as a genotoxicity indicator

    SciTech Connect

    Russell, L.B.

    1982-01-01

    This paper examined the mammalian spat test as an indicator of genotoxicity and evaluated the weight that may be given to results from this test with respect to their predictiveness for human health hazards. The evaluation was based on theoretical considerations and the performance of the test to date. (PSB)

  16. Estimating potential genotoxicity for direct coal-liquefaction materials

    SciTech Connect

    Wilson, B.W.; Pelroy, R.A.; Renne, R.A.

    1981-05-01

    Fuels derived from coal liquefaction processes are chemically complex, highly aromatic mixtures, the specific constituency of which is fairly process-dependent. Genotoxicity, when found in these materials, is generally confined to the heavy-end fractions or full boiling range materials which contain heavy ends. The moderately polar or nitrogen base fractions of these heavy-end materials are generally the most mutagenically active. In some SRC-II heavy-end bottoms and the SRC-I solid product, however, the highly polar fractions contribute substantially to the mutagenicity. Specific compounds presently recognized as contributors or potential contributors to genotoxicity of the coal liquids studied include polycyclic primary aromatic amines, and to a much lesser extent, polycyclic aromatic hydrocarbons having four or more rings, certain polycyclic nitrogen heterocycles as well as certain polycyclic sulfur heterocyclics. The degree to which a given material has been subjected to reducing conditions during production appears to be an important parameter in determining its potential genotoxicity, the more severely reduced materials tending to be less genotoxic.

  17. 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.

  18. 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...

  19. 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...

  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. 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.

  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.

  4. 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...

  5. 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…

  6. 19 CFR 158.13 - Allowance for moisture and impurities.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 19 Customs Duties 2 2013-04-01 2013-04-01 false Allowance for moisture and impurities. 158.13... EXPORTED Damaged or Defective Merchandise § 158.13 Allowance for moisture and impurities. (a) Application... section 507, Tariff Act of 1930, as amended (19 U.S.C. 1507), for all detectable moisture and...

  7. 19 CFR 158.13 - Allowance for moisture and impurities.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 19 Customs Duties 2 2010-04-01 2010-04-01 false Allowance for moisture and impurities. 158.13... EXPORTED Damaged or Defective Merchandise § 158.13 Allowance for moisture and impurities. (a) Application... section 507, Tariff Act of 1930, as amended (19 U.S.C. 1507), for all detectable moisture and...

  8. 19 CFR 158.13 - Allowance for moisture and impurities.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 19 Customs Duties 2 2011-04-01 2011-04-01 false Allowance for moisture and impurities. 158.13... EXPORTED Damaged or Defective Merchandise § 158.13 Allowance for moisture and impurities. (a) Application... section 507, Tariff Act of 1930, as amended (19 U.S.C. 1507), for all detectable moisture and...

  9. 19 CFR 158.13 - Allowance for moisture and impurities.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 19 Customs Duties 2 2012-04-01 2012-04-01 false Allowance for moisture and impurities. 158.13... EXPORTED Damaged or Defective Merchandise § 158.13 Allowance for moisture and impurities. (a) Application... section 507, Tariff Act of 1930, as amended (19 U.S.C. 1507), for all detectable moisture and...

  10. 19 CFR 158.13 - Allowance for moisture and impurities.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 19 Customs Duties 2 2014-04-01 2014-04-01 false Allowance for moisture and impurities. 158.13... EXPORTED Damaged or Defective Merchandise § 158.13 Allowance for moisture and impurities. (a) Application... section 507, Tariff Act of 1930, as amended (19 U.S.C. 1507), for all detectable moisture and...

  11. 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.

  12. 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.

  13. 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.

    2010-08-01

    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 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. 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, Svalbard 13, Northern Norway 21, Western Arctic Russia 26, Northeastern Siberia 17. Concentrations are more variable in the European Arctic than in Arctic Canada or the Arctic Ocean, probably because of the proximity to BC sources. Individual

  14. 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

  15. Impurity transport driven by fishbones in MAST

    NASA Astrophysics Data System (ADS)

    Cecconello, M.; Jones, O. M.; Garzotti, L.; McClements, K. G.; Carr, M.; Henderson, S. S.; Sharapov, S. E.; Klimek, I.; the MAST Team

    2015-03-01

    In MAST, bursting toroidal Alfvén eigenmodes and fishbones are observed to give rise to an asymmetric perturbation to the soft x-ray (SXR) emission close to the magnetic axis which grows and decays on the time scale of the fishbone evolution. As the fishbone nears its maximum amplitude, the SXR emission starts to increase (decrease) at radial positions smaller (larger) than the radial position of the magnetic axis. This trend in the SXR emission persists for a few milliseconds, until the fishbone starts to decay in amplitude and the slower overall trend of the SXR emission once again becomes dominant. A preliminary analysis suggests that the change in the SXR emission is due to the localized accumulation of high-Z impurities, sustained against parallel transport by the effects of fishbones on the fast ion population.

  16. 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.

  17. 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.

  18. 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

  19. Single atom impurity in a single molecular transistor

    NASA Astrophysics Data System (ADS)

    Ray, S. J.

    2014-10-01

    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.

  20. 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.

    1999-03-01

    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. {copyright} {ital 1999 American Institute of Physics.}

  1. 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.

  2. 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).

  3. 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.

  4. 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.

  5. Quantum dynamics of impurities coupled to a Fermi sea

    NASA Astrophysics Data System (ADS)

    Parish, Meera M.; Levinsen, Jesper

    2016-11-01

    We consider the dynamics of an impurity atom immersed in an ideal Fermi gas at zero temperature. We focus on the coherent quantum evolution of the impurity following a quench to strong impurity-fermion interactions, where the interactions are assumed to be short range like in cold-atom experiments. To approximately model the many-body time evolution, we use a truncated basis method, where at most two particle-hole excitations of the Fermi sea are included. When the system is initially noninteracting, we show that our method exactly captures the short-time dynamics following the quench, and we find that the overlap between initial and final states displays a universal nonanalytic dependence on time in this limit. We further demonstrate how our method can be used to compute the impurity spectral function, as well as describe many-body phenomena involving coupled impurity spin states, such as Rabi oscillations in a medium or highly engineered quantum quenches.

  6. Impurity State and Variable Range Hopping Conduction in Graphene

    NASA Astrophysics Data System (ADS)

    Liang, Sang-Zi; Sofo, Jorge O.

    2012-12-01

    The variable range hopping theory, as formulated for exponentially localized impurity states, does not necessarily apply in the case of graphene with covalently attached impurities. We analyze the localization of impurity states in graphene using the nearest-neighbor, tight-binding model of an adatom-graphene system with Green’s function perturbation methods. The amplitude of the impurity state wave function is determined to decay as a power law with exponents depending on sublattice, direction, and the impurity species. We revisit the variable range hopping theory in view of this result and find that the conductivity depends as a power law of the temperature with an exponent related to the localization of the wave function. We show that this temperature dependence is in agreement with available experimental results.

