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Sample records for pharmaceutical genotoxic impurities

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

    PubMed

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

    2010-04-01

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

  2. A simple and sensitive method to analyze genotoxic impurity hydrazine in pharmaceutical materials.

    PubMed

    Wang, Jenny; Yang, Samuel; Zhang, Kelly

    2016-07-15

    Hydrazine (N2H4) is a known genotoxic impurity that typically needs to be controlled down to low ppm level in pharmaceutical development. Hydrazine, however, is a challenging molecule to analyze using conventional analytical techniques due to its physical and chemical properties (e.g. lack of chromophore, absence of any carbon atom, low molecular weight, high polarity and volatility). Additionally, analysis in pharmaceutical samples commonly encounters significant interference from matrix components that greatly overshadow the response of hydrazine. This work describes a simple, accurate and sensitive reversed-phase liquid chromatography-UV derivatization method for determination of trace amount hydrazine in pharmaceutical materials featuring three prominent strategies to address the problems associated with hydrazine analysis. First, the derivatization reaction attaches chromophores to hydrazine, which greatly increases its sensitivity by UV-vis detection. Secondly, the derivatization reaction generates a lambda max that is well-shifted away from the absorption wavelengths of pharmaceutical matrix interferences. Thirdly, from a separation standpoint, the derivatization further removes matrix interference effects through chromatography by achieving higher resolution of the derivative product from the active pharmaceutical ingredient (API) and its related impurities for accurate quantitation for trace level of genotoxic impurities (GTIs). 2-Hydroxy-1-Naphthalaldehyde (HNA) was chosen as the derivatizing reagent, and the resulting hydrazone product has a maximum UV absorbance at wavelength of 406/424nm which is in the visible range. Since most drug substance and impurities have UV absorbance ranging from 190 to 380nm, interference from the matrix was minimized and the appropriate selectivity was obtained, the detection limit is 0.25ppm (0.25μg/g API). This method was validated and applied as a generic method to determine hydrazine for pharmaceutical process control

  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. PMID:27311479

  4. Matrix deactivation: A general approach to improve stability of unstable and reactive pharmaceutical genotoxic impurities for trace analysis.

    PubMed

    Sun, Mingjiang; Bai, Lin; Terfloth, Gerald J; Liu, David Q; Kord, Alireza S

    2010-05-01

    Trace analysis of unstable and reactive pharmaceutical genotoxic impurities (GTIs) is a challenging task in pharmaceutical analysis. Many method issues such as insufficient sensitivity, poor precision, and unusual (too high/low) spiking recovery are often directly related to analytes' instability. We report herein a matrix deactivation approach that chemically stabilizes these analytes for analytical method development. In contrast to the conventional chemical derivatization approach where the analytes are transformed into stable detectable species, the matrix deactivation approach chemically deactivates the hypothetical reactive species in the sample matrix. The matrix deactivation approach was developed on the premise that the instability of certain analytes at trace level is caused by reactions between the analytes and low level reactive species in the sample matrix. Thus, quenching the reactivity of the reactive species would be a key to stabilizing the unstable and reactive analytes. For example, electrophilic alkylators could be destabilized by nucleophiles or bases through either nucleophilic substitution or elimination reactions. One way to mask those reactive species is via protonation by adding acids to the diluent. Alternatively, one can use nucleophile scavengers to deplete reactive unknown species in the sample matrix completely, in analogy to the use of antioxidants and metal chelators to prevent oxidation in the analysis of compounds liable to oxidation. This paper reports the application of the matrix deactivation to the analyses of unstable and reactive pharmaceutical genotoxic impurities. Some of the methods have been used to support development of manufacturing processes for drug substances and a recent regulatory filing. PMID:20036478

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

    PubMed

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

    2008-08-01

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

  6. 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. PMID:25921639

  7. Analytical advances in pharmaceutical impurity profiling.

    PubMed

    Holm, René; Elder, David P

    2016-05-25

    Impurities will be present in all drug substances and drug products, i.e. nothing is 100% pure if one looks in enough depth. The current regulatory guidance on impurities accepts this, and for drug products with a dose of less than 2g/day identification of impurities is set at 0.1% levels and above (ICH Q3B(R2), 2006). For some impurities, this is a simple undertaking as generally available analytical techniques can address the prevailing analytical challenges; whereas, for others this may be much more challenging requiring more sophisticated analytical approaches. The present review provides an insight into current development of analytical techniques to investigate and quantify impurities in drug substances and drug products providing discussion of progress particular within the field of chromatography to ensure separation of and quantification of those related impurities. Further, a section is devoted to the identification of classical impurities, but in addition, inorganic (metal residues) and solid state impurities are also discussed. Risk control strategies for pharmaceutical impurities aligned with several of the ICH guidelines, are also discussed. PMID:26690047

  8. Fast identification of selective resins for removal of genotoxic aminopyridine impurities via screening of molecularly imprinted polymer libraries.

    PubMed

    Kecili, Rustem; Billing, Johan; Nivhede, David; Sellergren, Börje; Rees, Anthony; Yilmaz, Ecevit

    2014-04-25

    This study describes the identification and evaluation of molecularly imprinted polymers (MIPs) for the selective removal of potentially genotoxic aminopyridine impurities from pharmaceuticals. Screening experiments were performed using existing MIP resin libraries to identify resins selective towards those impurities in the presence of model pharmaceutical compounds. A hit resin with a considerable imprinting effect was found in the screening and upon further investigation, the resin was found to show a broad selectivity towards five different aminopyridines in the presence of the two model active pharmaceutical ingredients (APIs) piroxicam and tenoxicam. PMID:24661866

  9. 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

  10. 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

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

    PubMed

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

    2007-06-28

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

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

    PubMed Central

    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. PMID:25550941

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

    PubMed

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

    2015-01-01

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

  14. Potentials and mechanisms of genotoxicity of six pharmaceuticals frequently detected in freshwater environment.

    PubMed

    Liu, Xiaoshan; Lee, Jinyoung; Ji, Kyunghee; Takeda, Shunichi; Choi, Kyungho

    2012-05-20

    Genotoxic potentials and the mechanisms of six pharmaceuticals, which are frequently detected in surface water worldwide, were investigated using isogenic chicken DT40 mutant cell lines. These pharmaceuticals include erythromycin, sulfamethazine, sulfathiazole, chlortetracycline, oxytetracycline, and diclofenac. The genotoxic effects of these pharmaceuticals were determined based on growth kinetics of several mutant cell lines. Genotoxic chemicals were expected to decrease the growth kinetics in at least one of the mutants more significantly than DNA-repair-proficient wild-type cells. The test pharmaceuticals sensitized the cells deficient in homologous recombination (HR) repair (RAD54⁻/⁻), nucleotide excision repair (XPA⁻/), or translesion DNA synthesis (REV3⁻/⁻), suggesting that these pharmaceuticals may induce bulky adducts covalently bound to duplex DNA, like ultraviolet (UV) light. Genotoxicity was confirmed again by analyzing chromosome aberrations (CAs) and γ-H2AX foci in both wild-type and the susceptible mutants (i.e., RAD54⁻/⁻ and XPA⁻/) following the exposure to all the test pharmaceuticals except for erythromycin. The data indicate that these pharmaceuticals induce the DNA damages that stall DNA replication, leading to chromosomal breaks as well as translesion DNA synthesis mediated mutagenesis in DT40 cells. PMID:22450446

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

    PubMed

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

    2016-01-01

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

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

    PubMed

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

    2016-09-10

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

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

    PubMed

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

    2010-01-01

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

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

    PubMed

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

    2014-12-01

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

  19. 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. PMID:26436477

  20. 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. PMID:26452655

  1. 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. PMID:16213548

  2. 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

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

    PubMed

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

    2016-10-14

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

  4. HILIC-MS Determination of Genotoxic Impurity of 2-Chloro-N-(2-Chloroethyl)Ethanamine in the Vortioxetine Manufacturing Process.

    PubMed

    Douša, Michal; Klvaňa, Robert; Doubský, Jan; Srbek, Jan; Richter, Jindřich; Exner, Marek; Gibala, Petr

    2016-02-01

    In the last decade, pharmaceutical regulatory agencies are focused on monitoring and evaluation of trace-level genotoxic impurities (GTIs) in drug substances, which requires manufacturers to deliver innovative approaches for their analysis and control. GTIs in the low p.p.m. level rising from the process of drug production have to be positively identified and quantified. Therefore, sensitive and selective analytical methods are necessary for required quantification level of these GTIs. Unfortunately, general guidance on how to develop strategy of the analysis and control of GTIs is currently missing in the pharmaceutical industry. Therefore, practical example of the analytical control of 2-chloro-N-(2-chloroethyl)ethanamine GTI in the vortioxetine (VOR) manufacturing process was demonstrated in this work. QDa mass detection with electrospray ionization in selected-ion recording mode was utilized for quantitation of GTIs. The method of hydrophilic interaction liquid chromatography coupled with mass spectrometry detection (HILIC-MS) was validated as per International Conference on Harmonization guidelines and was able to quantitate GTIs at 75 p.p.m. with respect to VOR. The HILIC-MS method was achieved using a Primesep B column (150 × 4.6 mm, 5.0 µm; Sielc, USA) using mobile phase consisting of 10 mM ammonium formate buffer pH 3.0 and acetonitrile (5 : 95, v/v) at 0.8 mL/min flow rate. The QDa mass detector was operated in the positive ion mode. Quadrupole mass analyzer was employed in selected-ion monitoring mode using target ion at m/z 142 as [M+H](+). PMID:26223463

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

    PubMed

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

    2015-09-18

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

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

    PubMed

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

    2014-01-01

    In recent years, the use of halogen-containing molecules has proliferated in the pharmaceutical industry, where the incorporation of halogens, especially fluorine, has become vitally important for blocking metabolism and enhancing the biological activity of pharmaceuticals. The chromatographic separation of halogen-containing pharmaceuticals from associated isomers or dehalogenation impurities can sometimes be quite difficult. In an attempt to identify the best current tools available for addressing this important problem, a survey of the suitability of four chromatographic method development platforms (ultra high-performance liquid chromatography (UHPLC), core shell HPLC, achiral supercritical fluid chromatography (SFC) and chiral SFC) for separating closely related mixtures of halogen-containing pharmaceuticals and their dehalogenated isosteres is described. Of the 132 column and mobile phase combinations examined for each mixture, a small subset of conditions were found to afford the best overall performance, with a single UHPLC method (2.1 × 50 mm, 1.9 μm Hypersil Gold PFP, acetonitrile/methanol based aqueous eluents containing either phosphoric or perchloric acid with 150 mM sodium perchlorate) affording excellent separation for all samples. Similarly, a survey of several families of closely related halogen-containing small molecules representing the diversity of impurities that can sometimes be found in purchased starting materials for synthesis revealed chiral SFC (Chiralcel OJ-3 and Chiralpak IB, isopropanol or ethanol with 25 mM isobutylamine/carbon dioxide) as well as the UHPLC (2.1 × 50 mm, 1.8 μm ZORBAX RRHD Eclipse Plus C18 and the Gold PFP, acetonitrile/methanol based aqueous eluents containing phosphoric acid) as preferred methods. PMID:24359254

  7. 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. PMID:27020927

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

    PubMed

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

    2016-02-01

    An important step during the development of high-performance liquid chromatography (HPLC) methods for quantitative analysis of drugs is choosing the appropriate detector. High sensitivity, reproducibility, stability, wide linear range, compatibility with gradient elution, non-destructive detection of the analyte and response unaffected by changes in the temperature/flow are some of the ideal characteristics of a universal HPLC detector. Topiramate is an anticonvulsant drug mainly used for the treatment of different types of seizures and prophylactic treatment of migraine. Different analytical approaches to quantify topiramate by HPLC have been described because of the lack of chromophoric moieties on its structure, such as derivatization with fluorescent moieties and UV-absorbing moieties, conductivity detection, evaporative light scattering detection, refractive index detection, chemiluminescent nitrogen detection and MS detection. Some methods for the determination of topiramate by capillary electrophoresis and gas chromatography have also been published. This systematic review provides a description of the main analytical methods presented in the literature to analyze topiramate in the drug substance and in pharmaceutical formulations. Each of these methods is briefly discussed, especially considering the detector used with HPLC. In addition, this article presents a review of the data available regarding topiramate stability, degradation products and impurities. PMID:26276847

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

    PubMed

    Thummala, Veera Raghava Raju; Lanka, Mohana Krishna

    2015-10-01

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

  10. Analysis of pharmaceutical impurities using multi-heartcutting 2D LC coupled with UV-charged aerosol MS detection.

    PubMed

    Zhang, Kelly; Li, Yi; Tsang, Midco; Chetwyn, Nik P

    2013-09-01

    To overcome challenges in HPLC impurity analysis of pharmaceuticals, we developed an automated online multi-heartcutting 2D HPLC system with hyphenated UV-charged aerosol MS detection. The first dimension has a primary column and the second dimension has six orthogonal columns to enhance flexibility and selectivity. The two dimensions were interfaced by a pair of switching valves equipped with six trapping loops that allow multi-heartcutting of peaks of interest in the first dimension and also allow "peak parking." The hyphenated UV-charged aerosol MS detection provides comprehensive detection for compounds with and without UV chromophores, organics, and inorganics. It also provides structural information for impurity identification. A hidden degradation product that co-eluted with the drug main peak was revealed by RP × RP separation and thus enabled the stability-indicating method development. A poorly retained polar component with no UV chromophores was analyzed by RP × hydrophilic interaction liquid chromatography separation with charged aerosol detection. Furthermore, using this system, the structures of low-level impurities separated by a method using nonvolatile phosphate buffer were identified and tracked by MS in the second dimension. PMID:23821312

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

    PubMed

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

    2016-01-01

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

  12. 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

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

    PubMed

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

    2015-10-14

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

  14. Human mesenchymal stem cells as a novel platform for simultaneous evaluation of cytotoxicity and genotoxicity of pharmaceuticals.