  7. 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

    2016-06-05

    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).

  8. A Validated RP-HPLC Method for the Analysis of 1-Fluoronaphthalene and Its Process-Related Impurities.

    PubMed

    Karagiannidou, Evrykleia G; Bekiari, Eleni T; Vastardi, Elli I

    2015-09-01

    A simple and precise reversed-phase high-performance liquid chromatography method was developed and validated for the determination of 1-fluoronaphthalene and its process-related impurities, 1-aminonaphthalene, 1-nitronaphthalene, naphthalene and 2-fluoronaphthalene. 1-Fluoronaphthalene is the key starting material for the synthesis of duloxetine hydrochloride active pharmaceutical ingredient and is therefore a potential impurity of the API. The determination of the impurity profile is critical for the safety assessment of a substance and manufacturing process thereof. In duloxetine hydrochloride active pharmaceutical ingredient, only 1-fluoronaphthalene is detected and neither of its related impurities of 1-aminonaphthalene, 1-nitronaphthalene, naphthalene and 2-fluoronaphthalene. Chromatography was carried out on a Symmetry C18 (250 × 4.6 mm, 5 μm) column, using mobile phase A-a mixture of 0.01 Μ KH2PO4 buffer (pH 2.5 ± 0.1):methanol:acetonitrile in the ratio of 35:52:13 v/v/v and mobile phase B-a mixture of methanol:acetonitrile in the ratio of 80:20 v/v at a flow rate of 1.0 mL/min. The analytes were monitored using photo diode array detector at 230 nm. The proposed method is found to be having linearity in the concentration of 0.075-5.000 μg/mL, 0.150-5.000 μg/mL, 0.3125-5.000 μg/mL and 0.3125-5.000 μg/mL for 1-aminonaphthalene, 1-nitronaphthalene, naphthalene and 2-fluoronaphthalene, respectively, with correlation coefficients of 0.9998, 0.9998, 0.9997 and 0.9997, respectively. The proposed method was validated as per the International Conference on Harmonization guidelines. The mean recoveries for all the studied impurities are in the range of 90-110%. Due to its specificity, high precision and accuracy, the developed method can be used for the determination of 1-fluoronaphthalene, key starting material for the synthesis of duloxetine hydrochloride API.

  9. 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...

  10. Pharmaceutical and Medicine Manufacturing Sector (NAICS 3254)

    EPA Pesticide Factsheets

    Find environmental regulatory and compliance information for the pharmaceutical manufacturing sector, including essential uses of CFCs, NESHAP for pharmaceutical production, effluent guidelines for wastewater and management of hazardous waste.

  11. Pharmaceutical Research and Manufacturers of America

    MedlinePlus

    ... The New Era of Medicine SHARE THIS The Pharmaceutical Research and Manufacturers of America, PhRMA, represents the ... PhRMA Privacy Policy Terms of Service Site Map Pharmaceutical Research and Manufacturers of America® 950 F Street, ...

  12. Hydrocyclones for the separation of impurities in pretreated biowaste.

    PubMed

    Jank, Anna; Müller, Wolfgang; Waldhuber, Sebastian; Gerke, Frédéric; Ebner, Christian; Bockreis, Anke

    2017-03-13

    The aim of the mechanical pretreatment in case of anaerobic digestion of biowaste is to produce a substrate without impurities. To facilitate a failure free operation of the anaerobic digestion process even small impurities like stones or sand should be separated. As a result of an insufficient pretreatment or impurities separation, plant malfunctions, increased equipment wear or pipe clogging are reported. Apart from grit chambers or pulper systems, a hydrocyclone is a cost-efficient and space-saving option to remove impurities. The aim of this work was to investigate the efficiency of hydrocyclones for the separation of impurities. Two hydrocyclones at two different plants were investigated regarding their capability to separate the small inert impurities from pretreated source separated biowaste. In plant A, the hydrocyclone is part of the digester system. In plant B, the hydrocyclone is part of the biowaste pretreatment line (after milling and sieving the biowaste) before digestion. Separation rates of inert impurities such as stones, glass and sand were determined as well as the composition of the concentrated solids separated by the hydrocyclone. Due to the heterogeneity of the biowaste the impurity separation rates showed variations, therefore the following mean results were obtained in average: the investigated hydrocyclones of plant B, part of the biowaste treatment, separated more than 80% of the inert impurities in the waste stream before anaerobic digestion. These impurities had a size range of 0.5-4mm. The hydrocyclone integrated in the digester system of plant A showed separation rates up to 80% only in the size range of 2-4mm.

  13. 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.

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

    PubMed

    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(SM), 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.

  15. Modeling picking on pharmaceutical tablets

    NASA Astrophysics Data System (ADS)

    Swaminathan, Shrikant

    Tablets are the most popular solid dosage form in the pharmaceutical industry because they are cheap to manufacture, chemically and mechanically stable and easy to transport and fairly easy to control dosage. Pharmaceutical tableting operations have been around for decades however the process is still not well understood. One of the common problems faced during the production of pharmaceutical tablets by powder compaction is sticking of powder to the punch face, This is known as 'sticking'. A more specialized case of sticking is picking when the powder is pulled away form the compact in the vicinity of debossed features. In the pharmaceutical industry, picking is solved by trial and error which is an expensive, labor intensive and time consuming affair. The objective of this work was to develop, validate, and implement a modeling framework for predicting picking in powder compacts. The model was developed in Abaqus a commercially available finite element package. The resulting model was used to investigate the influence of debossed feature geometry viz. the stroke angle and degree of pre-pick, and, influence of lubricant on picking. (Abstract shortened by ProQuest.).

  16. Financing pharmaceuticals in transition economies.

    PubMed

    Kanavos, P

    1999-06-01

    This paper (a) provides a methodological taxonomy of pricing, financing, reimbursement, and cost containment methodologies for pharmaceuticals; (b) analyzes complex agency relationships and the health versus industrial policy tradeoff; (c) pinpoints financing measures to balance safety and effectiveness of medicines and their affordability by publicly funded systems in transition; and (d) highlights viable options for policy-makers for the financing of pharmaceuticals in transition. Three categories of measures and their implications for pharmaceutical policy cost containing are analyzed: supply-side measures, targeting manufacturers, proxy demand-side measures, targeting physicians and pharmacists, and demand-side measures, targeting patients. In pursuing supply side measures, we explore free pricing for pharmaceuticals, direct price controls, cost-plus and cost pricing, average pricing and international price comparisons, profit control, reference pricing, the introduction of a fourth hurdle, positive and negative lists, and other price control measures. The analysis of proxy-demand measures includes budgets for physicians, generic policies, practice guidelines, monitoring the authorizing behavior of physicians, and disease management schemes. Demand-side measures explore the effectiveness of patient co-payments, the impact of allowing products over-the-counter and health promotion programs. Global policies should operate simultaneously on the supply, the proxy demand, and the demand-side. Policy-making needs to have a continuous long-term planning. The importation of policies into transition economy may require extensive and expensive adaptation, and/or lead to sub-optimal policy outcomes.

  17. 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

  18. Immunotoxicology in the pharmaceutical industry.

    PubMed Central

    Norbury, K C

    1982-01-01

    Development of an immunotoxicology program within the pharmaceutical industry is described. With few guidelines in the area and a multitude of factors to consider, a basic screen for evaluating immune competence in species routinely used in toxicologic studies has been proposed. The future of immunotoxicology depends upon the ability of the selected immune function tests to be predictive of human risk. PMID:7037389

  19. 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.

  20. An Investigation of the Genotoxicity and Interference of Gold Nanoparticles in Commonly Used In Vitro Mutagenicity and Genotoxicity Assays.

    PubMed

    George, Jiya M; Magogotya, Millicent; Vetten, Melissa A; Buys, Antoinette V; Gulumian, Mary

    2017-01-20

    The suitability of 4 in vitro assays, commonly used for mutagenicity and genotoxicity assessment, was investigated in relation to treatment with 14 nm citrate-stabilized gold nanoparticles (AuNPs). Specifically, the Ames test was conducted without metabolic activation, where no mutagenic effects were observed. High resolution transmission electron microscopy and Cytoviva dark-field image analysis showed that AuNPs did not enter the bacterial cells, thus confirming the unreliability of the Ames test for nanoparticle mutagenicity studies. In addition, the Chinese hamster ovary (CHO) cell line was used for Comet, Chromosome aberration and Micronucleus assays. CHO cells were treated with AuNPs for 20 h at 37 °C. Cytotoxicity was not detected by cell impedance studies even though AuNP uptake was confirmed using Cytoviva image analysis. The DNA damage was statistically significant in treated cells when assessed by the Comet assay. However, minimal and nonstatistically significant chromosomal DNA damage was observed using the chromosome aberration and micronucleus assays. In this study, we showed that false positive results obtained with Comet assay may have been due to the possibility of direct contact between the residual, intracellular AuNPs and DNA during the assay procedure. Therefore, the chromosome aberration and micronucleus assays are better suited to assess the genotoxic effects of nanoparticles due to low probability of such direct contact occurring. Genotoxic effect of 14 and 20 nm citrate-stabilized, as well as, 14 nm PCOOH AuNPs were also investigated using chromosome aberration and micronucleus assays. Based on our acceptance criteria for a positive genotoxic response, none of the AuNPs were found to be genotoxic in either of these assays.

  1. 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.

  2. Genotoxic activity of organic chemicals in drinking water.

    PubMed

    Meier, J R

    1988-11-01

    The information summarized in this review provides substantial evidence for the widespread presence of genotoxins in drinking water. In many, if not most cases, the genotoxic activity can be directly attributed to the chlorination stage of drinking water treatment. The genotoxic activity appears to originate primarily from reactions of chlorine with humic substances in the source waters. Genotoxic activity in drinking water concentrates has been most frequently demonstrated using bacterial mutagenicity tests but results with mammalian cell assay systems are generally consistent with the findings from the bacterial assays. There is currently no evidence for genotoxic damage following in vivo exposures to animals. In some locations genotoxic contaminants of probable industrial and/or agricultural origin occur in the source waters and contribute substantially to the genotoxic activity of finished drinking waters. The method used for sample concentration can have an important bearing on study results. In particular, organic acids account for most of the mutagenicity of chlorinated drinking water, and their recovery from water requires a sample acidification step prior to extraction or XAD resin adsorption. Considerable work has been done to determine the identity of the compounds responsible for the mutagenicity of organic concentrates of drinking water. Recently, one class of acidic compounds, the chlorinated hydroxyfuranones, has been shown to be responsible for a major part of the mutagenic activity. Strategies for drinking water treatment that have been evaluated with respect to reduction of genotoxins in drinking water include granular activated carbon (GAC) filtration, chemical destruction, and the use of alternative means of treatment (i.e., ozone, chlorine dioxide, and monochloramine). GAC treatment has been found to be effective for removal of mutagens from drinking water even after the GAC is beyond its normal use for organic carbon removal. All disinfectant

  3. 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.

  4. 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.

  5. 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

  6. Complexity in estimation of esomeprazole and its related impurities' stability in various stress conditions in low-dose aspirin and esomeprazole magnesium capsules.

    PubMed

    Reddy, Palavai Sripal; Hotha, Kishore Kumar; Sait, Shakil

    2013-01-01

    A complex, sensitive, and precise high-performance liquid chromatographic method for the profiling of impurities of esomeprazole in low-dose aspirin and esomeprazole capsules has been developed, validated, and used for the determination of impurities in pharmaceutical products. Esomeprazole and its related impurities' development in the presence of aspirin was traditionally difficult due to aspirin's sensitivity to basic conditions and esomeprazole's sensitivity to acidic conditions. When aspirin is under basic, humid, and extreme temperature conditions, it produces salicylic acid and acetic acid moieties. These two byproducts create an acidic environment for the esomeprazole. Due to the volatility and migration phenomenon of the produced acetic acid and salicylic acid from aspirin in the capsule dosage form, esomeprazole's purity, stability, and quantification are affected. The objective of the present research work was to develop a gradient reversed-phase liquid chromatographic method to separate all the degradation products and process-related impurities from the main peak. The impurities were well-separated on a RP8 column (150 mm × 4.6mm, X-terra, RP8, 3.5μm) by the gradient program using a glycine buffer (0.08 M, pH adjusted to 9.0 with 50% NaOH), acetonitrile, and methanol at a flow rate of 1.0 mL min(-1) with detection wavelength at 305 nm and column temperature at 30°C. The developed method was found to be specific, precise, linear, accurate, rugged, and robust. LOQ values for all of the known impurities were below reporting thresholds. The drug was subjected to stress conditions of hydrolysis, oxidation, photolysis, and thermal degradation in the presence of aspirin. The developed RP-HPLC method was validated according to the present ICH guidelines for specificity, linearity, accuracy, precision, limit of detection, limit of quantification, ruggedness, and robustness.

  7. 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

    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.

  8. 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

  9. 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

  10. 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

  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. 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.

  13. Coupling of impurity modes in one-dimensional periodic systems.

    PubMed

    Royo, P; Stanley, R P; Ilegems, M

    2001-07-01

    One-dimensional periodic dielectric structures are known to exhibit band gaps because of their symmetry. Defect states can be found in the band gaps if an impurity layer is added to the lattice such that the symmetry of the structure is broken. In this paper, we consider the case where a second impurity layer is added and we discuss the existence of coupling between the two defects. We discuss the possibility of exploiting the coupling of impurity modes in the realization of tunable wavelength emitting devices and dual-wavelength vertical-cavity surface-emitting lasers.

  14. 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.

  15. 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.

  16. Extraction process for removing metallic impurities from alkalide metals

    DOEpatents

    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.

  17. Extraction process for removing metallic impurities from alkalide metals

    DOEpatents

    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.

  18. Long-range exchange interaction between magnetic impurities in graphene

    NASA Astrophysics Data System (ADS)

    Agarwal, M.; Mishchenko, E. G.