    PubMed

    Sharma, Shikha; Venkatesan, Vijayalakshmi; Prakhya, Balakrishna Murthy; Bhonde, Ramesh

    2015-05-01

    The in vitro micronucleus test is a well-known test for the screening of genotoxic compounds. However until now, most studies have been performed on either human peripheral lymphocytes or established cancer cell lines. This study provides human mesenchymal stem cells as an alternative to the conventional micronucleus test. We grew umbilical cord mesenchymal stem cells (UC-MSCs) on coverslips eliminating the cumbersome technique involving hypotonic treatment, fixation and preparing smears required for suspension culture (lymphocytes). The background frequency of nuclear blebs and micronuclei in UC-MSCs was found to be 7±5, in lymphocytes 16±3.5 and 9±3 and that for A549 cell line was 65±5 and 15±5 per 1000 cells, respectively, suggesting differences in the repair mechanism of normal and cancer cell lines. We inspected the cytotoxic and genotoxic effects of two known mutagens, mitomycin-C and hydrogen peroxide (H2O2), on UC-MSCs, lymphocytes and A549 cells. Treatment with mitomycin-C and H2O2 demonstrated drastic differences in the degree of cytotoxicity and genotoxicity suggesting a constitutional difference between normal and cancer cells. In addition we tested two solvents, dimethyl sulfoxide (DMSO) and ethanol, and two drugs, metformin and rapamycin. DMSO above 1% was found to be cytotoxic and genotoxic, whereas ethanol at same concentration was neither cytotoxic nor genotoxic indicating the minimal non-toxic level of the solvents. This study thus offers UC-MSCs as a better substitute to peripheral lymphocytes and cancer cell lines for high throughput screening of compounds and reducing the animal studies. PMID:25552518

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

    PubMed

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

    2016-09-01

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

  16. 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

  17. Selective extraction of genotoxic impurities and structurally alerting compounds using polymeric ionic liquid sorbent coatings in solid-phase microextraction: Alkyl halides and aromatics.

    PubMed

    Ho, Tien D; Joshi, Manishkumar D; Silver, Mark A; Anderson, Jared L

    2012-06-01

    A series of polymeric ionic liquids (PILs) possessing varied chemical makeup and composition were applied as selective solid-phase microextraction (SPME) sorbent coatings for the analysis of genotoxic impurities (GTIs) and related structurally alerting compounds, namely, alkyl halides and aromatics. In addition to exploiting two previously synthesized PILs as selective coatings, two new PILs, namely, N,N-didecyl-N-methyl-D-glucaminium poly(2-methyl-acrylic acid 2-[1-(3-{2-[2-(3-trifluoromethanesulfonylamino-propoxy)-ethoxy]-ethoxy}-propylamino)-vinylamino]-ethyl ester) (poly([DDMGlu][MTFSI])), and poly(1-vinyl-3-propylphenylimidazolium) chloride (poly([VPPIM][Cl])), were designed, synthesized, and their selectivity examined in the extraction of the selected analytes. The glucaminium-based coating was developed to exploit the hydrogen bond-acidic hydroxyl groups within the carbohydrate moiety of the PIL in addition to dispersive capabilities resulting from the cation and anion. The poly([VPPIM][Cl]) coating was tailored to possess π-π interaction capabilities through the phenyl functionality while also containing the hydrogen bond-basic chloride anion. Calibration studies were performed via headspace extraction to determine the sensitivity and limit of detection (LOD) for all analytes with respect to each PIL-based sorbent coating and compared to the polyacrylate (PA) and polydimethylsiloxane (PDMS) sorbent coatings. PILs containing the chloride anion exhibited high selectivity for aniline-based compounds. The glucaminium-based PIL exhibited good sensitivity for larger aliphatic alkyl halides. The poly(1-4-vinylbenzyl-3-hexadecylimidazolium) bis[(trifluoromethyl)sulfonyl] imide (poly([VBHDIM][NTf₂])) PIL coating demonstrated superior selectivity for larger aliphatic/aromatic analytes. The LODs of both commercial and PIL-based coatings for the two classes of GTIs ranged from low part-per-billion (ppb) to mid part-per-trillion (ppt) levels. Recovery studies were

  18. 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. PMID:24667566

  19. 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

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

    PubMed

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

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

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

    PubMed

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

    2015-05-01

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

  2. 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. PMID:26845202

  3. Different sample stacking strategies for the determination of ertapenem and its impurities by micellar electrokinetic chromatography in pharmaceutical formulation.

    PubMed

    Michalska, Katarzyna; Pajchel, Genowefa; Tyski, Stefan

    2009-04-01

    Ertapenem, a Group 1 carbapenem, is most recently introduced into the market. It is a beta-lactam antibiotic that possesses a broad antibacterial spectrum including common community-acquired Gram-positive and Gram-negative aerobic and anaerobic pathogens, but low activity against some nosocomial pathogens such as Pseudomonas aeruginosa, Acinetobacter spp., enterococci and methicillin-resistant staphylococci. The elaborated method of micellar electrokinetic chromatography (MEKC) of ertapenem separation from its impurities was successfully performed using normal stacking mode (NSM) and stacking with reverse migrating micelles (SRMM), followed by UV absorption detection at 214 nm. The best results were obtained with 60mM sodium dihydrogen phosphate and 20mM boric acid buffer pH 6.0, as background electrolyte. Uncoated fused-silica capillary and neutral-coated capillary with normal and reverse polarity, and voltage values of +18 and -12 kV, respectively, were used throughout the investigation. Sodium dodecyl sulfate was employed as the pseudostationary phase. A comparison of applied techniques, including sensitivity enhancement factors and limits of detection (LOD), is presented. The optimized method was validated in terms of linearity, accuracy and precision. Comparable LOD was obtained using both stacking methods (0.3 microg/mL) but better efficiency of ertapenem peak was obtained using NSM. Under the optimum stacking conditions, about 183-4.75-fold and 1289-4.07-fold improvements in peak areas were obtained for NSM and SRMM, respectively, compared to the usual hydrodynamic sample injection (10s). The reproducibility, expressed by relative standard deviations (RSD) of the migration times, for NSM was about 0.96-1.25 and for SRMM was 0.32-0.45. The RSD of corrected peak areas, for NSM was about 1.07-8.14 and for SRMM was 0.74-8.12. The difference in separation time between the two techniques was not obvious. Satisfactory separation was possible after less than 11min

  4. 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

    2012-03-01

    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. PMID:22178334

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

    PubMed

    Brigo, Alessandro; Muster, Wolfgang

    2016-01-01

    The present contribution describes how in silico models are applied at different stages of the drug discovery process in the pharmaceutical industry. A thorough description of the most relevant computational methods and tools is given along with an in-depth evaluation of their performance in the context of potential genotoxic impurities assessment.The challenges of predicting the outcome of highly complex studies are discussed followed by considerations on how novel ways to manage, store, share and analyze data may advance knowledge and facilitate modeling efforts. PMID:27311478

  6. 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.

  7. 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.

  8. 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. PMID:24673907

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

    PubMed

    Jain, Deepti; Basniwal, Pawan Kumar

    2013-12-01

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

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

    PubMed

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

    2015-10-01

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

  11. Identification, Characterization, Synthesis and Quantification of Related Impurities of Liguzinediol.

    PubMed

    Cheng, Dong; Zhou, Ying; Li, Wei; Shan, Chen-Xiao; Chai, Chuan; Cui, Xiao-Bing; Kang, Bi; Wang, Tian-Lin; Wen, Hong-Mei

    2015-09-01

    An HPLC method was employed to create an impurity profile for liguzinediol as an active pharmaceutical ingredient (API), which resulted in the identification of two related impurities. Therefore, in order to improve the quality control of the liguzinediol-API, we identified and then developed a method for quantifying the two impurities (impurity-1 and impurity-2) by LC-TOF-MS-MS and then chemically synthesized them for further studies. Based on spectral data from IR, MS, (1)H and (13)C NMR, the structures of impurity-1 and impurity-2 were characterized as 2-hydroxymethyl-3,6-dimethylpyrazine and 2-hydroxymethyl-3,5,6-trimethylpyrazine, respectively. We further validated the method according to the International Conference on Harmonization guidelines to demonstrate the sensitivity, precision, linearity, accuracy and stability of the method described. In addition, the potential mechanisms underlying formation of impurity-1 and impurity-2 in the liguzinediol-API are discussed in detail. PMID:25680683

  12. 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.

  13. 77 FR 33748 - International Conference on Harmonisation; Guidance on S2(R1) Genotoxicity Testing and Data...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-06-07

    .... In the Federal Register of March 26, 2008 (73 FR 16024), FDA published a notice announcing the... Regulatory Genotoxicity Tests for Pharmaceuticals'' and ``S2B Genotoxicity: A Standard Battery for... guidance on optimizing the standard genetic toxicology battery for prediction of potential human risks,...