    2017-02-01

    The effective spin exchange RKKY coupling between impurities (adatoms) on graphene mediated by conduction electrons is studied as a function of the strength of the potential part of the on-site energy U of the electron-adatom interaction. With increasing U , the exchange coupling becomes long range, determined largely by the impurity levels with energies close to the Dirac points. When adatoms reside on opposite sublattices, their exchange coupling, normally antiferromagnetic, becomes ferromagnetic and resonantly enhanced at a specific distance where an impurity level crosses the Dirac point.

  19. Genotoxic and mutagenic effects of sewage sludge on higher plants.

    PubMed

    Corrêa Martins, Maria Nilza; de Souza, Victor Ventura; Souza, Tatiana da Silva

    2016-02-01

    Sewage treatment yields sludge, which is often used as a soil amendment in agriculture and crop production. Although the sludge contains elevated concentrations of macro and micronutrients, high levels of inorganic and organic compounds with genotoxic and mutagenic properties are present in sludge. Application of sludge in agriculture is a pathway for direct contact of crops to toxic chemicals. The objective of this study was to compile information related to the genotoxic and mutagenic effects of sewage sludge in different plant species. In addition, data are presented on toxicological effects in animals fed with plants grown in soils supplemented with sewage sludge. Despite the benefits of using sewage sludge as organic fertilizer, the data showcased in this review suggest that this residue can induce genetic damage in plants. This review alerts potential risks to health outcomes after the intake of food cultivated in sewage sludge-amended soils.

  20. Hexavalent Chromium Is Cytotoxic and Genotoxic to American Alligator Cells

    PubMed Central

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

    2016-01-01

    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

  1. Genotoxic and cytotoxic effects of testosterone cypionate (deposteron(®)).

    PubMed

    Meireles, José Roberto C; Oliveira, Susie V; Costa-Neto, Antônio O; Cerqueira, Eneida M M

    2013-05-15

    The indiscriminate use of anabolic androgenic steroids (AAS) has motivated researchers to investigate the mutagenic action of these substances. The present study, using the mouse bone marrow micronucleus test, evaluates the genotoxic potential of testosterone cypionate (deposteron). Male Swiss mice received intramuscular injections of deposteron at three doses. The animals were sacrificed 24, 48, or 72h after treatment and bone marrow was removed immediately, followed by scoring to count the micronuclei in 2000 polychromatic erythrocytes (PCE). Two hundred erythrocytes/animal were analyzed to determine the PCE-NCE (normochromatic erythrocyte) relationship and to determine the cytotoxic effects. The animals treated with deposteron at the highest dose presented greater numbers of micronuclei. The highest dose caused a decrease in the PCE/NCE relationship, indicating a cytotoxic effect. We conclude that deposteron is genotoxic and cytotoxic in mice.

  2. Genotoxicity of Euphorbia hirta: an Allium cepa assay.

    PubMed

    Yuet Ping, Kwan; Darah, Ibrahim; Yusuf, Umi Kalsom; Yeng, Chen; Sasidharan, Sreenivasan

    2012-06-26

    The potential genotoxic effects of methanolic extracts of Euphorbia hirta which is commonly used in traditional medicine to treat a variety of diseased conditions including asthma, coughs, diarrhea and dysentery was investigated using Allium cepa assay. The extracts of 125, 250, 500 and 1,000 µg/mL were tested on root meristems of A. cepa. Ethylmethanesulfonate was used as positive control and distilled water was used as negative control. The result showed that mitotic index decreased as the concentrations of E. hirta extract increased. A dose-dependent increase of chromosome aberrations was also observed. Abnormalities scored were stickiness, c-mitosis, bridges and vagrant chromosomes. Micronucleated cells were also observed at interphase. Result of this study confirmed that the methanol extracts of E. hirta exerted significant genotoxic and mitodepressive effects at 1,000 µg/mL.

  3. 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

  4. 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.

  5. Genotoxicity of indium tin oxide by Allium and Comet tests.

    PubMed

    Ciğerci, İbrahim Hakkı; Liman, Recep; Özgül, Emre; Konuk, Muhsin

    2015-01-01

    Genotoxic effects of indium tin oxide (ITO) were investigated on root cells of Allium cepa by employing both Allium and Comet assays. A. cepa roots were treated with the aqueous dispersions of ITO at 5 different concentrations (12.5, 25, 50, 75, and 100 ppm) for 4 h. Exposure of ITO significantly increased mitotic index, and total chromosomal aberrations by the Allium test. While chromosome laggards, stickiness, disturbed anaphase-telophase and anaphase bridges were observed in anaphase-telophase cells, c-metaphase and binuclear cells were observed in other cells. A significant increase in DNA damage was also observed at all concentrations of ITO by the Comet assay. These results indicate that ITO exhibits genotoxic activity in A. cepa root meristematic cells.

  6. Genotoxicity of industrial wastes and effluents. A review

    SciTech Connect

    Houk, V.S.

    1992-01-01

    A review of the literature published on the genotoxicity of industrial wastes and effluents using short-term genetic bioassays is presented in the document. The importance of this task arises from the ubiquity of genotoxic compounds in the environment and the need to identify the sources of contamination so that efforts aimed at control and minimization can be implemented. Of even greater significance is the immediate concern for the welfare of human health and the environment. Subheadings of the document include an introduction, a summary of the various genetic bioassays that have been used to test industrial wastes, a compendium of methods commonly used to prepare crude waste samples for bioassay, and a review of the genetic toxicity of wastes and effluents. Wastes have been grouped according to major industrial source. Within each industrial category, a synopsis of individual studies is presented, followed by an interpretation of results on an industry-wide basis.

  7. Genotoxicity of copper oxide nanoparticles in Drosophila melanogaster.

    PubMed

    Carmona, Erico R; Inostroza-Blancheteau, Claudio; Obando, Veroska; Rubio, Laura; Marcos, Ricard

    2015-09-01

    Copper oxide nanoparticles (CuONPs) are used as semiconductors, catalysts, gas sensors, and antimicrobial agents. We have used the comet and wing-spot assays in Drosophila melanogaster to assess the genotoxicity of CuONPs and ionic copper (CuSO4). Lipid peroxidation analysis was also performed (Thiobarbituric Acid Assay, TBARS). In larval hemocytes, both CuONPs and CuSO4 caused significant dose-dependent increases in DNA damage (comet assay). In the wing-spot assay, an increase in the frequency of mutant spots was observed in the wings of the adults; CuONPs were more effective than was CuSO4. Both agents induced TBARS; again, CuONPs were more active than was CuSO4. The results indicate that CuONPs are genotoxic in Drosophila, and these effects may be mediated by oxidative stress. Most of the effects appear to be related to the presence of copper ions.

  8. Public policy and pharmaceutical innovation.

    PubMed

    Grabowski, H G

    1982-09-01

    Historically, new drug introductions have played a central role in medical progress and the availability of cost-effective therapies. Nevertheless, public policy toward pharmaceuticals has been characterized in recent times by increasingly stringent regulatory controls, shorter effective patent terms, and increased encouragement of generic product usage. This has had an adverse effect on the incentives and capabilities of firms to undertake new drug research and development activity. The industry has experienced sharply rising research and development costs, declining annual new drug introductions, and fewer independent sources of drug development. This paper considers the effects of government regulatory policies on the pharmaceutical innovation process from several related perspectives. It also examines the merits of current public policy proposals designed to stimulate drug innovation including patent restoration and various regulatory reform measures.

  9. Public Policy and Pharmaceutical Innovation

    PubMed Central

    Grabowski, Henry G.

    1982-01-01

    Historically, new drug introductions have played a central role in medical progress and the availability of cost-effective therapies. Nevertheless, public policy toward pharmaceuticals has been characterized in recent times by increasingly stringent regulatory controls, shorter effective patent terms, and increased encouragement of generic product usage. This has had an adverse effect on the incentives and capabilities of firms to undertake new drug research and development activity. The industry has experienced sharply rising research and development costs, declining annual new drug introductions, and fewer independent sources of drug development. This paper considers the effects of government regulatory policies on the pharmaceutical innovation process from several related perspectives. It also examines the merits of current public policy proposals designed to stimulate drug innovation including patent restoration and various regulatory reform measures. PMID:10309721

  10. 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

  11. 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.

  12. 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

  13. Assessment of the Genotoxic Effects of High Peak-Power Pulsed Electromagnetic Fields

    DTIC Science & Technology

    2003-06-01

    the Genotoxic Effects of High Peak-Power Pulsed Electromagnetic Fields 5c. PROGRAM ELEMENT NUMBER 5d. PROJECT NUMBER 5d. TASK NUMBER 6. AUTHOR(S) Dr... Genotoxic Effects of High Peak-Power Pulsed Electromagnetic Fields (EMFs) (From 1 June 2002 to 31 May 2003 for 12 months) Nikolai Konstantinovich Chemeris...International Science and Technology Center (ISTC), Moscow. 2 ISTC 2350 Assessment of the Genotoxic Effects of High Peak-Power Pulsed Electromagnetic Fields

  14. Gyrokinetic simulations of ion and impurity transport

    NASA Astrophysics Data System (ADS)

    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.

  15. Dynamics of impurities in ultracold Bose gas

    NASA Astrophysics Data System (ADS)

    Shchadilova, Yulia; Grusdt, Fabian; Rubtsov, Alexey; Demler, Eugene

    2015-05-01

    A system of an impurity immersed in a Bose-Einstein condensate (BEC) exhibits the polaronic effect, which is known to be an ubiquitous phenomenon in a wide range of physical systems including semiconductors, doped Mott insulators, and high-Tc superconductors. Recent analysis of the BEC-polaron problem showed that existing analytical approaches do not provide reliable results in the experimentally relevant range of parameters when tested against Monte Carlo (MC) simulations. In this contribution we demonstrate that the description of polarons at finite momentum can be done by employing an analytical class of wavefunctions based on the correlated Gaussian ansatz (CGWs). We show that CGWs show excellent agreement with known MC results for the polaron binding energy for a wide range of interactions. We discuss the properties of the polarons and atomic mixtures in systems of ultracold atoms in which polaronic effects can be observed with current experimental technology. Our CGWs predicts a specific pattern of correlations between host atoms that can be measured in time-of-flight experiments. Department of Physics, Harvard University.

  16. 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.

  17. 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

  18. Genotoxicity and growth inhibition effects of aniline on wheat.

    PubMed

    Tao, Nan; Liu, Guanyi; Bai, Lu; Tang, Lu; Guo, Changhong

    2017-02-01

    Aniline is a synthetic compound widely used in industrial and pesticide production, which can lead to environmental pollution. Its high concentration in rivers and lakes is hazardous to aquatic species. Although the mechanism of aniline toxicity has been studied extensively in animals and algae, little is known about its genotoxicity in plants. In this study, we investigated the genotoxicity effects of aniline on wheat root tip cells. The mitotic index of wheat root tip cells decreased when the aniline test concentration was higher than 10 mg L(-1). The frequency of micronucleus and chromosomal aberrations increased at aniline concentrations ranging between 5 and 100 mg L(-1), and reached 23.3‰ ± 0.3‰ and 8.9‰ ± 0.68‰, respectively, at an aniline concentration of 100 mg L(-1). These values were sevenfold higher than those in the control group. The wheat seedlings showed various growth toxicity effects under different concentrations of aniline. The shoot height, root length, fresh weight, and dry weight of wheat seedlings decreased at aniline test concentrations ranging between 25 and 200 mg L(-1). At 200 mg L(-1) aniline, the dry weight was only one-third that of the control group. Overall, the findings of this study provide evidence that aniline is a serious environmental pollutant causing deleterious genotoxic effects on wheat root tip cells and growth toxic effects on wheat seedlings. However, understanding the mechanisms that underlie aniline genotoxicity in plants needs further study.

  19. 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.

  20. [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.

  1. 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.

  2. 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.

  3. PHARMACEUTICALS AND PERSONAL CARE PRODUCTS ...

    EPA Pesticide Factsheets

    Modern sanitary practices result in large volumes of human waste, as well as domestic and industrial sewage, being collected and treated at common collection points, wastewater treatment plants (WWTP). In recognition of the growing use of sewage sludges as a fertilizers and as soilamendments, and the scarcity of current data regarding the chemical constituents in sewage sludges, the United States National Research Council (NRC) in 2002 produced a report on sewage sludges. Among the NRC's recommendations was the need for investigating the occurrence of pharmaceuticals and personal care products (PPCPs) in sewage sludges. PPCPsare a diverse array of non-regulated contaminants that had not been studied in previous sewage sludges surveys but which are likely to be present. The focus of this paper will be to review the current analytical methodologies available for investigating whether pharmaceuticals are present in WWTP-produced sewage sludges, to summarize current regulatory practices regarding sewage sludges, and to report on the presence of pharmaceuticals in sewage sludges. The research focused on in the subtasks is the development and application of state-of the-art technologies to meet the needs of the public, Office of Water, and ORD in the area of Water Quality. Located In the subtasks are the various research projects being performed in support of this Task and more in-depth coverage of each project. Briefly, each project's objective is stated below.Subta

  4. International Conference on Harmonisation; final recommendation for the revision of the permitted daily exposure for the solvent cumene according to the maintenance procedures for the guidance Q3C Impurities: Residual Solvents; availability. Notice.

    PubMed

    2012-02-23

    The Food and Drug Administration (FDA) is announcing the availability of a final recommendation for the revision of the permitted daily exposure (PDE) for the solvent cumene according to the maintenance procedures for the guidance for industry entitled ``Q3C Impurities: Residual Solvents.'' The recommendation was prepared under the auspices of the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH).

  5. Haloacetonitriles: metabolism, genotoxicity, and tumor-initiating activity

    SciTech Connect

    Lin, E.L.C.; Daniel, F.B.; Herren-Freund, S.L.; Pereira, M.A.