  14. 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

  15. Genotoxicity of phthalates.

    PubMed

    Erkekoglu, Pınar; Kocer-Gumusel, Belma

    2014-12-01

    Many of the environmental, occupational and industrial chemicals are able to generate reactive oxygen species (ROS) and cause oxidative stress. ROS may lead to genotoxicity, which is suggested to contribute to the pathophysiology of many human diseases, including inflammatory diseases and cancer. Phthalates are ubiquitous environmental chemicals and are well-known peroxisome proliferators (PPs) and endocrine disruptors. Several in vivo and in vitro studies have been conducted concerning the carcinogenic and mutagenic effects of phthalates. Di(2-ethylhexyl)-phthalate (DEHP) and several other phthalates are shown to be hepatocarcinogenic in rodents. The underlying factor in the hepatocarcinogenesis is suggested to be their ability to generate ROS and cause genotoxicity. Several methods, including chromosomal aberration test, Ames test, micronucleus assay and hypoxanthine guanine phosphoribosyl transferase (HPRT) mutation test and Comet assay, have been used to determine genotoxic properties of phthalates. Comet assay has been an important tool in the measurement of the genotoxic potential of many chemicals, including phthalates. In this review, we will mainly focus on the studies, which were conducted on the DNA damage caused by different phthalate esters and protection studies against the genotoxicity of these chemicals. PMID:25174766

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

    PubMed

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

    2013-10-01

    Genotoxicity hazard identification is part of the impurity qualification process for drug substances and products, the first step of which being the prediction of their potential DNA reactivity using in silico (quantitative) structure-activity relationship (Q)SAR models/systems. This white paper provides information relevant to the development of the draft harmonized tripartite guideline ICH M7 on potentially DNA-reactive/mutagenic impurities in pharmaceuticals and their application in practice. It explains relevant (Q)SAR methodologies as well as the added value of expert knowledge. Moreover, the predictive value of the different methodologies analyzed in two surveys conveyed in the US and European pharmaceutical industry is compared: most pharmaceutical companies used a rule-based expert system as their primary methodology, yielding negative predictivity values of ⩾78% in all participating companies. A further increase (>90%) was often achieved by an additional expert review and/or a second QSAR methodology. Also in the latter case, an expert review was mandatory, especially when conflicting results were obtained. Based on the available data, we concluded that a rule-based expert system complemented by either expert knowledge or a second (Q)SAR model is appropriate. A maximal transparency of the assessment process (e.g. methods, results, arguments of weight-of-evidence approach) achieved by e.g. data sharing initiatives and the use of standards for reporting will enable regulators to fully understand the results of the analysis. Overall, the procedures presented here for structure-based assessment are considered appropriate for regulatory submissions in the scope of ICH M7. PMID:23669331

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

    PubMed

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

    2013-01-01

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

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

    PubMed Central

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

    2013-01-01

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

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

    PubMed Central

    Jamrógiewicz, Marzena

    2016-01-01

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

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

    PubMed

    Jamrógiewicz, Marzena

    2016-01-01

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

  1. 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

  2. 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. PMID:26929995

  3. Genotoxicity of glycol ethers.

    PubMed Central

    McGregor, D B

    1984-01-01

    The genetic toxicology of glycol ethers is reviewed. Ethylene glycol monomethyl ether (EGME) and diglyme have been more extensively studied than other members of this series. Most results indicate a lack of genotoxic potential, but certain tests have yielded positive responses with certain compounds. Ethylene glycol monoethyl ether (EGEE) induced sister chromatid exchanges and chromosomal aberrations in cultured cells. Both EGME and diglyme induced mouse sperm head morphological changes, male rat weak dominant lethal mutations and marked, but reversible, loss of male rat fertility. PMID:6541999

  4. Indirect mechanisms of genotoxicity.

    PubMed

    Kirsch-Volders, Micheline; Vanhauwaert, Annelies; Eichenlaub-Ritter, Ursula; Decordier, Ilse

    2003-04-11

    Indirect mechanisms of genotoxicity correspond to interactions of mutagens with non-DNA targets, and are expected to show threshold concentration-effect response curves. If these thresholds can be proven experimentally they may provide a third alternative for risk assessment, besides the No Effect Level/Safety Factor approach and the low dose linear extrapolation method. We contributed significantly to the in vitro assessment of thresholds in human lymphocytes exposed to the spindle inhibitors nocodazole and carbendazim showing dose dependency and existence of lower thresholds for induction of non-disjunction as compared to chromosome loss. Micronuclei correlated with p53-independent or p53-dependent apoptosis and elimination of aneuploid cells. Extrapolation from in vitro threshold values to the in vivo situation remains unsolved. Comparing the in vitro threshold values for griseofulvin in human and rat lymphocytes with in vivo NOAEL/LOAEL in bone marrow/gut/erythrocytes suggests that the in vitro human system is the most sensitive. The threshold for induction of non-disjunction in in vitro maturing, nocodazole-exposed mouse oocytes was in the same low range. Regulators (UK Committee on Mutagenicity, http://www.doh.gov.uk/com/com.htm) considered the importance of thresholds for indirect mechanisms of genotoxicity. Acceptance of a non-linear extrapolation for mutagens requires mechanistic studies identifying the mutagen/target interactions. Moreover appropriate risk evaluation will require additional studies on individual susceptibility for indirect mutagenic effects and on interactions of aneugens in complex mixtures. PMID:12676452

  5. 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.

  6. The genotoxicity of selenium.

    PubMed

    Shamberger, R J

    1985-07-01

    Selenium at nutritional levels has been shown to have numerous anticarcinogenic or preventative effects against carcinogen-induced breast, colon, liver and skin cancer in animals. Many of these anticarcinogenic effects have been summarized. In addition, numerous mutagenic and antimutagenic effects of selenium compounds have been reported. Some of the selenium compounds frequently tested for mutagenicity are listed in Table 1. Because of the numerous reported anticarcinogenic and preventative effects of selenium, many individuals are supplementing their diets with amounts of selenium that are greater than the recommended daily requirement. Selenium is also used widely in industrial products such as selenium rectifiers, photoelectric batteries, alloys and paints. Because selenium at higher levels is known to be toxic, there should be a greater understanding about its genotoxic as well as its beneficial effect. The object of this review is to summarize experimental evidence both for the antimutagenic and the mutagenic effect of selenium. PMID:3923345

  7. Mild Pd-catalyzed N-arylation of methanesulfonamide and related nucleophiles: avoiding potentially genotoxic reagents and byproducts.

    PubMed

    Rosen, Brandon R; Ruble, J Craig; Beauchamp, Thomas J; Navarro, Antonio

    2011-05-20

    A convenient, general, and high yielding Pd-catalyzed cross-coupling of methanesulfonamide with aryl bromides and chlorides is reported. The use of this method eliminates concern over genotoxic impurities that can arise when an aniline is reacted with methanesulfonyl chloride. The application of this method to the synthesis of dofetilide is also reported. PMID:21510692

  8. A review of the nonclinical safety of Transcutol®, a highly purified form of diethylene glycol monoethyl ether (DEGEE) used as a pharmaceutical excipient.

    PubMed

    Sullivan, Dexter W; Gad, Shayne C; Julien, Marjorie

    2014-10-01

    Transcutol® (Diethylene glycol monoethyl ether, DEGEE), CAS # 111-90-0, is commonly used as a vehicle in the formulation or manufacturing process of pharmaceuticals, cosmetics, and food additives. This paper presents unpublished nonclinical safety data using a form of DEGEE which includes a significantly decreased level of impurities, specifically ethylene glycol and diethylene glycol. It also reviews the history of use, regulatory status, and previously published toxicity data for DEGEE. The review supports that DEGEE is well tolerated across animal species and gender with toxicity occurring only at levels well above those intended for human use. At high levels of exposure, the kidney is identified as the critical target organ of DEGEE toxicity. DEGEE is negative for genotoxicity in in vitro and in vivo studies. Subchronic and chronic toxicity studies produced no reports of preneoplastic changes in organs, but the animal data is insufficient to allow a definitive opinion as to carcinogenicity. In silico data suggested that DEGEE is not carcinogenic or genotoxic. Developmental toxicity was seen in rats but only at levels 200 times greater than the estimated oral Permissible Daily Exposure Level of 10 mg/kg/day. The nonclinical data along with the long history of DEGEE use as a vehicle and solvent by multiple routes provide evidence of its safety. Furthermore, the novel data discussed herein provides evidence that toxicity previously associated with high levels of DEGEE in nonclinical studies conducted prior to 1990 could possibly be attributed to the presence of significant amounts of ethylene glycol or other impurities. PMID:25016034

  9. Genotoxicity of pyrrolizidine alkaloids.

    PubMed

    Chen, Tao; Mei, Nan; Fu, Peter P

    2010-04-01

    Pyrrolizidine alkaloids (PAs) are common constituents of many plant species around the world. PA-containing plants are probably the most common poisonous plants affecting livestock and wildlife. They can inflict harm to humans through contaminated food sources, herbal medicines and dietary supplements. Half of the identified PAs are genotoxic and many of them are tumorigenic. The mutagenicity of PAs has been extensively studied in different biological systems. Upon metabolic activation, PAs produce DNA adducts, DNA cross-linking, DNA breaks, sister chromatid exchange, micronuclei, chromosomal aberrations, gene mutations and chromosome mutations in vivo and in vitro. PAs induced mutations in the cII gene of rat liver and in the p53 and K-ras genes of mouse liver tumors. It has been suggested that all PAs produce a set of (+/-)-6,7-dihydro-7-hydroxy-1-hydroxymethyl-5H-pyrrolizine-derived DNA adducts and similar types of gene mutations. The signature types of mutations are G : C --> T : A transversion and tandem base substitutions. Overall, PAs are mutagenic in vivo and in vitro and their mutagenicity appears to be responsible for the carcinogenesis of PAs. PMID:20112250

  10. Genotoxicity and anti-genotoxicity of some traditional medicinal herbs.

    PubMed

    Romero-Jiménez, Magdalena; Campos-Sánchez, Juan; Analla, Mohamed; Muñoz-Serrano, Andrés; Alonso-Moraga, Angeles

    2005-08-01

    Six herbal infusions used worldwide (Matricaria chamomilla, Tilia cordata, Mentha piperita, Mentha pulegium, Uncaria tomentosa and Valeriana officinalis) were assayed for anti-genotoxicity using the Somatic Mutation And Recombination Test (SMART) in Drosophila melanogaster. All these infusions are traditionally used for various medical purposes, including anti-inflammatory processes. Hydrogen peroxide was used as an oxidative genotoxicant to test the anti-genotoxic potency of the medicinal infusions. None of these infusions showed a significant genotoxicity, quite the reverse they were able to behave as desmutagens, detoxifying the mutagen hydrogen peroxide. The phenolic content of such herbal infusions is argued to be the possible scavenger of reactive oxygen radicals produced by the hydrogen peroxide. PMID:16005256

  11. 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

  12. Genotoxicity of Endodontic Materials: A Critical Review.

    PubMed

    Mohammadi, Zahed; Shalavi, Sousan; Jafarzadeh, Hamid; Bhandi, Shilpa; Patil, Shankargouda

    2015-08-01

    Genotoxicity is an action on cell's genetic material which may affect its integrity. This includes certain types of radiations and also certain chemical compounds. Genotoxic materials are those with affinity to interact with DNA but render them potentially carcinogenic or mutagenic. This review will address the genotoxicity of endodontic irrigants, medicaments and sealers. PMID:26423507

  13. 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...

  14. 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.

  15. 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.

  16. Pharmaceutical Analysis as a Branch of Pharmaceutics

    ERIC Educational Resources Information Center

    Connors, Kenneth A.

    1977-01-01

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

  17. Impurity control in TFTR

    SciTech Connect

    Cecchi, J.L.

    1980-06-01

    The control of impurities in TFTR will be a particularly difficult problem due to the large energy and particle fluxes expected in the device. As part of the TFTR Flexibility Modification (TEM) project, a program has been implemented to address this problem. Transport code simulations are used to infer an impurity limit criterion as a function of the impurity atomic number. The configurational designs of the limiters and associated protective plates are discussed along with the consideration of thermal and mechanical loads due to normal plasma operation, neutral beams, and plasma disruptions. A summary is given of the materials-related research, which has been a collaborative effort involving groups at Argonne National Laboratory, Sandia Laboratories, and Princeton Plasma Physics Laboratory. Conceptual designs are shown for getterng systems capable of regenerating absorbed tritium. Research on this topic by groups at the previously mentioned laboratories and SAES Research Laboratory is reviewed.

  18. Dynamical impurity problems

    SciTech Connect

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

    1993-12-31

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

  19. 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

  20. 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.

  1. Quasiparticle interference from magnetic impurities

    NASA Astrophysics Data System (ADS)

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

    2015-07-01

    Fourier transform scanning tunneling spectroscopy (FT-STS) measures the scattering of conduction electrons from impurities and defects, giving information about the electronic structure of both the host material and adsorbed impurities. We interpret such FT-STS measurements in terms of the quasiparticle interference (QPI), here investigating in detail the QPI due to single magnetic impurities adsorbed on a range of representative nonmagnetic host surfaces, and contrasting with the case of a simple scalar impurity or point defect. We demonstrate how the electronic correlations present for magnetic impurities markedly affect the QPI, showing, e.g., a large intensity enhancement due to the Kondo effect, and universality at low temperatures/scanning energies. The commonly used joint density of states interpretation of FT-STS measurements is also considered, and shown to be insufficient in many cases, including that of magnetic impurities.