    1986-11-01

    Haloacetonitriles (HAN) are drinking water contaminants produced during chlorine disinfection. This paper evaluates metabolism, genotoxicity, and tumor-initiating activity of these chemicals. The alkylating potential of the HAN to react with the electrophile-trapping agent, 4-(p-nitrobenzyl)pyridine, followed the order dibromoacetonitrile (DBAN) > bromochloroacetonitrile (BCAN) > chloroacetonitrile (CAN) > dichloroacetonitrile (DCAN) > trichloroacetonitrile (TCAN). When administered orally to rats, the HAN were metabolized to cyanide and excreted in the urine as thiocyanate. The extent of thiocyanate excretion was CAN > BCAN > DCAN > DDAN >> TCAN. Haloacetonitriles inhibited in vitro microsomal dimethylnitrosamine demethylase (DMN-DM) activity. The most potent inhibitors were DBAN and BCAN. The HAN produced DNA strand breaks in cultured human lymphoblastic (CCRF-CEM) cells. TCAN was the most potent DNA strand breaker. DCAN reacted with polyadenylic acid and DNA to form adducts in a cell-free system. None of the HAN initiated ..gamma..-glutamyltranspeptidase (GGT) foci when assayed for tumor-initiating activity in rat liver foci bioassay. In summary, the HAN were demonstrated to possess alkylating activity and genotoxicity in vitro and appeared after oral administration to possess biological activity as indicated by the inhibition of DMN-DM by TCAN but appeared to lack genotoxic and tumor-initiating activity in rat liver. It is proposed that if the HAN found in drinking water pose a carcinogenic hazard it would be limited to the gastrointestinal tract.

  6. 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.

  7. 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.

  8. 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.

  9. 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.

  10. Genotoxicity of drinking water from three Korean cities.

    PubMed

    Park, J H; Lee, B J; Lee, S K; Kim, K; Lee, K H; Che, J H; Kang, K S; Lee, Y S

    2000-03-23

    Organic content of drinking tap water from Seoul, Taejon, and Suwon was extracted with an XAD-2 resin column and organic solvents. Four doses of the extract equivalent to 4, 2, 1, and 0.5 l water were tested for mutagenicity in Salmonella typhimurium strains TA98 and TA100 in the presence and absence of S9 mix. The organic extracts of the water from all three cities were mutagenic in TA 98 without S9 mix and in TA 100 with and without S9 mix. The highest number of revertants per plate was found in the absence of S9 mix. Three doses of the extract (equivalent to 22, 11, and 3.7 l water) were also tested in the bone marrow micronucleus test using BDF1 mice. At the highest dose, a significant increase of the micronucleus frequency was observed. The time required to be on the effect, however, varied with the source of the water. Our results indicate that the drinking tap waters from the three cities were genotoxic clearly in the bacterial test and also in the in vivo assay with mice. As we found no genotoxicity of the source water as seen in a previous study, it is likely that the chlorination process leads to the genotoxicity of the tap water.

  11. Genotoxic Potential and Physicochemical Parameters of Sinos River, Southern Brazil

    PubMed Central

    Scalon, Madalena C. S.; Rechenmacher, Ciliana; Siebel, Anna Maria; Kayser, Michele L.; Rodrigues, Manoela T.; Maluf, Sharbel W.; Rodrigues, Marco Antonio S.

    2013-01-01

    The present study aimed to evaluate the physicochemical parameters and the genotoxic potential of water samples collected in the upper, middle, and lower courses of the Sinos River, southern Brazil. The comet assay was performed in the peripheral blood of fish Hyphessobrycon luetkenii exposed under laboratory conditions to water samples collected in summer and winter in three sampling sites of Sinos River. Water quality analysis demonstrated values above those described in Brazilian legislation in Parobé and Sapucaia do Sul sites, located in the middle and in the lower courses of the Sinos River, respectively. The Caraá site, located in the upper river reach, presented all the physicochemical parameters in accordance with the allowed limits in both sampling periods. Comet assay in fish revealed genotoxicity in water samples collected in the middle course site in summer and in the three sites in winter when compared to control group. Thus, the physicochemical parameters indicated that the water quality of the upper course complies with the limits set by the national guidelines, and the ecotoxicological assessment, however, indicated the presence of genotoxic agents. The present study highlights the importance of combining water physicochemical analysis and bioassays to river monitoring. PMID:24285934

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

    PubMed

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

    2010-01-01

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

  13. Genotoxicity studies on fucoidan from Sporophyll of Undaria pinnatifida.

    PubMed

    Kim, Kui-Jin; Lee, Ok-Hwan; Lee, Boo-Yong

    2010-04-01

    The sulfated seaweed extract, fucoidan, has anticoagulant, antithrombotic, and antiviral activities. Despite extensive work on the biological activities of fucoidan, detailed studies on the genotoxicity of fucoidan from Sporophyll of Undaria pinnatifida sources have not been tested before. The objective of this study was to investigate the genotoxicity effects of fucoidan extracted from Sporophyll of U. pinnatifida using a test battery of three different methods. In a reverse mutation assay using four Salmonella typhimurium strains and Escherichia coli, fucoidan did not increase the number of revertant colonies in any tester strain regardless of metabolic activation by S9 mix, and did not cause chromosomal aberration in short tests with S9 mix or in the continuous (24 h) test. A bone marrow micronucleus test in ICR mice dosed by oral gavage at doses up to 2000 mg/kg bw/day showed no significant or dose-dependent increases in the frequency of micronucleated polychromatic erythrocytes (MNPCE), and the high dose suppressed the ratio of polychromatic erythrocytes (PCE) to total erythrocytes. We conclude that fucoidan presents no significant genotoxic concern under the anticipated conditions of use.

  14. Genotoxic evaluation of terbinafine in human lymphocytes in vitro.

    PubMed

    Tolomeotti, Danielle; de Castro-Prado, Marialba Avezum Alves; de Sant'Anna, Juliane Rocha; Martins, Ana Beatriz Tozzo; Della-Rosa, Valter Augusto

    2015-01-01

    Terbinafine is an antimycotic drug usually used against several superficial fungal infections and with a potential application in the treatment of human cancers. Since to date there are few data on the genotoxic effects of terbinafine in mammalian cells, current study evaluated the potential genotoxic of such antifungal agent in cultured human peripheral blood lymphocytes. Terbinafine was used at the peak plasma concentration (1.0 μg/ml) and in four additional concentrations higher than the human plasmatic peak (5.0 μg/ml, 25.0 μg/ml, 50.0 μg/ml and 100.0 μg/ml). Chromosomal aberrations (CA), sister chromatid exchanges (SCE), micronuclei (MN), nucleoplasmic bridges (NP) and nuclear buds (NB) were scored as genetic endpoints. In all analysis no significant differences (α = 0.05, Kruskal-Wallis test) were observed. Complementary criterion adopted to obtain the final response in cytogenetic agreed with statistical results. Therefore, results of this study showed that terbinafine neither induced CA, SCE, MN, NP and NB nor affected significantly mitotic, replication and cytokinesis-block proliferation indices in any of the tested concentrations. It may be assumed that terbinafine was not genotoxic or cytotoxic to cultured human peripheral blood lymphocytes in our experimental conditions.

  15. 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.

  16. Laser pyrolysis products: sampling procedures, cytotoxic and genotoxic effects.

    PubMed

    Stocker, B; Meier, T; Fliedner, T M; Plappert, U

    1998-01-30

    The use of lasers in medical applications has grown enormously in the last few years. Recent chemical analysis of the laser pyrolysis products revealed that aerosols generated by pyrolytic decomposition of tissue could be health hazards. Therefore we analysed the genotoxic and mutagenic effects of laser pyrolysis products from different types of porcine tissue. The tissues were irradiated with a surgical CO2 laser and the generated aerosols were sampled as particulate fractions as well as low and highly volatile fractions. Then human leukocytes were incubated with the pyrolysis products and subjected to the comet assay. The results of the comet assay indicated the pyrolysis products being inducers of DNA damage. The ability to induce genotoxic effects turned out to be strongly dependent on the type of tissue that had been irradiated during laser treatment. To check whether the pyrolysis products also have mutagenic properties the Salmonella mutagenicity assay was performed. The particulate aerosol fractions of skin, muscle tissue and liver tissue clearly proved to be mutagenic in TA98 in the presence of S9 mix. There was no mutagenic effect detectable without metabolic activation. In conclusion, our experiments showed that the laser pyrolysis products originating from porcine tissues induced very potent genotoxic as well as mutagenic effects and therefore they could be potential health hazards for humans.

  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. 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.

  19. Assessing the genotoxicity of two commonly occurring byproducts of water disinfection: Chloral hydrate and bromal hydrate.

    PubMed

    Manasfi, Tarek; De Méo, Michel; Di Giorgio, Carole; Coulomb, Bruno; Boudenne, Jean-Luc

    2017-01-01

    Water disinfection treatments result in the formation of disinfection byproducts (DBPs) that have been linked to adverse human health outcomes including higher incidence of bladder and colorectal cancer. However, data about the genotoxicity of DBPs is limited to only a small fraction of compounds. Chloral hydrate (CH) and bromal hydrate (BH) are two trihaloacetaldehydes commonly detected in disinfected waters, but little is known about their genotoxicity, especially BH. We investigated the genotoxicity of CH and BH using a test battery that includes three in vitro genotoxicity assays. We conducted the Ames test using Salmonella bacterial strains TA97a, TA98, TA100 and TA102, and the alkaline comet assay and the micronucleus test both using Chinese hamster ovary cells. We carried out the tests in the absence and presence of the metabolic fraction S9 mix. CH did not exhibit statistically significant genotoxic effects in any of the three assays. In contrast, BH exhibited mutagenic activity in the Salmonella strain TA100 and induced statistically significant DNA lesions in CHO cells as appeared in the comet assay. The genotoxic potential of BH in both assays decreased in the presence of the metabolic fraction S9 mix. BH did not induce chromosomal damage in CHO cells. Our results show that BH exhibited genotoxic activity by causing mutations and primary DNA damage while CH did not induce genotoxic effects. Our findings highlight concerns about the higher genotoxicity of brominated DBPs in comparison to their chlorinated analogues.

  20. Diagram theory for the twofold-degenerate Anderson impurity model

    NASA Astrophysics Data System (ADS)

    Moskalenko, V. A.; Dohotaru, L. A.; Digor, D. F.; Cebotari, I. D.

    2014-02-01

    We develop a diagram technique for investigating the twofold-degenerate Anderson impurity model in the normal state with the strong electronic correlations of d electrons of the impurity ion taken into account. We discuss the properties of the Slater-Kanamori model of d electrons. After finding the eigenfunctions and eigenvalues of all 16 local states, we determine the local one-particle propagator. We construct the perturbation theory around the atomic limit of the impurity ion and obtain a Dyson-type equation establishing the relation between the impurity electron propagator and the normal correlation function. As a result of summing infinite series of ladder diagrams, we obtain an approximation for the correlation function.

  1. Transport Simulations of DIII-D Discharges with Impurity Injection

    NASA Astrophysics Data System (ADS)

    Mandrekas, J.; Stacey, W. M.; Murakami, M.

    2001-10-01

    Several recent DIII-D discharges with external impurity injection into L-mode plasmas are analyzed with a coupled main plasma and multi-charge state 1frac 12-D impurity transport code. These discharges exhibit various degrees of confinement improvement, which has been attributed to the synergistic effects of impurity induced enhancement of the E×B shearing rate and reduction of the drift wave turbulence growth rate (M. Murakami, et. al., Nucl. Fusion 41) (2001) 317.. Impurity transport is described by empirical and neoclassical transport models. Both the standard neoclassical theory as well as an enhanced theory which takes into account the effects of external momentum input and radial momentum transport (W.M. Stacey, Phys. Plasmas 8) (2001) 158. have been considered.

  2. Effect of impurities in industrial salts on aluminum scrap melting

    SciTech Connect

    Ye, J.; Sahai, Y.; Revet, A.

    1996-10-01

    Aluminum scrap such as Used Beverage Containers (UBC) is melted under a protective molten salt cover. An appropriate salt protects metal from oxidation, promotes coalescence of molten droplets, and separates clean metal from the oxide contamination. Generally, the salt compositions for aluminum scrap recycling are based on equimolar mixtures of NaCl and KCl. A small amount of fluoride is also added in the salt. In the past, laboratory research at universities and industrial laboratories have been limited to pure salts. However, the industrial salts have impurities such as sulfates and other insoluble materials. These impurities have a pronounced effect on the efficiency of the scrap remelting process. In this paper, the role of impurities in industrial salts in terms of their chemical interactions with the metal are summarized. The efficiency of different industrial grade salts containing varying amounts of sulfates and other insoluble impurities for scrap recycling is compared.

  3. 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.

  4. Photon-modulated impurity scattering on a topological insulator surface

    NASA Astrophysics Data System (ADS)

    Deng, Ming-Xun; Deng, W. Y.; Shao, D. X.; Wang, Rui-Qiang; Shen, R.; Sheng, L.; Xing, D. Y.

    2017-03-01

    We consider the Dirac electron scattering off a pointlike impurity absorbed on the surface of a topological insulator, which is irradiated by a beam of circularly polarized light. It is found that the Dirac electron backscattering is allowed even for a nonmagnetic impurity due to the reshuffled spectrum caused by the light, and so exhibits interesting spin texture and Friedel oscillation in the real space. Furthermore, in the charge density of states, the interplay of the light irradiation and impurity scattering can lead to an in-gap bound state around the Dirac point, heavily modulating the Dirac dispersion. We discuss the different scenarios for resonant and off-resonant lights in detail. The impurity scattering feature is sensitive to the parameters of the polarized light, which suggests a possibility to optically manipulate the topological surface states.