  2. Genotoxicity of streptonigrin: a review.

    PubMed

    Bolzán, A D; Bianchi, M S

    2001-03-01

    Streptonigrin (SN, CAS no. 3930-19-6) is an aminoquinone antitumor antibiotic isolated from cultures of Streptomyces flocculus. This compound is a member of a group of antitumor agents which possess the aminoquinone moiety and that includes also mitomycin C, porfiromycin, actinomycin, rifamycin and geldanamycin. Because of the potential use of SN in clinical chemotherapy, the study of its genotoxicity has considerable practical significance.SN inhibits the synthesis of DNA and RNA, causes DNA strand breaks after reduction with NADH, induces unscheduled DNA synthesis and DNA adducts and inhibits topoisomerase II. At the chromosome level, this antibiotic causes chromosome damage and increases the frequency of sister-chromatid exchanges.SN cleaves DNA in cell-free systems by a mechanism that involves complexing with metal ions and autoxidation of the quinone moiety to semiquinone in the presence of NADH with production of oxygen-derived reactive species. Recent evidence strongly suggests that the clastogenic action of this compound is partially mediated by free radicals. The present review aims at summarizing past and current knowledge concerning the genotoxic effects of SN. PMID:11223403

  3. Impurity profile of rifaximin produced in China.

    PubMed

    Liuchao; Maixi; Wangchao; Wan, Chunpeng

    2012-04-01

    Impurity profiles of rifaximin produced in China were investigated systematically by LCMS methods. Eleven impurities from the raw materials of rifaximin produced in China were detected. We adopted the Diagnostic fragment-ion-based extension strategy (DFIBES) for deducing the structure of unknown impurities. Impurity 1 was the 30-hydroxylated product of rifaximin. Impurity 2 was the 25-deacetyled rifaximin. Impurity 6 was the isomeride of rifaximin. Impurity 9 was rifamycin-O. PMID:22570932

  4. 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

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

    PubMed

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

    2016-09-01

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

  6. Impurity Extraction by Droplets

    NASA Technical Reports Server (NTRS)

    Morrison, G.; Kincaid, J. M.

    1985-01-01

    The goals are to model and to measure the phase equilibrium properties of a finely divided fluid containing a large number of chemically similar species. The objective is to develop an accurate, usable model for such phenomena as pollutant extraction of rain clouds, industrial separation in spray towers, and separation in emulsions. The project was designed as a hierarchy of complementary theoretical and experimental steps. A theory was developed to describe the segregation of complex impurities at the interface of a solvent. This phenomenon is important in phase behavior when a large fraction of molecules in a material are near an interface, the situation in a finely divided material. The theory will be modified to account for the effect of surface curvature on the surface tension. The study of mixtures differs from pure fluids not only because of the surface effects but also because composition differences between the droplet and the surrounding vapor can stabilize a droplet with respect to a bulk phase.

  7. The impurity of radioiodinated triolein

    PubMed Central

    Kennedy, J. A.; Kinloch, J. D.

    1964-01-01

    Commercially supplied radioiodinated triolein has been shown by thin-layer chromatography and silicic acid column chromatography to contain impurities, consisting mainly of diglycerides and monoglycerides, but also a small amount of free fatty acid. The effect of these impurities on the radioiodinated triolein absorption test requires further investigation. Images PMID:14149942

  8. 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.

  9. METABOLISM AND GENOTOXICITY OF 1-NITROPYRENE

    EPA Science Inventory

    1-Nitropyrene (NP), a nitrated polycyclic aromatic hydrocarbon and a potent bacterial mutagen, has been identified in combustion emissions and may contribute to the burden of genotoxicity associated with air pollution. NP undergoes rapid metabolism by rat hepatic subcellular frac...

  10. Pharmaceutical expenditure in Sweden.

    PubMed

    Henriksson, F; Hjortsberg, C; Rehnberg, C

    1999-05-01

    Recently, the responsibility for prescribed pharmaceuticals in Sweden was transferred from national level to the regional health authorities (county councils). The purpose was that a closer integration and balance between pharmaceuticals and other factors of production in health care should produce better opportunities for a cost-effective use of the total health care resources. The purpose of this paper is to present a deeper analysis of pharmaceuticals as a production factor in Sweden, mainly during the 1990s, and to discuss the future development and future policy decisions in Sweden. Pharmaceuticals have increased their share of total health care expenditure in Sweden, from about 9% in 1990 to about 14% in 1995. The Swedish pharmaceutical market can be divided into sub-markets, where the prescription sub-market accounts for the greater part of pharmaceutical expenditure. Further, a few disease categories account for a larger fraction of the cost of prescribed pharmaceuticals. The importance of pharmaceuticals as a production factor also differs between different age groups. Several factors are expected to contribute to a future increase in Swedish pharmaceutical expenditure, for instance an ageing population and the rapid introduction of expensive new pharmaceuticals. PMID:10538288

  11. Biological and Pharmaceutical Nanomaterials

    NASA Astrophysics Data System (ADS)

    Kumar, Challa S. S. R.

    2006-01-01

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

  12. 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.

  13. Impact of isomalathion on malathion cytotoxicity and genotoxicity in human HepaRG cells.

    PubMed

    Josse, Rozenn; Sharanek, Ahmad; Savary, Camille C; Guillouzo, Andre

    2014-02-25

    Isomalathion is a major impurity of technical grade malathion, one of the most abundantly applied insecticides; however little is known about its hepatotoxicity. In the present study, cytotoxicity and genotoxicity of malathion and isomalathion either individually or in combination, were assessed using the metabolically competent human liver HepaRG cell line. Isomalathion reduced cell viability starting at a 100 μM concentration after a 24h exposure. It also significantly induced caspase-3 activity in a dose-dependent manner starting at 5 μM. On the contrary, even at concentrations as high as 500 μM malathion affected neither cell viability nor caspase-3 activity. Moreover, co-exposure of both compounds resulted in decreased toxicity of isomalathion. By contrast, malathion and isomalathion either separately or in combination, slightly induced micronuclei formation at low concentrations and had additive genotoxic effects when combined at 25 μM. Individually or combined isomalathion directly inhibited activity of carboxyesterases which are involved in detoxication of malathion. In addition, transcripts of CYP2B6 and CYP3A4, two CYPs responsible for malathion phase I metabolism, were strongly induced by the mixture while isomalathion alone only moderately decreased CYP1A2 and increased CYP2B6 transcripts. However, these CYPs were not altered at the protein or activity levels. Taken altogether, our results showed that isomalathion was much more cytotoxic than malathion while both compounds had comparable genotoxic effects in HepaRG hepatocytes at low concentrations and brought further support to the importance of considering impurities and interactions during evaluation of health risks of pesticides. PMID:24333466

  14. 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. PMID:26891274

  15. 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.

  16. Herbicide and pharmaceutical relationships

    Technology Transfer Automated Retrieval System (TEKTRAN)

    For many years, virtually all pharmaceutical companies had an agrochemical division. This was partly to maximize the benefits of expensive chemical synthesis efforts by searching for many types of useful biological activities. Leads for pharmaceuticals and pesticides often overlap, in some cases l...

  17. Pharmaceutical Education in Poland

    ERIC Educational Resources Information Center

    Furmanowa, Miroslawa; Borke, Mitchell L.

    1978-01-01

    The content and organization of Poland's system of pharmaceutical education is described. Tables are presented of the subjects of the basic studies curriculum and the following areas of specialization: applied pharmacy, pharmaceutical analysis, clinical analysis, drug technology, herbal pharmacy, and bioanalysis and environmental studies. (SW)

  18. Genotoxic sensitivity of the developing hematopoietic system.

    PubMed

    Udroiu, Ion; Sgura, Antonella

    2016-01-01

    Genotoxic sensitivity seems to vary during ontogenetic development. Animal studies have shown that the spontaneous mutation rate is higher during pregnancy and infancy than in adulthood. Human and animal studies have found higher levels of DNA damage and mutations induced by mutagens in fetuses/newborns than in adults. This greater susceptibility could be due to reduced DNA repair capacity. In fact, several studies indicated that some DNA repair pathways seem to be deficient during ontogenesis. This has been demonstrated also in murine hematopoietic stem cells. Genotoxicity in the hematopoietic system has been widely studied for several reasons: it is easy to assess, deals with populations cycling also in the adults and may be relevant for leukemogenesis. Reviewing the literature concerning the application of the micronucleus test (a validated assay to assess genotoxicity) in fetus/newborns and adults, we found that the former show almost always higher values than the latter, both in animals treated with genotoxic substances and in those untreated. Therefore, we draw the conclusion that the genotoxic sensitivity of the hematopoietic system is more pronounced during fetal life and decreases during ontogenic development. PMID:27036061

  19. 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. PMID:26027494

  20. 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...

  1. Cytotoxic and genotoxic effects of in vitro exposure to triclosan and trimethoprim on zebra mussel (Dreissena polymorpha) hemocytes.

    PubMed

    Binelli, A; Cogni, D; Parolini, M; Riva, C; Provini, A

    2009-07-01

    Pharmaceuticals and personal care products (PPCPs) have been detected in several aquatic ecosystems for a number of years, but the potential for biological effects in exposed non-target organisms is only now being reported. In this study the potential cellular damage due to two of the main PPCPs found in aquatic environments was investigated by in vitro exposures. Hemolymph samples of the freshwater bivalve Dreissena polymorpha were collected and treated with increasing concentrations of the antibacterial agent Triclosan (TCS) and the antibiotic Trimethoprim (TMP). Doses selected for TCS were 0.1, 0.15, 0.2, and 0.3 microM, while 0.2, 1, and 5 microM for TMP exposures, respectively. We evaluated the potential genotoxicity on hemocytes by the SCGE (single cell gel electrophoresis) assay and apoptosis frequency evaluation, while the cytotoxicity was measured by the lysosomal membranes stability test (NRRA, neutral red retention assay). TCS genotoxicity increased in a dose-dependent manner and this pharmaceutical significantly affects hemocyte functionality due to severe DNA injuries at very low doses. In contrast, TMP seems to be less dangerous than TCS for D. polymorpha because the cytotoxic and the moderate genotoxic effects noticed were obtained only at very high concentration levels. PMID:19232398

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

    PubMed

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

    2015-07-01

    The potential toxicity of pharmaceuticals towards aquatic invertebrates is still poorly understood and sometimes controversial. This study aims to document the in vitro genotoxicity and immunotoxicity of psychotropic drugs and antibiotics on Mytilus edulis. Mussel hemocytes were exposed to fluoxetine, paroxetine, venlafaxine, carbamazepine, sulfamethoxazole, trimethoprim and erythromycin, at concentrations ranging from μg/L to mg/L. Paroxetine at 1.5 μg/L led to DNA damage while the same concentration of venlafaxine caused immunomodulation. Fluoxetine exposure resulted in genotoxicity, immunotoxicity and cytotoxicity. In the case of antibiotics, trimethoprim was genotoxic at 200 μg/L and immunotoxic at 20 mg/L whereas erythromycin elicited same detrimental effects at higher concentrations. DNA metabolism seems to be a highly sensitive target for psychotropic drugs and antibiotics. Furthermore, these compounds affect the immune system of bivalves, with varying intensity. This attests the relevance of these endpoints to assess the toxic mode of action of pharmaceuticals in the aquatic environment. PMID:25829077

  3. Mechanisms of non-genotoxic carcinogenesis.

    PubMed

    Shaw, I C; Jones, H B

    1994-03-01

    Until recently, the mechanism of carcinogenesis has been regarded as a two-stage phenomenon involving damage to the genetic material, which initiates the process, followed by a cell-division stimulus, which promotes the development of the tumour. However, exposure to some chemicals has been shown to result in carcinogenesis without involvement of the initiation step. The mechanism of non-genotoxic carcinogenesis is not fully understood, but is believed to involve stimulation of cell division with a consequent increased probability of a mutation occurring spontaneously. In this article, Ian Shaw and Huw Jones review the theories of non-genotoxic carcinogenesis with reference to specific examples of known non-genotoxic carcinogens. PMID:8184492

  4. 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.

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

    PubMed

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

    2010-11-01

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

  6. 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. PMID:24534338

  7. Evaluation of the genotoxic potential of alkylalkanolamines.

    PubMed

    Leung, H W; Ballantyne, B

    1997-09-18

    Three alkylalkanolamines, N,N-dimethylethanolamine, N-methyldiethanolamine, and tert-butyldiethanolamine, were evaluated for potential genotoxic activity using the Salmonella/microsome reverse gene mutation test, the CHO/HGPRT forward gene mutation test, a sister chromatid exchange test in cultured CHO cells, and an in vivo peripheral blood micronucleus test in Swiss-Webster mice. None of the three alkylalkanolamines produced any significant or dose-related increases in the frequencies of mutations, sister chromatid exchanges or micronuclei. These results indicate that N,N-dimethylethanolamine, N-methyldiethanolamine, and tert-butyldiethanolamine are not genotoxic in the tests conducted. PMID:9357557

  8. 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.

  9. 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. PMID:25019496

  10. Simultaneous Determination of Genotoxic Impurities in Fudosteine Drugs by GC-MS.

    PubMed

    Gooty, Amarnatha Reddy; Katreddi, Hussain Reddy; S, Raghavender Reddy; Hunnur, Raveendra K; Sharma, Hemant Kumar; Masani, Narendra Kumar

    2016-09-01

    A simple, sensitive and reliable gas chromatography mass spectrometry (GC-MS) method has been developed, optimized and validated for the simultaneous determination of 3-chloro-1-propanol (CHP), 1,3-dichloropropane (DCP), 3-chloropropylacetate (CPA) and chloropropyl hydroxypropyl ether (CHE) contents in fudosteine, using chlorobenzene as internal standard. Efficient chromatographic separations were achieved on an Agilent J&W DB-WAXetr, 30 m long with 0.32 mm i.d., 1.0 µm particle diameter column that consists of bonded and cross-linked polyethylene glycol as a stationary phase by passing helium as the carrier gas. The analytes were extracted in dichloromethane and monitored by gas chromatography electron ionization mass spectrometry (GC-EI-MS) with selective ion monitoring (SIM) mode. The performance of the method was assessed by evaluating specificity, precision (repeatability and reproducibility), sensitivity, linearity and accuracy. The limit of detection and limit of quantification established for CHP, DCP, CPA and CHE were in the range of 0.05-0.08 µg mL(-1) and 0.10-0.17 µg mL(-1), respectively. The recoveries for CHP, DCP, CPA and CHE were in the range of 92.0-101.5%. The results proved that the method is suitable for the simultaneous determination of contents of CHP, DCP, CPA and CHE in fudosteine. PMID:27261527

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

    PubMed

    Kirkland, David; Gatehouse, David

    2015-10-01

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

  12. ASSESSMENT OF HAZARDOUS WASTES FOR GENOTOXICITY

    EPA Science Inventory

    The authors have evaluated a group of short-term bioassays to identify those that may be suitable for screening large numbers of diverse hazardous industrial wastes for genotoxicity. Fifteen wastes (and dichloromethane extracts of these wastes) from a variety of manufacturing pro...

  13. GENOTOXICITY STUDIES OF BENZ(1)ACEANTHRYLENE

    EPA Science Inventory

    The genotoxicity of the cyclopenta-fused polycyclic aromatic hydrocarbon, benz(1)aceanthrylene (B(1)A),was evaluated in vitro using the L5178Y/T (K sup +/-) mouse lymphoma assay and in vivo using the mouse peripheral blood lymphocyte (PBL) culture system. The mutagenicity and sis...

  14. 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 ...

  15. Endohedral impurities in carbon nanotubes.

    PubMed

    Clougherty, Dennis P

    2003-01-24

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

  16. Endohedral Impurities in Carbon Nanotubes

    NASA Astrophysics Data System (ADS)

    Clougherty, Dennis

    2003-03-01

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

  17. Endohedral Impurities in Carbon Nanotubes

    NASA Astrophysics Data System (ADS)

    Clougherty, Dennis P.

    2003-01-01

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

  18. 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.

  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. PMID:25410580

  20. 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.

  1. Spectroscopic studies of impurity densities and impurity transport

    NASA Astrophysics Data System (ADS)

    Behringer, K.

    1992-06-01

    Spectrometers and spectra, mainly from JET, are discussed with respect to diagnostic potential and calibration problems. Spatial scan facilities or multichord diagnostics are essential for transport investigations, and several possibilities are shown. The interpretation of spectral line radiation usually requires the availability of impurity transport codes, which calculate the ionization balance in the presence of transport, the line emissivities and the total impurity radiation. Some atomic physics prerequisites of such codes are discussed. Theoretical and experimental approaches to the transport problem are investigated using ASDEX and JET results for anomalous transport. The occasional observation of neoclassical accumulation, for example after pellet injection, is presented and respective modeling is described. Some H mode transport phenomena are mentioned.

  2. 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.

  3. 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.

  4. Genaissance pharmaceuticals, inc.

    PubMed

    Oestreicher, Paul

    2002-03-01

    Genaissance Pharmaceuticals, Inc. (Nasdaq: GNSC) is the world leader in the discovery and use of gene variation for the development of personalized medicines. In addition, the company has established partnerships with some of the world's top biopharmaceutical companies. The company has initiated the development of its own pipeline of products -- HAP Clozapine for schizophrenia and HAP Statin for cholesterol management -- utilizing its proprietary genetic markers. The company also markets its technology and clinical development skills to the pharmaceutical industry as a complete solution for improving the development, marketing and prescribing of drugs. PMID:11972448

  5. Tandem column for the simultaneous determination of arginine, ibuprofen and related impurities by liquid chromatography.

    PubMed

    Huidobro, A L; Rupérez, F J; Barbas, C

    2006-06-30

    Ibuprofen arginate is a rapidly absorbed salt designed to promote more rapid onset of analgesia than commercially available forms of ibuprofen. Ibuprofen and arginine have very different polarities and this becomes in a chromatographic problem, further complicated with the determination of related compounds, which is necessary in stability assays of the pharmaceutical forms. The common solution is the employment of two separate methods, but this is time consuming. A LC method has been developed to determinate both compounds and related impurities in one run. Ibuprofen, arginine and three ibuprofen related impurities (B, E and J) have been baseline separated with isocratic conditions at pH 3.0 and run time under 20 min by employing a tandem combination of two different stationary phases: first a ZORBAX SB-C18 column from Agilent (250 mm x 4.6 mm and 5 microm) and downstream a SUPELCOSIL LC-NH2 column from Supelco (150 mm x 4.6 mm and 3 microm). The octadecyldiisobutylsilane column provides the separation of ibuprofen and its impurities by a hydrophobic mechanism, whereas aminopropyl column offers selective retention of arginine by dipolar interaction mechanism. Method has been successfully validated following ICH guidelines and it has been demonstrated to be reliable for arginine, ibuprofen and related impurities determination in sachets of two different dosages as pharmaceutical forms. Moreover, stress test has proved the selectivity of the method for degradation products, such as those that can emerge throughout long-term stability assays. PMID:16364348

  6. Mutagenic and Genotoxic Effect of Hydroxyurea

    PubMed Central

    Santos, Jean L.; Bosquesi, Priscila L.; Almeida, Adélia E.; Chin, Chung Man; Varanda, Eliana A.

    2011-01-01

    The hydroxyurea, a cytotoxic drug, is the mainly available therapeutical strategy for the treatment of sickle cell disease. This study aimed to evaluate the mutagenic and genotoxic potential of the hydroxyurea through the Salmonella/Microsome assay and micronucleus test in peripheral blood of mice. The doses were evaluated at 29.25-468 μmol/plate in Salmonella/Microsome assay in presence and absence of metabolic activation the drug. In the micronucleus test the doses were evaluated at 12.5; 25; 50; 75 and 100 mg/kg. The results show that hydroxyurea present mutagenic activity in TA98 and TA100 in doses above 117 μmol/plate and 234 μmol/plate respectively. The drug induced a significant increase in the frequency of micronuclei in reticulocytes of mice at concentrations of 50, 75 and 100 mg/kg, compared to negative control (water). These results demonstrated the mutagenic and genotoxic potential of hydroxyurea. PMID:23675245

  7. Metabolism, genotoxicity, and carcinogenicity of comfrey.

    PubMed

    Mei, Nan; Guo, Lei; Fu, Peter P; Fuscoe, James C; Luan, Yang; Chen, Tao

    2010-10-01

    Comfrey has been consumed by humans as a vegetable and a tea and used as an herbal medicine for more than 2000 years. Comfrey, however, produces hepatotoxicity in livestock and humans and carcinogenicity in experimental animals. Comfrey contains as many as 14 pyrrolizidine alkaloids (PA), including 7-acetylintermedine, 7-acetyllycopsamine, echimidine, intermedine, lasiocarpine, lycopsamine, myoscorpine, symlandine, symphytine, and symviridine. The mechanisms underlying comfrey-induced genotoxicity and carcinogenicity are still not fully understood. The available evidence suggests that the active metabolites of PA in comfrey interact with DNA in liver endothelial cells and hepatocytes, resulting in DNA damage, mutation induction, and cancer development. Genotoxicities attributed to comfrey and riddelliine (a representative genotoxic PA and a proven rodent mutagen and carcinogen) are discussed in this review. Both of these compounds induced similar profiles of 6,7-dihydro-7-hydroxy-1-hydroxymethyl-5H-pyrrolizine (DHP)-derived DNA adducts and similar mutation spectra. Further, the two agents share common mechanisms of drug metabolism and carcinogenesis. Overall, comfrey is mutagenic in liver, and PA contained in comfrey appear to be responsible for comfrey-induced toxicity and tumor induction. PMID:21170807

  8. Genotoxicity assessment in patients with thalassemia minor.

    PubMed

    Al-Sweedan, Suleimman A; Khabour, Omar; Isam, Ruba

    2012-05-15

    Thalassemia is an inherited blood disorder that affects both genders and results in reduced synthesis of hemoglobin, and thus causing anemia. Previous studies have shown that the severe form of this disease, thalassemia major, is associated with genotoxicity. This includes increases in the level of sister chromatid exchange (SCEs), chromosomal aberrations (CAs) and micronuclei. In this study, we assessed genotoxicity in the lymphocytes of thalassemia minor subjects using sister chromatid exchange (SCE) and chromosomal aberration (CA) assays. In addition, we investigated the level of oxidative DNA damage by measuring 8-hydroxy-2'-deoxyguanosine (8OHdG) biomarker in urine samples. Eighteen thalassemia minor subjects and eighteen matched normal healthy controls were volunteered in the study. In addition, seven thalassemia major patients were recruited as positive controls. The results showed increases in the frequency of SCEs (P<0.05) in thalassemia minor compared to healthy controls. However, no difference in CAs frequency was detected between thalassemia minor and controls (P>0.05). Both SECs and CAs in thalassemia major patients were significantly higher compared to other groups (P<0.05). Regarding urine 8OHdG levels, the result showed a slight increase in thalassemia minor compared to healthy controls but the difference was not significant (P>0.05). In conclusion, our results showed that thalassemia minor is associated with genotoxicity to blood lymphocytes as indicated by SCEs assay. PMID:22414564

  9. 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.

  10. Anti-genotoxic hydrazide from Crinum defixum.

    PubMed

    Bordoloi, Manobjyoti; Kotoky, Rumi; Mahanta, Jiban J; Sarma, Tarun C; Kanjilal, Purnendu B

    2009-06-01

    Crinum defixum Ker-Gawl popularly known as Bon-naharu (meaning wild garlic) in Assam. It is found abundantly growing wild on riverbanks of Dhansiri River in Golaghat District of Assam. It is used as ethnomedicine in this part of India for a number of ailments. Bioassay guided chemical investigation of the bulbs of Crinum defixum Ker-Gawl afforded to isolate a new hydrazide derivative and its structure was determined as (E)-N'-[(E)-2-butenoyl]-2-butenoylhydrazide by spectroscopic methods. The compound was assayed for anti-genotoxic activity by onion root tip assay (by observing different types of chromosomal aberrations such as chromosomal bridges, stickiness, delayed anaphase, polyploidy and vagrant chromosome). The phyto-compound was found to have anti-genotoxic activity and imparted a clear dose dependent protective effect against the genotoxic effect of H(2)O(2). Further, the compound seems to be more effective against clastogenic aberrations than physiological aberration at the highest concentration used (250 ppm). PMID:18995928

  11. 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.