  5. 40 CFR 161.167 - Discussion of formation of impurities.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ...) Technical grade active ingredients and products produced by an integrated system. (1) Each impurity... measures used to produce the product. (b) Products not produced by an integrated system. Each...

  6. 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.

  7. 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.

  8. 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.

  9. 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.

  10. Removal of impurities from zirconium tetrafluoride using metallic zirconium chips

    NASA Astrophysics Data System (ADS)

    Rusakov, I. Yu.; Buinovskii, A. S.; Sofronov, V. L.

    2016-11-01

    The sublimation refining of zirconium tetrafluoride (ZTF) from impurities in the presence of metallic zirconium chips is studied. It is shown that, in the presence of metallic zirconium chips, the contents of aluminum, nickel, oxygen, chromium, iron, and silicon impurities in a desublimate decrease and the rate of ZTF sublimation increases. The method of refining is tested under laboratory and pilot conditions and can be recommended for commercial application.

  11. Interactions of Ultracold Impurity Particles with Bose-Einstein Condensates

    DTIC Science & Technology

    2015-06-23

    STATEMENT 13. SUPPLEMENTARY NOTES 14. ABSTRACT Research on interactions between quantum gases and impurities has become an active area of AMO . Here...2015 Abstract. Research on interactions between quantum gases and impurities (ions, other atoms etc.) has become an active area of AMO research...respectively. Green and red electrodes are grounded. PRL 107, 103001 (2011) P HY S I CA L R EV I EW LE T T E R S week ending 2 SEPTEMBER 2011 0031-9007=11

  12. 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.

  13. 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.

  14. Acetylated lysozyme as impurity in lysozyme crystals: constant distribution coefficient

    NASA Astrophysics Data System (ADS)

    Thomas, B. R.; Chernov, A. A.

    2001-11-01

    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 and B impurities added were 0.76, 0.38 and 0.1 mg/ml and 0.43, 0.22, 0.1 mg/ml, respectively. The HEWL concentration were 20, 30 and 40 mg/ml. The crystals grown in 18 experiments for each impurity concentration and supersaturation 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±0.13 for A and K=3.42±0.25 for B. According to definition of K by Eq. (1) in the text, the condition K=const is equivalent to a decrease of impurity amount in the crystal as the supersaturation increases. 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 the impurity adsorption and incorporation rates are proportional to the impurity concentration and that the growth rate is proportional to the concentration of crystallizing protein in solution. The frequency at which an impurity molecules irreversibly join the crystal was estimated to be 3 s -1, much higher than such frequency for regular crystal molecules 5×10 -2 s -1 at 30 mg/ml lysozyme concentration. Reasons for this inequality are discussed.

  15. 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.

  16. A novel two-dimensional liquid chromatographic system for the online toxicity prediction of pharmaceuticals and related substances.

    PubMed

    Li, Jian; Xu, Li; Shi, Zhi-guo; Hu, Min

    2015-08-15

    In this study, a novel two-dimensional liquid chromatographic (2D-LC) system was developed for simultaneous separation and toxicity prediction of pharmaceutical and its related substances. A conventional ODS column was used on the 1st-D to separate the sample; while, bio-partitioning micellar chromatography served as the 2nd-D to predict toxicity of the components. The established system was tested for the toxicity of ibuprofen and its impurities with known toxicity. With only one injection, ibuprofen and its impurities were separated on the 1st-D; and LC50 values of individual impurity were obtained based on the quantitative retention-activity relationships, which agreed well with the reported data. Furthermore, LC50 values of photolysis transformation products (TPs) of carprofen, ketoprofen and diclofenac acid (as unknown compounds) were screened in this 2D-LC system, which could be an indicator of the toxicity of these TPs and was meaningful for the environmental monitoring and drinking water treatment. The established 2D-LC system was cost-effective, time-saving and reliable, and was promising for fast online screening of toxicity of known and unknown analytes in the complex sample in a single step. It may find applications in environment, pharmaceutical and food, etc.

  17. 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.

  18. Impurities block the alpha to omega martensitic transformation in titanium.

    PubMed

    Hennig, Richard G; Trinkle, Dallas R; Bouchet, Johann; Srinivasan, Srivilliputhur G; Albers, Robert C; Wilkins, John W

    2005-02-01

    Impurities control phase stability and phase transformations in natural and man-made materials, from shape-memory alloys to steel to planetary cores. Experiments and empirical databases are still central to tuning the impurity effects. What is missing is a broad theoretical underpinning. Consider, for example, the titanium martensitic transformations: diffusionless structural transformations proceeding near the speed of sound. Pure titanium transforms from ductile alpha to brittle omega at 9 GPa, creating serious technological problems for beta-stabilized titanium alloys. Impurities in the titanium alloys A-70 and Ti-6Al-4V (wt%) suppress the transformation up to at least 35 GPa, increasing their technological utility as lightweight materials in aerospace applications. These and other empirical discoveries in technological materials call for broad theoretical understanding. Impurities pose two theoretical challenges: the effect on the relative phase stability, and the energy barrier of the transformation. Ab initio methods calculate both changes due to impurities. We show that interstitial oxygen, nitrogen and carbon retard the transformation whereas substitutional aluminium and vanadium influence the transformation by changing the d-electron concentration. The resulting microscopic picture explains the suppression of the transformation in commercial A-70 and Ti-6Al-4V alloys. In general, the effect of impurities on relative energies and energy barriers is central to understanding structural phase transformations.

  19. Ultrasoft X-ray Measurements of Impurity Profiles in NSTX*

    NASA Astrophysics Data System (ADS)

    Stutman, D.; Finkenthal, M.; Vero, R.; Fournier, K.; Soukhanovskii, V.; Menard, J.; Bell, M.; Bell, R.; Efthimion, P.; Kaye, S.; Leblanc, B.; Mueller, P.; Synakowski, E.; Maingi, R.; Houlberg, W.

    2001-10-01

    Three arrays of absolute photodiodes and several calibrated spectrometers measure the emission profiles and impurity spectra in the ultrasoft and soft X-ray range in NSTX. A multilayer mirror array for C VI Ly-alpha was also recently installed. Impurity density profiles are estimated by modeling these data with an atomic physics and impurity transport computational package. Many ohmic discharges show evidence for strong impurity peaking, which is reduced by either sawtooth crashes or early Reconnection Events. The peaking is associated with strong 1/1 activity. Peripheral impurity accumulation and cold island formation are observed in ELM-free H-modes.The profiles in center-stack -limited NBI discharges on the other hand, exhibit a pronounced 'well' at r/a <0.5-0.6. Modeling this profile requires a discontinuity in the core particle transport, suggesting the existence of a 'natural' internal barrier. Sheared MHD rotation is often observed at the radius of this discontinuity. Neon injection experiments were performed for a preliminary quantitative estimate of the impurity transport. The time-dependent simulation of the Ne profiles seems to support a large decrease in particle diffusion at about mid-radius. Comparison with neo-classical predictions will be discussed. *Work supported by DoE grant No. DE-FG02-99ER54523

  20. 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