  12. 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.

  13. 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.

  14. GW-1000. GW Pharmaceuticals.

    PubMed

    Smith, Paul F

    2004-07-01

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

  15. Free trade in pharmaceuticals.

    PubMed

    Outterson, M Kevin

    2004-09-01

    Provisions in the Australia-United States Free Trade Agreement (AUSFTA) may threaten the Australian Pharmaceutical Benefits Scheme (PBS), the "gold standard" of such programs worldwide. If Australia postpones passing of the US Free Trade Agreement Implementation Bill in the Senate, there will be opportunity for broader interests in both the United States and Australia to carefully study the agreement. The provisions of AUSFTA relating to the PBS are supposed to promote transparency, but the pharmaceutical manufacturers themselves (who are demanding transparency) do not reveal the content of their submissions to the Pharmaceutical Benefits Advisory Committee, or disclose all their financial relationships with researchers and policymakers. In AUSFTA, the "public health" language of affordable prescription drugs is missing and is replaced by language supporting "pharmaceutical innovation". Debate as to whether AUSFTA will force significant changes to the PBS, including higher drug prices, is currently under way in Australia. Perhaps the appropriate target of reforms should be the excessive US drug prices, and not the economically efficient Australian drug prices. PMID:15347274

  16. A predictive toxicogenomics signature to classify genotoxic versus non-genotoxic chemicals in human TK6 cells

    PubMed Central

    Williams, Andrew; Buick, Julie K.; Moffat, Ivy; Swartz, Carol D.; Recio, Leslie; Hyduke, Daniel R.; Li, Heng-Hong; Fornace, Albert J.; Aubrecht, Jiri; Yauk, Carole L.

    2015-01-01

    Genotoxicity testing is a critical component of chemical assessment. The use of integrated approaches in genetic toxicology, including the incorporation of gene expression data to determine the DNA damage response pathways involved in response, is becoming more common. In companion papers previously published in Environmental and Molecular Mutagenesis, Li et al. (2015) [6] developed a dose optimization protocol that was based on evaluating expression changes in several well-characterized stress-response genes using quantitative real-time PCR in human lymphoblastoid TK6 cells in culture. This optimization approach was applied to the analysis of TK6 cells exposed to one of 14 genotoxic or 14 non-genotoxic agents, with sampling 4 h post-exposure. Microarray-based transcriptomic analyses were then used to develop a classifier for genotoxicity using the nearest shrunken centroids method. A panel of 65 genes was identified that could accurately classify toxicants as genotoxic or non-genotoxic. In Buick et al. (2015) [1], the utility of the biomarker for chemicals that require metabolic activation was evaluated. In this study, TK6 cells were exposed to increasing doses of four chemicals (two genotoxic that require metabolic activation and two non-genotoxic chemicals) in the presence of rat liver S9 to demonstrate that S9 does not impair the ability to classify genotoxicity using this genomic biomarker in TK6cells. PMID:26425668

  17. 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.

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

    PubMed

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

    2016-07-01

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

  19. 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. PMID:17320957

  20. Impurity-induced divertor plasma oscillations

    DOE PAGESBeta

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

    2016-01-07

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

  1. 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.

  2. 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

  3. Rapid and comprehensive impurity profiling of synthetic thyroxine by ultrahigh-performance liquid chromatography-high-resolution mass spectrometry.

    PubMed

    Neu, Volker; Bielow, Chris; Gostomski, Iris; Wintringer, Reiner; Braun, Ralf; Reinert, Knut; Schneider, Peter; Stuppner, Hermann; Huber, Christian G

    2013-03-19

    Rapid and efficient quality control according to the public authority regulations is mandatory to guarantee safety of the pharmaceuticals and to save resources in the pharmaceutical industry. In the case of so-called "grandfather products" like the synthetic thyroid hormone thyroxine, strict regulations enforce a detailed chemical analysis in order to characterize potentially toxic or pharmacologically relevant impurities. We report a straightforward workflow for the comprehensive impurity profiling of synthetic thyroid hormones and impurities employing ultrahigh-performance liquid chromatography (UHPLC) hyphenated to high-resolution mass spectrometry (HRMS). Five different batches of synthetic thyroxin were analyzed resulting in the detection of 71 impurities within 3 min total analysis time. Structural elucidation of the compounds was accomplished via a combination of accurate mass measurements, computer based calculations of molecular formulas, multistage high-resolution mass spectrometry (HRMS(n)), and nuclear magnetic resonance spectroscopy, which enabled the identification of 71 impurities, of which 47 have been unknown so far. Thirty of the latter were structurally elucidated, including products of deiodination, aliphatic chain oxidation, as well as dimeric compounds as new class of thyroid hormone derivatives. Limits of detection for the thyroid compounds were in the 6 ng/mL range for negative electrospray ionization mass spectrometric detection in full scan mode. Within day and day-to-day repeatabilities of retention times and peak areas were below 0.5% and 3.5% R.SD. The performance characteristics of the method in terms of robustness and information content clearly show that UHPLC-HRMS is adequate for the rapid and reliable detection, identification, and semiquantitative determination of trace levels of impurities in synthetic pharmaceuticals. PMID:23394260

  4. 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. PMID:26215744

  5. 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}

  6. HPTLC Method for Quantitative Determination of Zopiclone and Its Impurity.

    PubMed

    Naguib, Ibrahim A; Abdelrahman, Maha M; El Ghobashy, Mohamed R; Ali, Nesma A

    2015-09-01

    This study was designed to establish, optimize and validate a sensitive, selective and accurate high-performance thin layer chromatographic (HPTLC) method for determination of zopiclone (ZPC) and its main impurity, 2-amino-5-chloropyridine, one of its degradation products, in raw material and pharmaceutical formulation. The proposed method was applied for analysis of ZPC and its impurity over the concentration range of 0.3-1.4 and 0.05-0.8 µg/band with accuracy of mean percentage recovery 99.92% ± 1.521 and 99.28% ± 2.296, respectively. The method is based on the separation of two components followed by densitometric measurement of the separated peaks at 305 nm. The separation was carried out on silica gel HPTLC F254 plates, using chloroform-methanol-glacial acetic acid (9:1:0.1, by volume) as a developing system. The suggested method was validated according to International Conference on Harmonization guidelines and can be applied for routine analysis in quality control laboratories. The results obtained by the proposed method were statistically compared with the reported method revealing high accuracy and good precision. PMID:25740427

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

    PubMed

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

    2014-09-01

    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

  8. 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

  9. Trade, TRIPS, and pharmaceuticals.

    PubMed

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

    2009-02-21

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

  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. Trace organic impurities in gaseous helium

    NASA Technical Reports Server (NTRS)

    Schehl, T. A.

    1973-01-01

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

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

    PubMed

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

    2016-03-01

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

  13. 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

  14. 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.

  15. Method for detecting trace impurities in gases

    DOEpatents

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

    1981-01-01

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

  16. On collisional impurity transport in nonaxisymmetric plasmas

    NASA Astrophysics Data System (ADS)

    Mollén, A.; Landreman, M.; Smith, H. M.

    2014-11-01

    The presence of impurity species in magnetic confinement fusion devices leads to radiation losses and plasma dilution. Thus it is important to analyze impurity dynamics, and search for means to control them. In stellarator plasmas the neoclassical ambipolar radial electric field often points radially inwards (referred to as the ion root regime), causing impurities to accumulate in the core. This can limit the performance of nonaxisymmetric devices. In the present work we analyze neoclassical impurity transport in stellarator plasmas using a recently developed continuum drift-kinetic solver, the SFINCS code (the Stellarator Fokker- Planck Iterative Neoclassical Conservative Solver). The study is performed for a case close to the edge of W7-X using the standard configuration magnetic geometry. We investigate the sensitivity of impurity transport to impurity charge, main species density and temperature gradients, as well as ion temperature. At the studied radial location we find that the neoclassical impurity peaking factor can be very large, particularly for high-Z impurities. The ambipolar radial electric field is in the ion root regime, and impurity accumulation can thus be expected. The accumulation is strengthened by the large main species density and temperature gradients. Moreover we find that the size of the bootstrap current is affected by the value of the plasma effective charge, suggesting that employing a realistic ion composition can be important when calculating the bootstrap current.

  17. 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

  18. Identification and Characterization of Potential Impurities in Raloxifene Hydrochloride

    PubMed Central

    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

  19. 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

  20. Genotoxicity of dried Hoodia parviflora aerial parts.

    PubMed

    Lynch, Barry; Lau, Annette; Baldwin, Nigel; Hofman-Hüther, Hana; Bauter, Mark R; Marone, Palma Ann

    2013-05-01

    Hoodia parviflora is being developed commercially for use in weight loss food and dietary supplement products. Its effects are ascribed to a number of glycosides that have been shown to be present in plant extracts from several Hoodia species, the best known of which is H. gordonii. H. parviflora has been identified as an alternative to H. gordonii, and, as part of the process to develop H. parviflora, in vitro genotoxicity tests, as recommended by recent European Food Safety Authority guidance, were conducted on a dried powder preparation of H. parviflora aerial parts. The preparation was tested for reverse mutation at doses up to 5,000μg/plate in Salmonella typhimurium strains TA98, TA100, TA1535, and TA1537, and in Escherichia coli WP2 uvrA TA, both in the presence and in the absence of an exogenous source of metabolic activation (rat liver S9). In addition, the dried powder was evaluated in an in vitro cytotoxicity chromosome aberration assay using human lymphocytes. Test conditions included both a 4 (up to 2500μg/mg) and 44-h exposure period (up to 1000μg/mg) and the incorporation of an exogenous source of metabolic activation (4-h exposure only). H. parviflora dried powder was non-genotoxic in both in vitro assays. PMID:23348409

  1. 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

  2. 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

  3. 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.

  4. 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.

  5. 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.

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

    PubMed

    Hose, J E

    1994-12-01

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

  7. 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

  8. Mechanochemistry of ibuprofen pharmaceutical.

    PubMed

    Andini, Salvatore; Bolognese, Adele; Formisano, Domenico; Manfra, Michele; Montagnaro, Fabio; Santoro, Luciano

    2012-07-01

    In this paper mechanochemistry has been studied in view of possible application to detoxification of expired pharmaceuticals. The experiments have been carried out with a commercial medication containing ibuprofen ((RS)-2-(4-(2-methylpropyl)phenyl)propanoic acid) which has been submitted to prolonged milling up to 40h. When Al(OH)(3) is used as co-reagent, the first degradation step induced by the mechanochemical treatment is an acid-base reaction with the ibuprofen carboxylic acid group. The subsequent degradation follows a complex pathway leading to 1-(4-isobutylphenyl)ethanone, 1-isobutyl-4-vinylbenzene and 2-(4-(3-methylbutan-2-yl)phenyl)propan-1-ol after 10h milling and, in addition, 1-(4-acetylphenyl)-2-methylpropan-1-one, 1-(4-(1-hydroxy-2-methylpropyl)phenyl)ethanone and 1-(4-(2-hydroxy-2-methylpropyl)phenyl)ethanone after 40h milling. The degradation reaction path and products have been identified by means of FT-IR spectroscopy, thin layer chromatography, NMR spectroscopy, mass spectroscopy and elemental analysis. The observed ibuprofen decarboxylation makes the drug simultaneously lose both its pharmaceutical activity and toxicity. PMID:22472100

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

    PubMed

    Federsel, Hans-Jürgen

    2009-05-19

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

  10. 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. PMID:16620508

  11. Genotoxicity testing of Maillard reaction products.

    PubMed

    Shibamoto, T

    1989-01-01

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

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

    EPA Science Inventory

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

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

  13. 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...

  14. Genotoxic and mutagenic potential of nitramines.

    PubMed

    Fjellsbø, Lise Marie; Verstraelen, Sandra; Kazimirova, Alena; Van Rompay, An R; Magdolenova, Zuzana; Dusinska, Maria

    2014-10-01

    Climate change is one of the major challenges in the world today. To reduce the amount of CO2 released into the atmosphere, CO2 at major sources, such as power plants, can be captured. Use of aqueous amine solutions is one of the most promising methods for this purpose. However, concerns have been raised regarding its impacts on human health and the environment due to the degradation products, such as nitrosamines and nitramines that may be produced during the CO2 capture process. While several toxicity studies have been performed investigating nitrosamines, little is known about the toxic potential of nitramines. In this study a preliminary screening was performed of the genotoxic and mutagenic potential of nitramines most likely produced during amine based CO2 capture; dimethylnitramine (DMA-NO2), methylnitramine (MA-NO2), ethanolnitramine (MEA-NO2), 2-methyl-2-(nitramino)-1-propanol (AMP-NO2) and piperazine nitramine (PZ-NO2), by the Bacterial Reverse Mutation (Ames) Test, the Cytokinesis Block Micronucleus (CBMN) Assay and the in vitro Single-Cell Gel Electrophoresis (Comet) Assay. MA-NO2 and MEA-NO2 showed mutagenic potential in the Ames test and a weak genotoxic response in the CBMN Assay. AMP-NO2 and PZ-NO2 significantly increased the amount of DNA strand breaks; however, the level of breaks was below background. Most previous studies on nitramines have been performed on DMA-NO2, which in this study appeared to be the least potent nitramine. Our results indicate that it is important to investigate other nitramines that are more likely to be produced during CO2 capture, to ensure that the risk is realistically evaluated. PMID:25042035

  15. Application of HPLC with ELSD Detection for the Assessment of Azelaic Acid Impurities in Liposomal Formulation

    PubMed Central

    Han, Stanislaw; Karlowicz-Bodalska, Katarzyna; Ozimek, Lukasz

    2013-01-01

    In the course of research and development of a new pharmaceutical formulation of azelaic acid in the liposomal form, we developed a rapid and accurate method for the detection of impurities using high-performance liquid chromatography. A chromatographic column from Merck (Purospher Star RP C18, 250–4 mm (5 μm) was used in the assay, and the mobile phase gradient consisted of three phases: A—methanol : water (5 : 95) + 1.5% (v/v) acetic acid; B—water : methanol (5 : 95) + 1.5% (v/v) acetic acid; and C—chloroform. Detection of the impurities and the active substance was performed by an evaporative light-scattering detector. The method was validated for selectivity, system precision, method precision, limit of detection, and response rates. The proposed method can be used to detect impurities in the liposomal formulation of azelaic acid. The method enables separation of azelaic acid from the identified and unidentified impurities and from the excipients used in the drug form. PMID:24228008

  16. 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. PMID:26617410

  17. 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.

  18. 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.

  19. 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

  20. Pharmaceutical considerations of nitroglycerin

    SciTech Connect

    Yacobi, A.; Amann, A.H.; Baaske, D.M.

    1983-04-01

    During the past few years, there have been rapid changes in the pharmaceutical uses of nitroglycerin. New dosage forms and new delivery systems have become available, which have resulted in potential confusion to all concerned with the proper use of these systems. The goal of this review is to prevent confusion and to bring all the relevant information together. The various analytical techniques available for quality control of the dosage forms and for the study of the pharmacokinetics are reviewed, with the intent of enabling the reader to identify pertinent references rapidly. The interaction of nitroglycerin with packaging and plastic delivery devices is also reviewed so that the reader can make informed choices. Finally, the clinical pharmacy and pharmacokinetics are reviewed so as to bring the reader up to date in that area. After reading this article, the areas of nitroglycerin research that still need to be explored should be apparent.

  1. Pharmaceutical study of Yashadabhasma

    PubMed Central

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

    2012-01-01

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

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

    PubMed

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

    2008-06-01

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

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

    PubMed

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

    2016-01-25

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

  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. Correlations between embryotoxic and genotoxic effects of phenytoin in mice.

    PubMed

    Barcellona, P S; Barale, R; Campana, A; Zucconi, D; Rossi, V; Caranti, S

    1987-01-01

    The anticonvulsant drug phenytoin (DPH) has been suspected to produce embryotoxicity through an arene oxide intermediate. This drug was also found to be a genotoxic agent. These hypotheses were tested in pregnant mice modulating the phases I and II metabolizing enzymes. DPH was studied by assessing embryotoxicity, teratogenicity, and genotoxicity, the latter by the micronucleus test on the polychromatic erythrocytes of dams and fetuses. DPH embryotoxicity was potentiated by inhibiting both cytochrome P-450 and epoxide hydrase and decreased by inducing cytochrome P-450. Equivocal results were obtained by modulating cytochrome P-448. The main DPH metabolite, p-hydroxyphenytoin (HPPH), was ineffective both per se and after cytochrome induction or epoxide hydrase inhibition. DPH did not exert genotoxicity on the maternal organism, no matter which modulating agent was used. In the fetus, however, weak genotoxic effects were observed. These effects significantly increased with inhibition of epoxide hydrase; they disappeared with induction of both cytochromes P-448 and P-450 or with inhibition of the latter. No genotoxicity was exerted by HPPH, even when the enzymatic pattern was modulated. It is concluded that the major role in DPH embryotoxicity is played by the unchanged drug, while the presence of the arene oxide is determinant for genotoxic effects. PMID:2885938

  6. 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. PMID:26430459

  7. Quantification of umu genotoxicity level of urban river water.

    PubMed

    Kameya, T; Nagato, T; Nakagawa, K; Yamashita, D; Kobayashi, T; Fujie, K

    2011-01-01

    In recent years, the request of environmental safety management for carcinogenic substances, mutagenic substances and/or reproductive toxicity substances (CMR) has increased. This study focused on clarifying the genotoxicity level of environmental water and its release source by using the umu test provided in ISO13829. Although a genotoxicity index "induction ratio (IR)" is used in ISO13829, we normalised it to make it possible to compare various environmental water quantitatively to each other as a new index "genotoxic activity (GA=(IR-1)/Dose)". Sample water was collected and concentrated to 100 times or 1,000 times by a solid phase extraction method. As the test results, it was found that GA level in actual river water varied widely from less than the determination limit of 23 [1/L] to 1,100 [1/L] by quantitative comparison, and the value was also equivalent to more than 50 times the level of tap water. The GA level of household wastewater was not so high, but the levels of treated water from wastewater treatment plant (WTP) were from 220 [1/L] to 3,200 [1/L]. Raw sewage of some WTP shows high level genotoxicity. A part of genotoxicity substances, for example 50%, could be removed by conventional wastewater treatment, but it was not enough to reduce the water environmental load of genotoxicity. PMID:21278461

  8. 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

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

    NASA Astrophysics Data System (ADS)

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

    2015-06-01

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

  10. 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. PMID:27189646

  11. Impurity induced resistivity upturns in underdoped cuprates

    NASA Astrophysics Data System (ADS)

    Das, Nabyendu; Singh, Navinder

    2016-01-01

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

  12. Influence of magnetic shear on impurity transport

    SciTech Connect

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

    2007-05-15

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

  13. DIVIMP Modeling of Impurity Transport in EAST

    NASA Astrophysics Data System (ADS)

    Wang, Fuqiong; Chen, Yiping; Hu, Liqun

    2014-07-01

    Simulations of carbon impurity transport in SOL/divertor plasmas with Ohmic heating on EAST tokamak were performed using the two-dimensional (2D) Monte Carlo impurity transport code DIVIMP. The background plasmas for DIVIMP simulations were externally taken from B2.5/Eirene calculation. Besides the basic output of DIVIMP, the 2D density distributions of the carbon impurity with different ionization states and neutral carbon atoms were obtained, the 2D distributions of CII and CIII emissivities from C+1 and C+2 radiation respectively were also calculated. Comparison between the measured and calculated CIII emissivities showed favorable agreement, indicating that the impurity physics transport models, as implemented in the DIVIMP code, are suitable for the EAST tokamak plasma condition.

  14. 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.

  15. Single impurity in ultracold Fermi superfluids

    SciTech Connect

    Jiang Lei; Baksmaty, Leslie O.; Pu, Han; Hu Hui; Chen Yan

    2011-06-15

    The role of impurities as experimental probes in the detection of quantum material properties is well appreciated. Here we study the effect of a single classical magnetic impurity in trapped ultracold Fermi superfluids. Depending on its shape and strength, a magnetic impurity can induce single or multiple midgap bound states in a superfluid Fermi gas. The multiple midgap states could coincide with the development of a Fulde-Ferrell-Larkin-Ovchinnikov (FFLO) phase within the superfluid. As an analog of the scanning tunneling microsope, we propose a modified rf spectroscopic method to measure the local density of states which can be employed to detect these states and other quantum phases of cold atoms. A key result of our self-consistent Bogoliubov-de Gennes calculations is that a magnetic impurity can controllably induce an FFLO state at currently accessible experimental parameters.

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

    PubMed

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

    2013-02-23

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

  17. Role of impurities in fusion plasmas

    SciTech Connect

    Tokar, M. Z.

    2008-10-15

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

  18. 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.

  19. Ultrashort pulses in graphene with Coulomb impurities

    NASA Astrophysics Data System (ADS)

    Konobeeva, N. N.; Belonenko, M. B.

    2016-06-01

    We have investigated the propagation of an electromagnetic field in graphene with impurities, including the two-dimensional case. The spectrum of electrons for the graphene subsystem is taken from a model that takes into account Coulomb impurities. Based on Maxwell's equations, we have obtained an effective equation for the vector potential of the electromagnetic field. It has been revealed that the pulse shape depends on free parameters.

  20. Method of removing phosphorus impurities from yellowcake

    SciTech Connect

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

    1983-04-05

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

  1. Mechanisms of impurity diffusion in rutile

    SciTech Connect

    Peterson, N.L.; Sasaki, J.

    1984-01-01

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

  2. Improved analysis of impurity transport coefficient profiles

    NASA Astrophysics Data System (ADS)

    Chilenski, M. A.; Greenwald, M.; Marzouk, Y.; Howard, N. T.; Rice, J.; White, A. E.

    2015-11-01

    Work is underway on the development of a novel technique to estimate impurity transport coefficient profiles and their uncertainties. Inference of impurity transport coefficient profiles using x-ray imaging crystal spectroscopy measurements of laser blow-off impurity injections has played a key role in the validation of gyrokinetic simulations of impurity transport in L-mode (Howard et al. 2012, Nucl. Fusion 52, 063002). Recent attempts to apply the existing methodology for interpreting such measurements to H-mode have failed to yield reliable estimates, however. This failure exposes key issues regarding the uniqueness of the solution and the rigorous estimation of the uncertainty. A new approach is under development which uses a combination of Markov chain Monte Carlo (MCMC) and global optimization techniques to estimate impurity transport coefficient profiles even when there are multiple possible solutions. This poster will present the new methodology in detail and will show preliminary results from applying it to Alcator C-Mod data. This new approach will enable us to test the existing understanding of L-mode impurity transport and to move towards multichannel validation of gyrokinetic simulations of H-modes. Supported by USDOE award DE-FC02-99ER54512.

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

    PubMed

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

    2016-01-01

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

  4. 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

  5. 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. PMID:25964273

  6. 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

  7. Reducing pharmaceutical risk.

    PubMed

    Spilker, B

    1998-08-01

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

  8. 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. PMID:12090559

  9. 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...

  10. 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. PMID:24986349

  11. Turbulent and neoclassical impurity transport in tokamak plasmas

    SciTech Connect

    Fueloep, T.; Nordman, H.

    2009-03-15

    Impurity particle transport in tokamaks is studied using an electrostatic fluid model for main ion and impurity temperature gradient (ITG) mode and trapped electron (TE) mode turbulence in the collisionless limit and neoclassical theory. The impurity flux and impurity density peaking factor obtained from a self-consistent treatment of impurity transport are compared and contrasted with the results of the often used trace impurity approximation. Comparisons between trace and self-consistent turbulent impurity transport are performed for ITER-like profiles. It is shown that for small impurity concentrations the trace impurity limit is adequate if the plasma is dominated by ITG turbulence. However, in case of TE mode dominated plasmas the contribution from impurity modes may be significant, and therefore a self-consistent treatment may be needed.

  12. 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...

  13. 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...

  14. 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. PMID:21928715

  15. 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.

  16. 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.

  17. Mutagenicity and genotoxicity assessment of industrial wastewaters.

    PubMed

    Masood, Farhana; Malik, Abdul

    2013-10-01

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

  18. 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

  19. Assessment of hazardous wastes for genotoxicity

    SciTech Connect

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

    1987-09-01

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

  20. Glycidamide genotoxicity modulated by Caspases genes polymorphisms.

    PubMed

    de Lima, João Pereira; Silva, Susana N; Rueff, José; Pingarilho, Marta

    2016-08-01

    Acrylamide (AA) is amongst acknowledged carcinogenic dietary factors. Its DNA-reactive metabolite is glycidamide (GA). The present study intended to correlate the role of key polymorphic genes of apoptosis (CASP7, CASP8, CASP9, CASP10, LTA and TNFRSF1B) with biomarkers of effect of DNA damage, namely the sister chromatid exchange assay (SCE) and the comet assay in whole blood cells exposed to GA. The aim was to assess as a proof of concept the role that pro-apoptotic effector proteins might have in the yields of genotoxic effects when those effector proteins are coded by polymorphic genes. Whole blood from a small group of volunteers was exposed to GA to assess DNA damage and the volunteers were genotyped for polymorphic genes related to apoptosis pathways. A relation between the induction of SCE and several variants of the polymorphism CASP8 rs1035142 G>T was observed. Also, a relation between the % tail DNA and the CASP10 I522L polymorphism was found. Furthermore, associations between % tail DNA and several SNP-SNP interactions of CASP8 and CASP10 were found. A possible correlation between DNA damage and the genetic susceptibility, bestowed by polymorphic genes in the apoptosis inducing pathways was verified. PMID:27062911

  1. 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

  2. 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

  3. 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

  4. High-altitude medicines: a short-term genotoxicity study.

    PubMed

    Ghosh, Manosij; Biswas, Dhrubojyoti; Mukherjee, Anita

    2010-08-01

    People live in the mountains distributed across the world and are exposed to reduced inspired oxygen and lower barometric pressure along with other factors that lead to high-altitude diseases. The present study was conducted to examine what extent of marketed medicines used in the management of high-altitude sickness has been tested for their genotoxic activity. Comet assay or the single-cell gel electrophoresis was utilized to evaluate genotoxicity of the six medicines on human peripheral whole blood cells and isolated lymphocytes at the concentrations 250 microg/mL, 500 microg/mL and 1 mg/mL. The comet assay endpoints included percentage Tail DNA (% Tail DNA) and olive tail moment (OTM) as they were considered to be sensitive and reliable scores across different laboratories. The results show that dexamethasone, deriphylline and furosemide can induce significant DNA damage in human whole blood and lymphocytes alike. Acetazolamide, ibuprofen and nifedipine show no genotoxic effect, neither on human whole blood nor on human lymphocytes. Taking into account the results of genotoxicity, it will be a prudent choice to restrict the use of these compounds for longer periods, until more information on the in vitro mutagenicity and in vivo genotoxicity studies are available. PMID:20504830

  5. Aripiprazole (Otsuka Pharmaceutical Co).

    PubMed

    Ozdemir, Vural; Fourie, Jeanne; Ozdener, Fatih

    2002-01-01

    Otsuka Pharmaceuticals in collaboration with Bristol-Myers Squibb is developing aripiprazole, a dual dopamine autoreceptor agonist and postsynaptic D2 receptor antagonist, for the potential treatment of psychoses including schizophrenia [281327], [340364]. A regulatory filing for schizophrenia in the US was submitted at the end of 2001 [340364]. The compound entered phase III trials in Japan in 1995 [192966]. Although presynaptic dopamine autoreceptor agonists may be efficacious in the treatment of schizophrenia, they may also potentially increase the risk for exacerbation of psychosis through stimulation of postsynaptic dopaminergic receptors [245791], [350478], [350479]. However, earlier neuropharmacology studies have shown that aripiprazole can act as a presynaptic D2 agonist while displaying an antagonistic effect at the postsynaptic D2 receptors [281327], [337126], [350479], [424587], [424588]. In animal models, aripiprazole inhibits the apomorphine-induced stereotypy, without causing catalepsy [281327], [337126]. Moreover, in contrast to classical antipsychotics that produce disabling movement disorders, aripiprazole does not cause an upregulation of D2 receptors or an increase in expression of the c-fos mRNA in the striatum, in agreement with the low risk for extrapyramidal side effects (EPS) during aripiprazole treatment [245781], [262096], [350481], [350483]. Collectively, aripiprazole is an important atypical antipsychotic candidate with a favorable safety profile. Moreover, the mechanism of action of aripiprazole differentiates it from both typical and atypical antipsychotics and hence, may provide important leads for pharmacotherapy of schizophrenia and other psychotic disorders. In January 2000, Lehman Brothers predicted peak sales of aripiprazole could reach US $500 million [357788]. In February 2001, Credit Suisse First Boston predicted sales of US $403 million in 2005 [399484]. PMID:12054061

  6. Modeling of Carbon Impurity Anomalous Transport

    NASA Astrophysics Data System (ADS)

    Stamm, Roland; Voitsekhovitch, Irina; Benkadda, Sadri; Beyer, Peter; Koubiti, Mohamed; Marandet, Yannick; Godbert-Mouret, Laurence; Bateman, Glenn; Kritz, Arnold; Pankin, Andre

    2001-10-01

    An improvement of plasma confinement by impurity seeding has been observed on different Tokamak. The understanding of the physics of the impurity transport is an important step towards the control of the plasma confinement in such regimes. Different physical mechanisms of the anomalous transport of carbon impurity and their impact on the evolution of the scenario of a tokamak discharge are analyzed in this work. This is done by using a self-consistent modeling of thermal electron and ion energy, and main ion and carbon impurity content with the multi-mode model taking into account the contributions from different types of plasma instabilities [1]. This study has been performed for the medium size tokamak with a central heating of the electron and ion species, and with both central (NBI) and wall particle source. The L-mode scenario and the scenario with an improved particle and energy confinement due to the reversed q-profile has been analyzed and the influence of the carbon impurity on the plasma evolution has been investigated by varying the starting time and the magnitude of the carbon influx. The effect of the main ion dilution on the growth rate as well as the effect of radiative cooling at the plasma edge on the power balance are analyzed under different conditions. 1. Bateman G., et al., Phys. Plasmas, 5 (1998) 1793

  7. Impurities in the Lithium Tokamak Experiment

    NASA Astrophysics Data System (ADS)

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

    2014-10-01

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

  8. Rydberg Impurity Probes in Ultracold Gases

    NASA Astrophysics Data System (ADS)

    Mitchison, Mark; Johnson, Tomi; Plenio, Martin; Jaksch, Dieter

    2015-03-01

    Impurities immersed in ultracold gases can act as highly sensitive, tunable and potentially non-destructive probes of their environment. In this setting, we propose the use of an atomic impurity in a Rydberg state to measure density fluctuations via Ramsey interferometry. The rapid collisional dynamics of the light Rydberg electron interacting with the heavy gas particles, combined with the capability to quickly change the state of the impurity with optical pulses, make such a probe ideal for measuring local properties of ultracold gases. Our proposed device promises angle-resolved density measurements with sub-micron spatial resolution, and with no need to integrate over the line of sight. We outline how Rydberg impurity probes could be applied to study various interesting quantum states of current experimental relevance. We also discuss the possibility of using multiple Rydberg atoms to extract the spatial pair distribution function g (2) (r). Our work is placed in the context of other recently proposed impurity-based probes.

  9. 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.

  10. 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

  11. 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.

  12. Evaluation of subchronic genotoxic potential of Swarna Makshika Bhasma

    PubMed Central

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

    2012-01-01

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

  13. 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

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

    PubMed

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

    2015-01-01

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

  15. A metabolomics investigation of non genotoxic carcinogenicity in the rat

    PubMed Central

    Ament, Zsuzsanna; Waterman, Claire L; West, James A; Waterfield, Catherine; Currie, Richard A; Wright, Jayne; Griffin, Julian L

    2014-01-01

    Non-genotoxic carcinogens (NGCs) promote tumour growth by altering gene expression which ultimately leads to cancer without directly causing a change in DNA sequence. As a result NGCs are not detected in mutagenesis assays. Whilst there are proposed biomarkers of carcinogenic potential, the definitive identification of non-genotoxic carcinogens still rests with the rat and mouse long term bioassay. Such assays are expensive, time consuming, require a large number of animals and their relevance to human health risk assessments is debatable. Metabolomics and lipidomics in combination with pathology and clinical chemistry were used to profile perturbations produced by 10 compounds which represented a range of rat non-genotoxic hepatocarcinogens (NGC), non-genotoxic non-hepatocarcinogens (non-NGC) and a genotoxic hepatocarcinogen. Each compound was administered at its maximum tolerated dose level for 7, 28 and 91 days to male Fisher 344 rats. Changes in liver metabolite concentration differentiated the treated groups across different time points. The most significant differences were driven by pharmacological mode of action, specifically by the peroxisome proliferator activated receptor alpha (PPAR-α) agonists. Despite these dominant effects, good predictions could be made when differentiating NGCs from non-NGCs. Predictive ability measured by leave one out cross validation was 87% and 77% after 28 days of dosing for NGCs and non-NGCs, respectively. Amongst the discriminatory metabolites we identified free fatty acids, phospholipids, triacylglycerols, as well as precursors of eicosanoid and the products of reactive oxygen species linked to processes of inflammation, proliferation and oxidative stress. Thus, metabolic profiling is able to identify changes due to the pharmacological mode of action of xenobiotics and contribute to early screening for non-genotoxic potential. PMID:24161236

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

    PubMed

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

    2014-03-01

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

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

    PubMed Central

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

    2013-01-01

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

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

    NASA Astrophysics Data System (ADS)

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

    2013-11-01

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

  19. On charged impurity structures in liquid helium

    NASA Astrophysics Data System (ADS)

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

    2016-03-01

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

  20. Impurity and particle control for INTOR

    SciTech Connect

    Post, D.

    1985-02-01

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

  1. 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.

  2. 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

  3. Mixed-mode chromatography in pharmaceutical and biopharmaceutical applications.

    PubMed

    Zhang, Kelly; Liu, Xiaodong

    2016-09-01

    Mixed-mode chromatography (MMC) is a fast growing area in recent years, thanks to the new generation of mixed-mode stationary phases and better understanding of multimode interactions. MMC has superior applications in the separation of compounds that are not retained or not well resolved by typical reversed-phase LC methods, especially for polar and charged molecules. Due to the multiple retention modes that a single MMC column can offer, often MMC provides additional dimension to a separation method by adjusting the mobile phase conditions. Mixed-mode media is also an effective way to clean up complex sample matrices for purification purposes or for sensitive detection of trace amounts of analytes. In this article, we discuss mixed-mode stationary phases and separation mechanisms and review recent advances in pharmaceutical and biopharmaceutical applications including the analysis and/or purification of counterions, small molecule drugs, impurities, formulation excipients, peptides and proteins. PMID:27236100

  4. The physics of Kondo impurities in graphene

    NASA Astrophysics Data System (ADS)

    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.

  5. 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. PMID:23411583

  6. Mapping itinerant electrons around Kondo impurities.

    PubMed

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

    2012-04-20

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

  7. Two-impurity helical Majorana problem

    NASA Astrophysics Data System (ADS)

    Eriksson, Erik; Zazunov, Alex; Sodano, Pasquale; Egger, Reinhold

    2015-02-01

    We predict experimentally accessible signatures for helical Majorana fermions in a topological superconductor by coupling to two quantum dots in the local moment regime (corresponding to spin-1 /2 impurities). Taking into account Ruderman-Kittel-Kasuya-Yosida interactions mediated by bulk and edge modes, where the latter cause a long-range antiferromagnetic Ising coupling, we formulate and solve the low-energy theory for this two-impurity helical Majorana problem. In particular, we show that the long-time spin dynamics after a magnetic field quench displays weakly damped oscillations with universal quality factor.

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

    PubMed

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

    2015-01-01

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

  9. Influence of impurities on the crystallization of dextrose monohydrate

    NASA Astrophysics Data System (ADS)

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

    2012-08-01

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

  10. Impurity Crystal in a Bose-Einstein Condensate

    SciTech Connect

    Roberts, David C.; Rica, Sergio

    2009-01-16

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